ISOFORMS OF GATA6 AND NKX2-1 AS MARKERS FOR DIAGNOSIS AND THERAPY OF CANCER AND AS TARGETS FOR ANTI-CANCER THERAPY

Abstract

The present invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, in particular lung cancer, comprising the measurement of the amounts of specific isoforms of GATA6 and/or NKX2-1 in a sample of said subject. Furthermore, the present invention relates to a composition for use in medicine comprising (an) inhibitor(s) of specific isoforms of GATA6 and/or NKX2-1. Additionally, the present invention relates to a kit for use in a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, in particular lung cancer.

Description

[0001] The present invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer comprising the measurement of the amounts of specific isoforms of GATA6 and/or NKX2-1 in a sample of said subject. Accordingly, the present invention relates to the fields of medicine as well as diagnostics, in particular to personalized medicine and molecular biomarkers. Furthermore, the present invention relates to a composition for use in medicine, in particular in cancer therapy, said composition comprising an inhibitor of specific isoforms of GATA6 and/or NKX2-1. Additionally, the present invention relates to a kit for use in a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer. Therefore, the present invention relates to means and methods for stratifying patients for the medical intervention with (a) anticancer therapy or specific additional close diagnostic screening for cancer development.

[0002] The term cancer covers a broad class of diseases, which is unified by the malignant hyperproliferation of cells. The term includes solid tumors as for example sarcoma and carcinoma as well as liquid tumors like leukemia, lymphoma and myeloma. Cancer can be initiated by the activation or deregulation of certain genes, so called proto-oncogenes. When upregulated and/or activated, these genes can initiate a cascade of molecular events eventually leading to a cell's ability to hyperproliferate thereby initiating the development of malignant neoplasms. The identification of novel specific proto-oncogenes provides novel targets for the treatment and/or the prevention of cancer.

[0003] Lung cancer is a typical model cancer with a very high prevalence. Lung cancer is the most frequent cause of cancer related deaths worldwide. There are two major classes of lung cancer, non small cell lung cancer (contributing to 85% of all lung cancers) and small cell lung cancer (the remaining 15%). Symptoms of lung cancer are often subtle in nascent stages (Herbst R S et al., (2008) N Engl J Med 359(13):1367-80). Consequently, the majority of patients are diagnosed at advanced stages making successful therapeutic approaches challenging and prognosis poor. Therefore, early diagnosis of lung cancer is crucial to increase the probability of a successful therapy. A better understanding of the molecular mechanisms responsible for lung cancer initiation is extremely important.

[0004] Lung cancer cells show an enhanced expression of transcription factors that are present during embryonic development in the endoderm as GATA6 (GATA Binding Factor 6), NKX2-1 (NK2 homeobox 1, also known as Ttf-1, Thyroid transcription factor-1), FOXA2 (Forkhead box protein A2), and ID2 (Inhibitor of DNA binding 2) (Guo M et al., (2004) Clin Cancer Res. 10(23): 7917-24; Kendall J et al., (2007) Proc Natl Acad Sci USA. 104(42): 16663-8; Tang Y et al., (2011) Cell Res. 21(2): 316-26; Rollin j et al., (2009) PLoS One. 4(1): e4158). It was recently demonstrated that lung adenocarcinoma initiates from clonal expansion of cells expressing high levels of Nkx2-1 and progress to a more aggressive state with low expression of Nkx2-1 (see Winslow (2011) Nature 473(7345): 101-104). GATA6 has been shown to be abundantly expressed in malignant mesotheliomas, and to a small extent, in metastatic adenocarcinomas (see Lindholm (2009) Journal of Clinical Pathology 62(4): 339-344). In addition, GATA6 regulates tumorigenesis related genes, such as KRAS, an oncogene activated by point mutations (see Gorshkove (2005) Biochemistry (Mosc):70: 1180-1184).

[0005] GATA6, FOXA2 and NKX2-1 are crucial for early lung development. Genetic analyses with knockout animals demonstrated their role in lung endoderm differentiation and postnatal repair and homeostasis. Nkx2-1, Gata6 and Foxa2 are expressed in respiratory epithelial cells throughout lung morphogenesis. They all have been shown to bind and trans-activate many lung specific promoters, including SftpA-, SftpB-, SftpC- and Scgb1a1-promoters (Bruno M D et al., (1995) 270(12): 6531-6; Margana R K and Boggaram V. (1997) J Biol Chem. 272(5): 3083-90). Mice harboring a Nkx2-1 null mutation show severe attentuation of lung airway branching. In addition, the lung epithelial cells present in these mice lack expression of putative targets like SftpC (Minoo P et al., (1999) Dev Biol. 209(1): 60-71). Conditional deletion of Gata6 in the lung endoderm demonstrated its central role in lung endoderm gene expression, proliferation and branching morphogensis. (Keijzer R et al., (2001) Development 128(4): 503-11). A loss of Foxa2 in the lung can be compensated by Foxa1. However, a loss of both Foxa1/2 also dramatically inhibits endoderm differentiation and branching morphogenesis. (Wan H et al., (2005) J Biol Chem. 280(14): 13809-16). Foxa2 has also been shown to be essential for the transition to breathing air at birth (Wan H et al., (2004) Proc Natl Acad Sci USA. 101(40): 14449-54).

[0006] Current cancer therapy is such that it treats cancer cells as a homogenous cell population. However, in recent years, it has been demonstrated that most tumors contain a mixture of principally two populations, the majority of the cells are able to proliferate and only a small population of these cells has the potential for self renewal. This small population of cells is highly tumorigenic, resistant to chemotherapy and shows a de-differentiated phenotype. Malignant cells with these properties have been termed as `cancer stem cells`. It has become clear that cancer treatment that fails to eliminate these cancer stem cells has a substantial risk of tumor relapse. Consequently, there is an enormous need to understand the origin of these cells and specifically target them for therapy (Eramo A et al., (2010) Oncogene 29(33): 4625-35).

[0007] As discussed above, late diagnosis of cancer is a main hindrance for successful cancer therapy. The prognosis of lung cancer patients depends on the severity of the disease. If detected early, at Stage I, the 5 year survival rate for lung cancer patients is about 80% and drops to about 1% if the disease is advanced to stage IV with the development of metastatic lesions (European Society for Medical Oncology (2009, May 9), Early Detection Of Lung Cancer, ScienceDaily, retrieved from the world wide web at sciencedaily.com/releases/2009/05/090502093211.htm). Therefore, early detection and subsequent treatment of lung cancer is the most promising strategy to reduce related mortality. This is not only true for lung cancer but also for a variety of further malignant neoplasms.

[0008] Accordingly, there is a need for new techniques allowing a reliable and early diagnosis of cancer as well as for further and/or alternative treatment options in cancer therapy. Thus, the technical problem underlying the present invention is the provision of reliable means and methods for the detection of cancer, in particular lung cancer, and for the determination of treatment options.

[0009] The solution to this technical problem is provided by the embodiments as defined herein and as characterized in the claims.

[0010] In accordance with this invention, a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer is found, said method comprising the steps of

[0011] a) measuring in a sample of said subject the amount of a specific transcription factor isoform wherein said specific transcription isoform is either

[0012] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0013] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0014] b) comparing the amount of said specific transcription factor Em isoform with the amount of said specific transcription factor Em isoform in a control sample;

[0015] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said specific transcription factor Em isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor Em isoform in (a)/(the) control sample.

[0016] It is demonstrated by the disclosure of this application that certain transcription factors share a common structure, with two promoters driving the expression of two distinct transcripts. It is surprisingly found that though different isoforms exist only one is oncogenic and is indicative of the presence/development of cancer (see Examples 2 and 3 of the present application). The embryonic GATA6 and NKX2-1 "Em" transcripts as defined by the present invention are found to be detectable in high levels in human lung cancer cell lines and patient lung cancer biopsies (see Examples 2 and 3 of the present application). Remarkably, these cancer specific isoforms are oncogenic and forced overexpression in cell lines as well as in mice results in a tumorigenic phenotype (see Examples 4, 6 and 7 of the present application). This is illustrated by the finding of the present invention that mice develop adenocarcinoma as early as 5 weeks after transfection with one of those specific embryonic "Em" isoforms. Further, it is surprisingly found that these specific "Em" isoforms can be detected in the blood of mice that are induced for tumor formation, showing their usability as early diagnostic markers for cancer, in particular lung cancer (see Example 3 of the present application).

[0017] The present invention has the technical advantage that the inventive means and methods provided herein enable the attending physician or medical personal to start preferably at an early point of time the relevant medicinal intervention, like anti-cancer medication and/or radiation therapy. Accordingly, the presence of an increased amount of the specific transcription factor Em (i.e. GATA6 Em and/or NKX2-1 Em isoform) in a (biological) sample as compared to a standard or control sample leads to (early) anti-cancer therapy and/or closer and more intense diagnostic cancer screening and/or cancer surveillance. An "increased amount"/"increased expression" of the specific transcription factor Em (i.e. GATA6 Em and/or NKX2-1 Em isoform) in a (biological) sample as compared to a standard or control sample can be, inter alia, an expression increase of at least about 1.3-fold in comparison to the control.

[0018] The present invention also provides in the appended examples for evidence that an increased amount (increased expression) of Ad (adult) isoform of e.g. Gata6 (in contrast to the embryonic "Em isoform" of Gata6) in comparison to a control sample can be indicative for fibrotic events, in particular for lung fibrosis; see also appended illustrative Example 9 and FIG. 8.

[0019] The method of assessing whether a subject suffers from cancer or is prone to suffering from cancer according to the present application preferably relates to an in vitro method of assessing whether a subject suffers from cancer or is prone to suffering from cancer. In accordance with the invention, the term "cancer" encompasses any malignant neoplasm. This includes but is not limited to solid tumors as for example sarcoma and carcinoma as well as to liquid tumors like leukemia, lymphoma and myeloma. Preferably, the present invention allows the detection of lung cancer.

[0020] The person skilled in the art understands that a subject which is prone to suffering from cancer is a subject which has an increased likelihood of developing cancer within the next 30 years or preferably within the next 20 or 10 years or even more preferably within the next 9, 8, 7, 6, 5, 4, 3 or 2 years or even furthermore preferably within the next year. An increased likelihood of a subject of developing cancer can be understood as that said subject has an increased likelihood of developing cancer within a given time period as if compared to the average likelihood that a subject of the same age or a subject of the same age and the same gender develops cancer.

[0021] The term "sample" according to the present invention relates to any kind of sample which can be obtained from a subject, preferably from a human subject. The sample is a biological sample. A sample according to the present invention can be for example, but is not limited to, a blood sample, a breath condensate sample, a bronchoalveolar lavage fluid sample, a mucus sample or a phlegm sample. Preferably, the sample according to the present invention is a blood sample or a breath condensate sample. The term "breath condensate sample" as used herein refers to an "exhaled breath condensate (sample)". The term "exhaled breath condensate (sample)" can be abbreviated as "EBC". Accordingly, the terms "breath condensate sample", "exhaled breath condensate", "exhaled breath condensate sample" and "EBC" are used interchangeably herein. The use of "breath condensate sample", in particular "exhaled breath condensate (sample)" allows the nom invasive obtaining of samples from a subject/patient and is therefore advantageous.

[0022] In accordance with this invention, a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer is found, said method comprising the steps of

[0023] a) measuring in a sample of said subject the amount of a specific transcription factor isoform selected from the group of specific transcription factor isoforms consisting of

[0024] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0025] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the N10(2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0026] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0027] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4;

[0028] b) comparing the amount of said specific transcription factor isoform with the amount of said specific transcription factor isoform in a control sample;

[0029] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said specific transcription factor isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor isoform in the control sample.

[0030] Again, as already pointed out herein above, the increased amount of said specific transcription factor isoform in said sample leads to fast medical intervention for example by means of corresponding anti-cancer therapy, like anti-cancer medication or radiation therapy. Early stage anti-cancer therapies include, but are not limited to, radiation therapy, such as external radiation therapy, photodynamic therapy (PDT) using an endoscope and surgery (i.e. wedge resection or segmental resection for carcinoma in situ and sleeve resection or lobectomy for StageI). In addition, chemotherapy is used alone or after surgery. The chemotherapy drugs may, inter alia, comprise compounds selected from the group consisting of Cisplatin, Carboplatin, Paclitaxel (Taxol.RTM.), Albumin-bound paclitaxel (nab-paclitaxel, Abraxane.RTM.), Docetaxel (Taxotere.RTM.), Gemcitabine (Gemzar.RTM.), Vinorelbine (Navelbine.RTM.), Irinotecan (Camptosar.RTM., CPT-11), Etoposide (VP-16.RTM.), Vinblastine and Pemetrexed (Alimta.RTM.).

[0031] The present invention provides also for a method for stratifying, subjecting or seek out subjects or groups of subjects (patients or patient groups) for the treatment with (a) anti-cancer drug(s) and/or radiation therapy, said method comprising the steps of

[0032] a) measuring in a sample of said subject the amount of a specific transcription factor isoform wherein said specific transcription isoform is either

[0033] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0034] ii) the NKX2-1 Ern isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0035] b) comparing the amount of said specific transcription factor Em isoform with the amount of said specific transcription factor Em isoform in a control sample; and

[0036] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said specific transcription factor Em isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor Em isoform in the control sample. wherein an increased amount of specific transcription factor Em (GATA6 Em isoform and/or NKX2-1 Em isform) indicates that the subjects or groups of subjects is/are suitable and in need for therapy with (a) anti-cancer drug(s) and/or radiation therapy and that the subjects or groups of subjects should be treated with said anti-cancer drug and/or radiation therapy. Said subject is preferably a human subject/patient.

[0037] Also in this context of the invention of, i.e. the stratification of patients/patient groups for the need of anti-cancer therapy and/or radiation therapy, FOXA2 Em isoform and/or ID2 Em isoform may be determined as described herein.

[0038] The term "specific transcription factor Em isoform" according to the present application relates to specific isoforms of the transcription factors GATA6 (Uniprot-ID: Q92908; Gene-ID: 2627), NKX2-1 (Uniprot-ID: P43699; Gene-ID: 7080), FOXA2 (Uniprot-ID: Q9Y261; Gene-ID: 3170) and ID2 (Uniprot-ID: Q02363; Gene-ID:3398). If, for example, the amount of a specific transcription factor is measured on mRNA level, the specific transcription factor can be mRNA molecules (or transcript or splice variants). In this context, the transcription factors can be defined as

[0039] i) the GATA6 Ern isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0040] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0041] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0042] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0043] If, for example, the amount of a specific transcription factor is measured on protein level, the specific transcription factor can be protein molecules. For example, they can be defined as

[0044] v) the GATA6 Em isoform comprising the polypeptide sequence of SEQ ID No: 50 or the GATA6 Em isoform comprising the polypeptide sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 50;

[0045] vi) the NKX2-1 Em isoform comprising the polypeptide sequence of SEQ ID No: 51 or the NKX2-1 Em isoform comprising the polypeptide sequence with up to 14 additions, deletions or substitutions of SEQ ID NO: 51;

[0046] vii) the FOXA2 Em isoform comprising the polypeptide sequence of SEQ ID No: 52 or the FOXA2 Em isoform comprising polypeptide sequence with up to 43 additions, deletions or substitutions of SEQ ID NO: 52; or

[0047] viii) the ID2 Em isoform comprising the polypeptide sequence of SEQ ID No: 53 or the ID2 Em isoform comprising polypeptide sequence with up to 13 additions, deletions or substitutions of SEQ ID NO: 53.

[0048] The present invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0049] a) measuring in a sample of said subject the amount of a specific transcription factor isoform as a polypeptide wherein said specific transcription isoform is either

[0050] i) the GATA6 Em isoform comprising the polypeptide sequence of SEQ ID No: 50 or the GATA6 Em isoform comprising the polypeptide sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 50; or

[0051] ii) the NKX2-1 Em isoform comprising the polypeptide sequence of SEQ ID No: 51 or the NKX2-1 Em isoform comprising the polypeptide sequence with up to 14 additions, deletions or substitutions of SEQ ID NO: 51;

[0052] b) comparing the amount of said specific transcription factor Em isoform with the amount of said specific transcription factor Em isoform in a control sample; and

[0053] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said specific transcription factor Em isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor Em isoform in the control sample.

[0054] Again, an increased amount or said specific transcription factor Em isoform as compared to a control sample leads to modified medical intervention and/or closer diagnostic surveillance.

[0055] The herein provided methods are primarily useful in the assessment whether a subject suffers from cancer or is prone to suffering from cancer before the subject undergoes therapeutic intervention. In other words, the sample of the subject is obtained from the subject and analyzed prior to therapeutic intervention, like conventional chemotherapy. If the subject is assessed "positive" in accordance with the present invention, i.e. assessed to suffer from cancer or prone to suffering from cancer, the appropriate therapy/therapeutic intervention can be chosen. For example, a subject may be suspected of suffering from cancer and the present methods can be used to assess whether the subject suffers indeed from said cancer in addition or in the alternative to conventional diagnostic methods.

[0056] Following positive diagnosis with the herein provided inventive method, the diagnosis may be elucidated/further verified with low-dose helical computed tomography and/or Chest X-Ray, by bronchoscopy and/or histological assessment. In early stage or Grade I tumors, surgery to to remove the lobe or the section of the lung that contains the tumor would be the first choice of treatment. It is feasible to supplement the surgery with chemotherapy, known as `adjuvant chemotherapy`, to prevent cancer relapse (Howington J A et al. (2013) CHEST Journal 143: e278S-e313S). At later stages, surgery is no longer feasible and a combination of chemotherapy and radiation are advised. Further, for metastatic lesions, chemotherapy and radiation are suggested, mainly for palliation of the symptoms.

[0057] The term "isoform" according to the present invention encompasses transcript variants (which are mRNA molecules) as well as the corresponding polypeptide variants (which are polypeptides) of a gene. Such transcription variants result, for example, from alternative splicing or from a shifted transcription initiation. Based on the different transcript variants, different polypeptides are generated. It is possible that different transcript variants have different translation initiation sites. A person skilled in the art will appreciate that the amount of an isoform can be measured by adequate techniques for the quantification of mRNA as far as the isoform relates to a transcript variant which is an mRNA. Examples of such techniques are polymerase chain reaction-based methods, in situ hybridization-based methods, microarray-based techniques and whole transcriptome shotgun sequencing. Further, a person skilled in the art will appreciate that the amount of an isoform can be measured by adequate techniques for the quantification of polypeptides as far as the isoform relates to a polypeptide. Examples of such techniques for the quantification of polypeptides are ELISA (Enzyme-linked Immunosorbent Assay)-based, gel-based, blot-based, mass spectrometry-based, and flow cytometry-based methods.

[0058] It was surprisingly found by the inventors that those specific Em transcription factor isoforms are markers of the development of cancer. It was further surprisingly found that those specific Em isoforms of the transcription factors can be detected with an increased abundance in a sample obtained from a subject who suffers from cancer or is prone to suffering from cancer if compared to a control sample from healthy control subjects. Genes can contain single nucleotide polymorphisms (SNPs). The specific transcription factor Em isoform sequences of the present invention encompass (genetic) variants thereof, for example, variants having SNPs. Without deferring from the gist of the present invention, all naturally occurring sequences of the respective isoform independent of the number and nature of the SNPs in said sequence can be used herein. To relate to currently known SNPs, the transcription factor Em isoforms of the present invention are defined such that they contain up to 55 (in the case of GATA6), up to 39 (in the case of NKX2-1), up to 68 (in the case of FOXA2) or up to 34 (in the case of ID2) additions, deletions or substitutions of the nucleic acid sequences defined by SEQ ID NOs: 1, 2, 3 and 4, respectively. Thus, respective Em transcripts of carriers of different nucleotides at the respective SNPs are covered by the present application.

[0059] The GATA6 Em isoform according to the invention is the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55; preferably up to 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 or 20; even more preferably up to 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2; or even furthermore preferably only 1 addition(s), deletion(s) or substitution(s) of SEQ ID NO: 1. The GATA6 Em isoform can also be defined as the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 with additions, deletions or substitutions at any of positions 163; 293; 320; 327; 339; 430; 462; 480; 759; 1128; 1256; 1304; 1589; 1597; 1627; 1651; 1652; 1803; 1844; 1849; 1879; 1882; 1911; 1940; 1949; 1982; 2000; 2002; 2008; 2026; 2031; 2106; 2137; 2142; 2163; 2294; 2390; 2391; 2627; 2691; 3036; 3102; 3240; 3265; 3266; 3290; 3358; 3366; 3578; 3632; 3646; 3670; 3690; 3708 and 3735. The GATA6 Em isoform according to the invention can also be defined as the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with at least 85% homology to SEQ ID No: 1, preferably up to 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% homology to SEQ ID No: 1; even more preferably up to 99% homology to SEQ ID No: 1.

[0060] The NKX2-1 Em isoform according to the invention is the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39; preferably up to 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10; even more preferably up to 9, 8, 7, 6, 5, 4, 3, or 2; or even furthermore preferably only 1 addition(s), deletion(s) or substitution(s) of SEQ ID NO: 2. The NKX2-1 Em isoform can also be defined as the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 with additions, deletions or substitutions at any of positions 269; 281; 305; 304; 420; 425; 439; 441; 450; 486; 781; 785; 825; 950; 1169; 1305; 1344; 1448; 1458; 1467; 1489; 1552; 1633; 1634; 1640; 1641; 1643; 1667; 1673; 1678; 1748; 1750; 1831; 1893; 1916; 1917; 1934; 2099 and 2319. The NKX2-1 Em isoform according to the invention can also be defined as the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with at least 90% homology to SEQ ID No: 2, preferably up to 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% homology to SEQ ID No: 2; even more preferably up to 99% homology to SEQ ID No: 2.

[0061] The FOXA2 Em isoform according to the invention is the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising a nucleic acid sequence with up to 68; preferably up to 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53 52, 51, 50, 49, 48 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 or 20; even more preferably up to 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2; or even furthermore preferably only 1 addition(s), deletion(s) or substitution(s) of SEQ ID NO: 3. The FOXA2 Em isoform can also be defined as the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 with additions, deletions or substitutions at any of positions 168; 208; 289; 361; 368; 374; 379; 383; 404; 459; 481; 483; 494; 529; 564; 577; 584; 590; 610; 623; 641; 650; 659; 674; 773; 845; 1040; 1075; 1186; 1188; 1240; 1242; 1243; 1304; 1374; 1391; 1408; 1414; 1432; 1458; 1475; 1487; 1522; 1539; 1582; 1583; 1594; 1627; 1631; 1687; 1723; 1737; 1738; 1754; 1812; 1831; 1838; 1940; 1966; 1970; 2070; 2083; 2084; 2093; 2105; 2112; 2200 and 2388. The FOXA2 Em isoform according to the invention can also be defined as the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising a nucleic acid sequence with at least 93% homology to SEQ ID No: 3, preferably up to 94%, 95%, 96%, 97% or 98% homology to SEQ ID No: 3; even more preferably up to 99% homology to SEQ ID No: 3.

[0062] The ID2 Em isoform according to the invention is the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising a nucleic acid sequence with up to 34; preferably up to 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10; even more preferably up to 9, 8, 7, 6, 5, 4, 3, or 2; or even furthermore preferably only 1 addition(s), deletion(s) or substitution(s) of SEQ ID NO: 4. The ID2 Em isoform can also be defined as the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 with additions, deletions or substitutions at any of positions 6; 43; 53; 55; 154; 195; 209; 224; 237; 263; 286; 360; 399; 405; 485; 501; 544; 547; 605; 662; 665; 716; 757; 871; 876; 975; 1085; 1115; 1119; 1149; 1151; 1251; 1333 and 1350. The ID2 Em isoform according to the invention can also be defined as the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising a nucleic acid sequence with at least 51% homology to SEQ ID No: 4, preferably up to 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% homology to SEQ ID No: 4; even more preferably up to 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homology to SEQ ID No: 4.

[0063] Preferably, the above referred "addition(s), deletion(s) or substitution(s)" of the transcription factor isoforms are substitutions.

[0064] Tables 1, 2, 3, 4, 5, 6, 7 and 8 provide information on different SNPs of the transcription factors of the present invention. The present invention relates to the respective isoforms independently from the various SNPs which may occur at the different positions of the mRNAs or polypeptides. The SNPs of tables 1, 2, 3, 4, 5, 6, 7 and 8 may occur in the isoforms of the present invention in any combination. For example, a (genetic) variant of the GATA6 Em isoform to be used herein may comprise a nucleic acid sequence of SEQ ID NO:1, whereby the "G" residue at position 293 of SEQ ID NO:1 is substituted by "A". Further variants of the isoforms to be used herein are apparent from Tables 1 to 8 to the person skilled in the art. The respective SNP information has been retrieved using dbSNP (short genetic variations) database of the NCBI. The SNP information is based on Contig Label GRCh37.p5. A person skilled in the art will understand that also SNPs which are not mentioned in tables 1 to 8 are encompassed by the present invention.

TABLE-US-00001 TABLE 1 SNPs of the GATA6 Em isoform S. Contig Poly- Codon Protein No. Region Position reference morphism Position Function residue 1 5'UTR 163 C G 2 CCDS 293 G A 6 Missense Gly-Ser 3 CCDS 320 G C 15 Missense Gly-Arg 4 CCDS 327 C G 17 Missense Ala-Gly 5 CCDS 339 C G 21 Missense Ala-Gly 6 CCDS 430 G T 51 Missense Glu-Asp 7 CCDS 462 -- T 62 Frameshift TA-Thr 8 CCDS 480 A T 68 Missense Glu-Val 9 CCDS 759 C T 161 Missense Ala-Val 10 CCDS 1128 C G 284 Missense Ala-Gly 11 CCDS 1256 C A 327 Missense His-Asn 12 CCDS 1304 G A 343 Missense Ala-Thr 13 CCDS 1589 C T 438 Missense Arg-Trp 14 CCDS 1597 T A 440 Synonymous Leu-Leu 15 CCDS 1627 A G 450 Synonymous Thr-Thr 16 CCDS 1651 C T 458 Synonymous Asn-Asn 17 CCDS 1652 G A 459 Missense Ala-Thr 18 CCDS 1803 A G 509 Missense Asn-Ser 19 CCDS 1844 T C 523 Missense Ser-Pro 20 CCDS 1849 T C 524 Synonymous Asp-Asp 21 CCDS 1879 A G 534 Synonymous Thr-Thr 22 CCDS 1882 A G 535 Synonymous Gln-Gln 23 CCDS 1911 T G 545 Missense Val-Gly 24 CCDS 1940 C G 555 Missense Pro-Ala 25 CCDS 1949 A G 558 Missense Ser-Gly 26 CCDS 1982 T C 569 Missense Tyr-His 27 CCDS 2000 G C 575 Missense Ala-Pro 28 CCDS 2002 C T 575 Synonymous Ala-Ala 29 CCDS 2008 G C 577 Synonymous Pro-Pro 30 CCDS 2026 C T 583 Synonymous Ser-Ser 31 CCDS 2031 G T 585 Missense Arg-Leu 32 3'UTR 2106 C T 33 3'UTR 2137 G A 34 3'UTR 2142 A G 35 3'UTR 2163 C T 36 3'UTR 2294 C T 37 3'UTR 2390 A G 38 3'UTR 2391 T A 39 3'UTR 2627 A G 40 3'UTR 2691 G T 41 3'UTR 3036 G T 42 3'UTR 3102 A G 43 3'UTR 3240 C T 44 3'UTR 3265 C G 45 3'UTR 3266 C T 46 3'UTR 3290 A G 47 3'UTR 3358 C T 48 3'UTR 3366 A T 49 3'UTR 3578 C T 50 3'UTR 3632 -- C 51 3'UTR 3646 C T 52 3'UTR 3670 A G 53 3'UTR 3690 C T 54 3'UTR 3708 A G 55 3'UTR 3735 A G

TABLE-US-00002 TABLE 2 SNPs of the GATA6 Ad isoform S. Contig Poly- Codon Protein No. Region Position reference morphism Position Function residue 1 5'UTR 138 C G 2 5'UTR 228 G A 3 5'UTR 255 G C 4 5'UTR 262 C G 5 5'UTR 274 C G 6 5'UTR 365 G T 7 5'UTR 397 -- T 8 5'UTR 415 A T 9 CCDS 694 C T 15 Missense Ala-Val 10 CCDS 1063 C G 138 Missense Ala-Gly 11 CCDS 1191 C A 181 Missense His-Asn 12 CCDS 1239 G A 197 Missense Ala-Thr 13 CCDS 1524 C T 292 Missense Arg-Trp 14 CCDS 1532 T A 294 Synonymous Leu-Leu 15 CCDS 1562 A G 304 Synonymous Thr-Thr 16 CCDS 1586 C T 312 Synonymous Asn-Asn 17 CCDS 1587 G A 313 Missense Ala-Thr 18 CCDS 1738 A G 363 Missense Asn-Ser 19 CCDS 1779 T C 377 Missense Ser-Pro 20 CCDS 1784 T C 378 Synonymous Asp-Asp 21 CCDS 1814 A G 388 Synonymous Thr-Thr 22 CCDS 1817 A G 389 Synonymous Gln-Gln 23 CCDS 1846 T G 399 Missense Val-Gly 24 CCDS 1875 C G 409 Missense Pro-Ala 25 CCDS 1884 A G 412 Missense Ser-Gly 26 CCDS 1917 T C 423 Missense Tyr-His 27 CCDS 1935 G C 429 Missense Ala-Pro 28 CCDS 1937 C T 429 Synonymous Ala-Ala 29 CCDS 1943 G C 431 Synonymous Pro-Pro 30 CCDS 1961 C T 437 Synonymous Ser-Ser 31 CCDS 1966 G T 439 Missense Arg-Leu 32 3'UTR 2041 C T 33 3'UTR 2072 G A 34 3'UTR 2077 A G 35 3'UTR 2098 C T 36 3'UTR 2229 C T 37 3'UTR 2325 A G 38 3'UTR 2326 T A 39 3'UTR 2562 A G 40 3'UTR 2626 G T 41 3'UTR 2971 G T 42 3'UTR 3037 A G 43 3'UTR 3175 C T 44 3'UTR 3200 C G 45 3'UTR 3201 C T 46 3'UTR 3225 A G 47 3'UTR 3293 C T 48 3'UTR 3301 A T 49 3'UTR 3513 C T 50 3'UTR 3567 -- C 51 3'UTR 3581 C T 52 3'UTR 3605 A G 53 3'UTR 3625 C T 54 3'UTR 3643 A G 55 3'UTR 3670 A G

TABLE-US-00003 TABLE 3 SNPs of the NKX2-1 Em isoform S. Contig Poly- Codon Protein No. Region Position reference morphism Position Function residue 1 5'UTR 269 C T 2 5'UTR 281 A G 3 5'UTR 305 -- A 4 5'UTR 304 -- AA 5 CCDS 420 G A 27 Missense Val-Met 6 CCDS 425 C T 28 Synonymous Gly-Gly 7 CCDS 439 G T 33 Missense Gly-Val 8 CCDS 441 C A 34 Missense Leu-Ile 9 CCDS 450 C T 37 Missense Pro-Ser 10 CCDS 486 C T 49 Missense Pro-Ser 11 CCDS 781 G T 147 Missense Gly-Val 12 CCDS 785 C T 148 Synonymous Asp-Asp 13 CCDS 825 A C 162 Synonymous Arg-Arg 14 CCDS 950 G T 203 Synonymous Thr-Thr 15 CCDS 1169 G A 276 Synonymous Ala-Ala 16 CCDS 1305 G A 322 Missense Gly-Ser 17 CCDS 1344 G T 335 Missense Ala-Ser 18 CCDS 1448 G A 369 Synonymous Arg-Arg 19 3'UTR 1458 C T 20 3'UTR 1467 C T 21 3'UTR 1489 G T 22 3'UTR 1552 G T 23 3'UTR 1633 A G 24 3'UTR 1634 A G 25 3'UTR 1640 -- T 26 3'UTR 1641 -- GT 27 3'UTR 1643 -- >6bp 28 3'UTR 1667 A T 29 3'UTR 1673 -- T 30 3'UTR 1678 -- T 31 3'UTR 1748 -- C 32 3'UTR 1750 -- C 33 3'UTR 1831 A T 34 3'UTR 1893 G T 35 3'UTR 1916 -- A 36 3'UTR 1917 -- A 37 3'UTR 1934 C G/T 38 3'UTR 2099 C G 39 3'UTR 2319 C G

TABLE-US-00004 TABLE 4 SNPs of the NKX2-1 Ad isoform S. Contig Poly- Codon Protein No. Region Position reference morphism Position Function residue 1 5'UTR 12 G T 2 CCDS 125 G A 10 Missense Arg-Gln 3 CCDS 265 G A 57 Missense Val-Met 4 CCDS 270 C T 58 Synonymous Gly-Gly 5 CCDS 284 G T 63 Missense Gly-Val 6 CCDS 286 C A 64 Missense Leu-Ile 7 CCDS 295 C T 67 Missense Pro-Ser 8 CCDS 331 C T 79 Missense Pro-Ser 9 CCDS 626 G T 177 Missense Gly-Val 10 CCDS 630 C T 178 Synonymous Asp-Asp 11 CCDS 670 A C 192 Synonymous Arg-Arg 12 CCDS 795 G T 233 Synonymous Thr-Thr 13 CCDS 1014 G A 306 Synonymous Ala-Ala 14 CCDS 1150 G A 352 Missense Gly-Ser 15 CCDS 1189 G T 365 Missense Ala-Ser 16 CCDS 1293 G A 399 Synonymous Arg-Arg 17 3'UTR 1303 C T 18 3'UTR 1312 C T 19 3'UTR 1334 G T 20 3'UTR 1397 G T 21 3'UTR 1478 A G 22 3'UTR 1479 A G 23 3'UTR 1478 -- >6bp 24 3'UTR 1485 -- T 25 3'UTR 1486 -- GT 26 3'UTR 1488 -- >6bp 27 3'UTR 1512 A T 28 3'UTR 1518 -- T 29 3'UTR 1523 -- T 30 3'UTR 1593 -- C 31 3'UTR 1595 -- C 32 3'UTR 1676 A T 33 3'UTR 1738 G T 34 3'UTR 1761 -- A 35 3'UTR 1762 -- A 36 3'UTR 1779 C G/T 37 3'UTR 1944 C G 38 3'UTR 2164 C G

TABLE-US-00005 TABLE 5 SNPs of the FOXA2 Em isoform S. Contig Poly- Codon Protein No. Region Position reference morphism Position Function residue 1 5'UTR 168 -- >6bp 2 CCDS 208 T C 8 Missense Leu-Pro 3 CCDS 289 G A 35 Missense Ser-Asn 4 CCDS 361 G A 59 Missense Ser-Asn 5 CCDS 368 G A 61 Synonymous Ser-Ser 6 CCDS 374 C T 63 Synonymous Asn-Asn 7 CCDS 379 G A 65 Missense Ser-Asn 8 CCDS 383 G A 66 Synonymous Ala-Ala 9 CCDS 404 G T 73 Synonymous Ser-Ser 10 CCDS 459 G A 92 Missense Ala-Thr 11 CCDS 481 C T 99 Missense Ser-Leu 12 CCDS 483 G C 100 Missense Ala-Pro 13 CCDS 494 C T 103 Synonymous Ala-Ala 14 CCDS 529 G A 115 Missense Ser-Asn 15 CCDS 564 A G 127 Missense Met-Val 16 CCDS 577 C G 131 Missense Ala-Gly 17 CCDS 584 C T 133 Synonymous Tyr-Tyr 18 CCDS 590 C A 135 Missense Asn-Lys 19 CCDS 610 T C 142 Missense Met-Thr 20 CCDS 623 G C 146 Synonymous Ala-Ala 21 CCDS 641 C T 152 Synonymous Arg-Arg 22 CCDS 650 G A 155 Synonymous Lys-Lys 23 CCDS 659 G T 158 Missense Arg-Ser 24 CCDS 674 C T 163 Synonymous His-His 25 CCDS 773 G T 196 Missense Met-Ile 26 CCDS 845 C T 220 Synonymous Asn-Asn 27 CCDS 1040 A G 285 Synonymous Gly-Gly 28 CCDS 1075 C T 297 Missense Ala-Val 29 CCDS 1186 C T 334 Missense Ala-Val 30 CCDS 1188 G C 335 Missense Ala-Pro 31 CCDS 1240 C T 352 Missense Ala-Val 32 CCDS 1242 G A 353 Missense Ala-Thr 33 CCDS 1243 C G 353 Missense Ala-Gly 34 CCDS 1304 A C 373 Missense Glu-Asp 35 CCDS 1374 AG -- 397 Frameshift Ser-Pro 36 CCDS 1391 A G 402 Synonymous Gln-Gln 37 CCDS 1408 T C 408 Missense Leu-Pro 38 CCDS 1414 C T 410 Missense Ala-Val 39 CCDS 1432 A C 416 Missense His-Pro 40 CCDS 1458 C A 425 Missense Pro-Thr 41 CCDS 1475 G A 430 Missense Met-Ile 42 CCDS 1487 G C 434 Synonymous Thr-Thr 43 CCDS 1522 C G 446 Missense Ala-Gly 44 CCDS 1539 C G 452 Missense Gln-Glu 45 3'UTR 1582 G T 46 3'UTR 1583 A G 47 3'UTR 1594 C T 48 3'UTR 1627 A G 49 3'UTR 1631 A G 50 3'UTR 1687 A G 51 3'UTR 1723 A C 52 3'UTR 1737 -- G 53 3'UTR 1738 -- G 54 3'UTR 1754 A G 55 3'UTR 1812 A G 56 3'UTR 1831 A T 57 3'UTR 1838 -- T 58 3'UTR 1940 A C 59 3'UTR 1966 -- G/T 60 3'UTR 1970 -- A 61 3'UTR 2070 A T 62 3'UTR 2083 A G 63 3'UTR 2084 -- T 64 3'UTR 2093 -- T 65 3'UTR 2105 A C 66 3'UTR 2112 C T 67 3'UTR 2200 C T 68 3'UTR 2388 A G

TABLE-US-00006 TABLE 6 SNPs of the FOXA2 Em isoform S. Contig Poly- Codon Protein No. Region Position reference morphism Position Function residue 1 5'UTR 5 C T 2 5'UTR 37 G T 3 5'UTR 65 C T 4 5'UTR 68 A C 5 5'UTR 70 A G 6 5'UTR 88 A G 7 5'UTR 128 C T 8 CCDS 195 T C 2 Missense Leu-Pro 9 CCDS 276 G A 29 Missense Ser-Asn 10 CCDS 348 G A 53 Missense Ser-Asn 11 CCDS 355 G A 55 Synonymous Ser-Ser 12 CCDS 361 C T 57 Synonymous Asn-Asn 13 CCDS 366 G A 59 Missense Ser-Asn 14 CCDS 370 G A 60 Synonymous Ala-Ala 15 CCDS 391 G T 67 Synonymous Ser-Ser 16 CCDS 446 G A 86 Missense Ala-Thr 17 CCDS 468 C T 93 Missense Ser-Leu 18 CCDS 470 G C 94 Missense Ala-Pro 19 CCDS 481 C T 97 Synonymous Ala-Ala 20 CCDS 516 G A 109 Missense Ser-Asn 21 CCDS 551 A G 121 Missense Met-Val 22 CCDS 564 C G 125 Missense Ala-Gly 23 CCDS 571 C T 127 Synonymous Tyr-Tyr 24 CCDS 577 C A 129 Missense Asn-Lys 25 CCDS 597 T C 136 Missense Met-Thr 26 CCDS 610 G C 140 Synonymous Ala-Ala 27 CCDS 628 C T 146 Synonymous Arg-Arg 28 CCDS 637 G A 149 Synonymous Lys-Lys 29 CCDS 646 G T 152 Missense Arg-Ser 30 CCDS 661 C T 157 Synonymous His-His 31 CCDS 760 G T 190 Missense Met-Ile 32 CCDS 832 C T 214 Synonymous Asn-Asn 33 CCDS 1027 A G 279 Synonymous Gly-Gly 34 CCDS 1062 C T 291 Missense Ala-Val 35 CCDS 1173 C T 328 Missense Ala-Val 36 CCDS 1175 G C 329 Missense Ala-Pro 37 CCDS 1227 C T 346 Missense Ala-Val 38 CCDS 1229 G A 347 Missense Ala-Thr 39 CCDS 1230 C G 347 Missense Ala-Gly 40 CCDS 1291 A C 367 Missense Gly-Glu 41 CCDS 1361 AG -- 391 Frameshift Ser-Pro 42 CCDS 1378 A G 396 Synonymous Gln-Gln 43 CCDS 1395 T C 402 Missense Leu-Pro 44 CCDS 1401 C T 404 Missense Ala-Val 45 CCDS 1419 A C 410 Missense His-Pro 46 CCDS 1445 C A 419 Missense Pro-Thr 47 CCDS 1462 G A 424 Missense Met-Ile 48 CCDS 1474 G C 428 Synonymous Thr-Thr 49 CCDS 1509 C G 440 Missense Ala-Gly 50 CCDS 1526 C G 446 Missense Gln-Glu 51 3'UTR 1569 G T 52 3'UTR 1570 A G 53 3'UTR 1581 C T 54 3'UTR 1614 A G 55 3'UTR 1618 A G 56 3'UTR 1674 A G 57 3'UTR 1710 A C 58 3'UTR 1724 -- G 59 3'UTR 1725 -- G 60 3'UTR 1741 A G 61 3'UTR 1799 A G 62 3'UTR 1818 A T 63 3'UTR 1825 -- T 64 3'UTR 1927 A C 65 3'UTR 1953 -- G/T 66 3'UTR 1957 -- A 67 3'UTR 2057 A T 68 3'UTR 2070 A G 69 3'UTR 2071 -- T 70 3'UTR 2080 -- T 71 3'UTR 2092 A C 72 3'UTR 2099 C T 73 3'UTR 2187 C T 74 3'UTR 2375 A G

TABLE-US-00007 TABLE 7 SNPs of the ID2 Em isoform S. Contig Poly- Codon Protein No. Region Position reference morphism Position Function residue 1 5'UTR 6 C T 2 5'UTR 43 A G 3 5'UTR 53 A G 4 5'UTR 55 C G 5 5'UTR 154 C G/T 6 CCDS 195 C T 4 Missense Phe-Phe 7 CCDS 209 C T 9 Missense Ser-Phe 8 CCDS 224 G A 14 Missense Ser-Asn 9 CCDS 237 C T 18 Synonymous His-His 10 CCDS 263 C A 27 Missense Thr-Asn 11 CCDS 286 C T 35 Synonymous Leu-Leu 12 CCDS 360 G A 59 Synonymous Val-Val 13 CCDS 399 C T 72 Synonymous Ile-Ile 14 CCDS 405 C T 74 Synonymous Asp-Asp 15 CCDS 485 C T 101 Missense Thr-Met 16 CCDS 501 C G/T 106 Synonymous Leu-Leu 17 CCDS 544 C T 121 Missense Pro-Ser 18 CCDS 547 T A 122 Missense Ser-Thr 19 3'UTR 605 A G 20 3'UTR 662 C G 21 3'UTR 665 G T 22 3'UTR 716 A T 23 3'UTR 757 C T 24 3'UTR 871 A G 25 3'UTR 876 A G 26 3'UTR 975 -- >6bp 27 3'UTR 1085 -- >6bp 28 3'UTR 1115 A G 29 3'UTR 1119 -- AT 30 3'UTR 1149 C T 31 3'UTR 1151 A T 32 3'UTR 1251 -- CA 33 3'UTR 1333 A G 34 3'UTR 1350 C G

TABLE-US-00008 TABLE 8 SNPs of the ID2 Ad isoform S. Contig Poly- Codon Protein No. Region Position reference morphism Position Function residue 5 5'UTR 93 C G/T 6 CCDS 134 C T 4 Missense Phe-Phe 7 CCDS 148 C T 9 Missense Ser-Phe 8 CCDS 163 G A 14 Missense Ser-Asn 9 CCDS 176 C T 18 Synonymous His-His 10 CCDS 202 C A 27 Missense Thr-Asn 11 CCDS 225 C T 35 Synonymous Leu-Leu 12 CCDS 299 G A 59 Synonymous Val-Val 13 CCDS 338 C T 72 Synonymous Ile-Ile 14 CCDS 344 C T 74 Synonymous Asp-Asp 15 CCDS 424 C T 101 Missense Thr-Met 16 CCDS 440 C G/T 106 Synonymous Leu-Leu 17 CCDS 483 C T 121 Missense Pro-Ser 18 CCDS 486 T A 122 Missense Ser-Thr 19 3'UTR 544 A G 20 3'UTR 601 C G 21 3'UTR 604 G T 22 3'UTR 655 A T 23 3'UTR 696 C T 24 3'UTR 810 A G 25 3'UTR 815 A G 26 3'UTR 914 -- >6bp 27 3'UTR 1024 -- >6bp 28 3'UTR 1054 A G 29 3'UTR 1058 -- AT 30 3'UTR 1088 C T 31 3'UTR 1090 A T 32 3'UTR 1190 -- CA 33 3'UTR 1272 A G 34 3'UTR 1289 C G

[0065] A control sample according to the present invention is a sample from a healthy control subject. Such a sample can be obtained for example from a subject known to be a healthy subject. It is also possible to generate a control sample according to the present invention as a mixture of samples obtained from several healthy subjects, for example from a group of 10, 20, 30, 50, 100 or even up to 1000 healthy subjects. A control sample according to the present invention can be generated for example from age-matched and or gender-matched healthy control subjects. A control sample according to the present invention can also be generated for example in vitro to mimic a control sample obtained from one or several healthy subjects.

[0066] Control samples used, inter alia, in appended Example 10 for the analysis of tumor biopsies were healthy tissues (i.e. biopsies) from diseased individuals/subjects. "Healthy tissue from diseased individuals/subjects" can refer to tissue that is pathologically classified as "normal" or "healthy" and/or that is distant or adjacent to a (suspected) tumor. For example, the "healthy tissue from diseased individuals/subjects" can be obtained e.g. by biopsy from adjacent healthy tissue of (suspected) cancer patients.

[0067] For example, the "healthy tissue" can be obtained from the subject(s) to be assessed in accordance with the present invention for suffering from cancer or being prone to suffering from cancer. In another example, the "healthy tissue" can be obtained from other diseased patients (e.g. patients that have already been diagnosed to suffer from cancer by conventional means and methods or patients that have a history of cancer); in that case, "healthy tissue" is not obtained from subject(s) to be assessed in accordance with the present invention for suffering from cancer or being prone to suffering from cancer.

[0068] Thus, also "healthy tissue from (a) diseased individual(s)" can be used as a control sample in accordance with the present invention.

[0069] Control samples used, inter alia, in appended Example 10 in the analysis of EBCs for assessing whether a subject suffers from cancer or is prone to suffer from cancer were samples from healthy individuals. The term "healthy individuals" as used herein can refer to individuals with no history of cancer, i.e. individuals that did not suffer from cancer or that do currently (i.e. at the time the control sample is obtained) not suffer from cancer. Thus, "healthy tissue/sample" (i.e. tissue (e.g. a biopsy) or another sample (e.g. EBC) obtained from a healthy individual" can be used as a control sample in accordance with the present invention.

[0070] A subject according to the present invention is preferably a human subject. The subject according to the present invention can be a human subject which has an increased likelihood of suffering from cancer. Such an increased likelihood of suffering from cancer can for example result from certain exposures to cancerogens, for example through the habit of smoking.

[0071] The "amount of said specific transcription isoform" according to the present invention can be a relative amount or an absolute amount. The relative amount can be determined relative to a control sample. To determine the "amount of said specific transcription isoform", the absolute or relative amount of a reference gene or reference protein can be determined in the sample from the subject and in the control sample. Non-limiting examples of reference genes/proteins are TUBA1A1 (Uniprot-ID: Q71U36, Gene-ID: 7846), HPRT1 (Uniprot-ID: P00492, Gene-ID: 3251), ACTB (Uniprot-ID: P60709, Gene-ID: 60), HMBS (Uniprot-ID: P08397, Gene-ID: 3145), RPL13A (Uniprot-ID: Q9BSQ6, Gene-ID: 23521) and UBE2A (Uniprot-ID: P49459, Gene-ID: 7319).

[0072] The term "is increased in comparison to the amount of said specific transcription factor isoform in the control sample" relates to an increase of the amount of the specific transcription factor isoform in the sample obtained from the subject in comparison to the amount of said specific transcription factor isoform in the control sample by at least 1.3-fold, by at least 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold or 2.0-fold, by at least 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold or 10-fold; by at least 20-fold, by at least 30-fold, by at least 40-fold; by at least 50-fold; or by at least 100-fold. Illustrative data provided herein for GATA6 and NKX2-1 are summarized in the following table and further illustrate the invention without being limiting:

TABLE-US-00009 Normal Grade I Grade II Grade III Gata6 Em 1.0 2.7 6.7 1.9 Ad 2.3 1.1 0.5 0.5 Ratio (Em/Ad) 0.435 2.5 13.4 3.8 Fold increase of Em 2.7 6.7 1.9 relative to control Nkx2-1 Em 1.0 1.6 5.3 5.7 Ad 2.9 1.6 0.9 1.8 Ratio (Em/Ad) 0.3 1.0 5.9 3.2 Fold increase of Em 1.6 5.3 5.7 related to ctrl

[0073] According to a more refined analysis in appended Example 10 the following thresholds were determined:

TABLE-US-00010 GATA6 Em NKX2-1 Em Mean .+-. s.e.m. 2.240 .+-. 0.453 3.359 .+-. 1.053 fold increase of Em relative 1.194 - 5.064 1.393 - 10.661 to control (range)

[0074] These data confirm that the methods provided herein allow a reliable assessment that a subject suffers from cancer, in particular lung cancer, such as NSCLC or small cell lung cancer (SLC), or is prone to suffering from said cancer, when the amount of the (analyzed) specific transcripton factor Em isoform GATA6 Em and/or NKX2-1 Em is increased by at least about 1.3 fold in comparison to the amount of the analyzed specific transcription factor Em isoform(s) in the control sample. In relation to the Em isoform GATA6 Em a reliable assessment that a subject suffers from cancer, in particular lung cancer, such as NSCLC or small cell lung cancer (SLC), or is prone to suffering from said cancer, is possible, when the amount of the (analyzed) specific transcripton factor Em isoform GATA6 Em and/or NKX2-1 Em is increased by at least about 1.2 fold in comparison to the amount of the analyzed specific transcription factor Em isoform(s) in the control sample.

[0075] Without being bound by theory and the concrete values provided herein in particular in the experimental part, for example for NKX2-1, an increase of at least 1.3 fold (over control) would be a reason to observe the subject in periodical manner (i.e. every 3 to 6 months). An increase of at least about 1.6 (over control) fold would be a reason for more detail analysis and elucidation of the most suitable treatment (i.e. targeting the isoform that is increased using, inter alia, but not limited to a "loss-of-function approach"; see also appended FIG. 2B and technical details provided in the appended examples. Potential and preferred treatment options have been provided herein above. Yet, the attending physician may also decide to make use of other and/or further medical and/or pharmaceutical intervention(s). For GATA6, as illustrated about, again, an increase of about 1.3-fold (over control) to about 2.7 (over control) merits closer observation of the subject/patient Potential and preferred treatment options have been provided herein above. Yet, the attending physician may also decide to make use of other and/or further medical and/or pharmaceutical intervention(s). Again, in accordance with the illustrative data provided herein for GATA6, an increase of at least about 2.7 (over control) merits a more detailed analysis and elucidation of the most suitable treatment form of the cancer.

[0076] The method according to the present invention may comprise the step of obtaining a sample from a patient, wherein this sample is preferably a blood sample.

[0077] The present invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0078] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor, wherein said transcription factor is either GATA6 or NKX2-1 and wherein the two specific isoforms are either:

[0079] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; or

[0080] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 6 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0081] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor

[0082] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0083] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; or

[0084] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3.

[0085] It is surprisingly found that the ratio of the transcription factor Em isoform and the transcription factor Ad isoform according to the present invention is increasing in the process of the development of cancer (see Example 3 of the present application). This allows a very early detection of cancer using any of the methods of the present invention. Further, this surprising finding also allows the staging of cancer, i.e. to assess the stage of a cancer of a subject with a method of the present invention alone or with a method of the present invention in combination with further methods for the staging of cancer (see, inter alia, Example 3 appended herewith).

[0086] To compute the ratio of the amount of the Em isoform and the amount of the Ad isoform according to the present invention, the person skilled in the art preferably divides the amount of the Em isoform by the amount of the Ad isoform. This is possible if the amounts are absolute amounts as well as if the amounts are relative amounts, for examples amounts which are given in relation to one or several reference genes. As documented herein (see FIG. 2B of Example 3 of the present application), the corresponding ratio for GATA6 is deduced at about 0.5 (0.435 in table presented herein above), for NKX2-1 at about 0.3 and for FOXA2 at about 0.8 when (as done in the appended examples) quantitative measures are taken by real time PCR for the ratio of Em/Ad.

[0087] As documented herein (see, inter alia, FIG. 2B of Example 3 of the present application), the Em-isoforms are highly expressed in human lung cancer tissue. In the appended examples, isoform specific expression was monitored by (for example) qRT-PCR after total RNA isolation from human lung tumor and normal lung cryosections. The expression of the Em-isoform/Em-transcipt of each one of the genes analyzed, in particular GATA6, NKX2-1 and FOXA2, was higher in the tested cancer samples when compared to the normal controls, documenting that indeed an increase in expression of the Em-isoforms of GATA6 and NKX2-1 and, in co-assessments also of FOXA2 and/or ID2 are relevant and indicative for the development/formation of cancer, in particular for lung cancer formation as documented herein. This was also confirmed in human cancer specimens, in particular when human lung biopsies from healthy donors and lung tumor patients were compared; see also appended FIG. 2B. The embryonic transcript of each one of the genes analyzed was enriched in the biopsies of lung tumor when compared to the healthy tissue. In accordance with the data presented herein for lung cancer, for GATA6 Em, NKX2-1 Em and FOXA2 Em isoforms, a diagnostic ratio for GATA6 is 0.5, for NKX2-1 is 0.3 and for FOXA2 is 0.8. In the following, non limiting examples for FOXA 2 as elucidated form the experimental part of this application are provided:

TABLE-US-00011 Normal Grade I Grade II Grade III Foxa2 var1 0.8 3.19 15.34 5.59 var2 1.00 1.44 1.50 0.45 Ratio (Em/Ad) 0.80 2.21 10.20 12.55 3.99 19.17 6.98 Id2 Em (Var 1) 1 1.182787 3.831565 1.639342 Ad (Var 2) 1.08543 0.78787 1.12586 0.62216 Ratio (Em/Ad) 0.9 1.5 3.4 2.6 1.182787 3.831565 1.639342

[0088] As demonstrated in the appended examples, the thresholds/ratios of 0.5 in relation to GATA6 or 0.3 in relation to NKX2-1 are useful to assess whether a patient suffers from cancer or is prone to suffering from cancer. If the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5 a subject is assessed herein as suffering from cancer or as being prone to suffering from cancer. If the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3, a subject is assessed herein as suffering from cancer or as being prone to suffering from cancer.

[0089] It is understood that different ethnic groups can show a certain variation in these ratios. For example, appended example 10 provides an assessment of a large sample set including patients from all ethnic groups (CEU, Utah residents with ancestry from northern and western Europe; CHB, Han Chinese in Beijing, China and MXL, Mexican ancestry in Los Angeles, Calif.). It is demonstrated therein that healthy tissue (biopsies) from all diseased patients in all ethnic groups had a mean Em/Ad ratio of 0.642 for GATA6 and 0.475 for NKX2-1. These values are slightly increased compared to the threshold values of 0.5 and 0.3 respectively, which is due to the inclusion of a more heterogeneous population set (including all three ethnic groups). Importantly, however, the majority of the healthy samples lies in the range of 0.3-0.7 for GATA6 and 0.3-0.5 for NKX2-1.

[0090] The data provided inter alia in appended Example 10 employed control samples (biopsies) obtained from adjacent healthy tissue of lung cancer patients.

[0091] Also healthy donor tissue from unaffected, healthy individuals (no current or history of tumors) can be used as control samples in the herein provided methods as "control samples". It is demonstrated herein that the ratio of Em/Ad was <0.3 for GATA6 and <0.2 for NKX2-1 in these control samples, as shown below:

[0092] The ratios obtained using "healthy" donor lung tissues are 0.17.+-.0.03 for GATA6 and 0.16.+-.0.02 for NKX2-1, lower than the ones obtained from healthy tissues from diseased individuals; see the table below:

TABLE-US-00012 Em/Ad GATA6 NKX2-1 0.219218 0.211487 0.08244 0.271615 0.06726 0.176477 0.346862 0.164339 0.224829 0.193047 0.219752 0.123482 0.06256 0.08117 0.176477 0.047586 Mean 0.17 0.16 s.e.m. 0.03505 0.025586

[0093] This demonstrates that the threshold values/ratios of 0.5 in relation to GATA6 or 0.3 in relation to NKX2-1 are indeed useful to assess whether a patient suffers from cancer or is prone to suffering from cancer.

[0094] Again, it is understood that these thresholds/ratios can vary depending on the values determined in control samples due to variations within ethnic groups, due to variations in sample types (e.g. biopsy or EBC), or origin (e.g. obtained from a healthy individual or obtained from healthy tissue from a diseased individual/subject). It is of note that subjects suffering from cancer or prone to suffering from cancer can reliably be diagnosed herein, because samples obtained from these subjects (e.g. a biopsy from a suspected tumor or EBC, exhaled breath condensate) show, even and in particular at early stages of the tumor, an increased Em/Ad ratio compared to the control. As shown in the appended examples, the Em/Ad ratios in samples from diseased patients is consistently increased compared to that of control samples (irrespective of the ethnic groups, sample type or origin of sample). The Em/Ad ratios in samples from diseased patients was always shown to be higher than 1. The lowest Em/Ad ratio shown in a sample from diseased patients was about 1.5.

[0095] The data shown in appended example 10 are summarized in the following table:

TABLE-US-00013 Mean values .+-. s.e.m. GATA6 Biopsies Healthy Tumor Grade I Grade II Grade III 0.64 .+-. 0.05 2.63 .+-. 019 2.39 .+-. 0.25 3.43 .+-. 0.24 2.83 .+-. 0.59 EBC Healthy Tumor 0.47 .+-. 0.11 1.53 .+-. 0.27 NKX2-1 Biopsies Healthy Tumor Grade I Grade II Grade III 0.46 .+-. 0.03 2.07 .+-. 0.22 1.87 .+-. 0.12 2.58 .+-. 0.25 3.78 .+-. 0.39 EBC Healthy Tumor 0.45 .+-. 0.05 2.77 .+-. 0.29

[0096] The data show that the Em/Ad ratios obtained from EBCs and biopsies are comparable supporting that the EBCs can be used as a non-invasive, sensitive and specific cancer diagnostic method, in particular lung cancer diagnostic method, that is advantageous for screening in particular high risk patients compared to conventional methods including chest X-ray and low dose computed tomography.

[0097] This shows that the present invention provides a reliable diagnosis of cancer patients, in particular of lung cancer patients.

[0098] Accordingly, in one embodiment of the invention, the transcription factor to be verified is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; at least higher than 0.6, 0.7, 0.8, 0.9 or preferably higher than 1. More preferably, the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 1.5. Thus, the ratio of the amount of said Em and said Ad isoform of GATA6 can be higher than 1.2, 1.4, 1.6, 1.8 or 2, or even higher, for example higher than 3, 4, 5, 6, 7, 8, 9 or 10.

[0099] In one embodiment, said transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3, at least higher than 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or preferably higher than 1. More preferably, the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 1.7. Thus, the ratio of the amount of said Em and said Ad isoform of NKX2-1 can be higher than 1.2, 1.4, 1.6, 1.8 or 2; or even higher for example higher than 3, 4, 5, 6, 7, 8, 9 or 10 in order to be indicative for the development/formation of cancer, in particular for lung cancer formation.

[0100] In one embodiment, said transcription factor is FOXA2 and the ratio of the amount of said Em and said Ad isoform of FOXA2 is higher than 0.8; at least higher than 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2; higher than 2.2, 2.4, 2.6, 2.8 or 3; higher than 4, 5, 6, 7, 8, 9, 10 or 15 in order to be indicative for the development/formation of cancer, in particular for lung cancer formation. In one embodiment, said the transcription factor is ID2 and the ratio of the amount of said Em and said Ad isoform of ID2 is higher than 1; at least higher than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2; higher than 2.2, 2.4, 2.6, 2.8 or 3; higher than 4, 5, 6, 7, 8, 9, 10 or 15 in order to be indicative for the development/formation of cancer, in particular for lung cancer formation.

[0101] Threshold values/ratios of the amount of said Em and said Ad isoform of GATA6 indicating that a subject suffers from cancer or is prone to suffering from cancer can be about 0.7 or higher (in particular 1.0 or higher), if control sample(s) is/are healthy tissue(s) (obtained preferably in this context by biopsy) from diseased patients. Threshold values/ratios of the amount of said Em and said Ad isoform of GATA6 indicating that a subject suffers from cancer or is prone to suffering from cancer can be about 0.25 or 0.3 or higher (in particular 1.0 or higher), if control sample(s) is/are healthy tissue(s) (obtained preferably in this context by biopsy) from healthy individuals. For example, ratios of the amount of said Em and said Ad isoform of GATA6 can be about 2.6 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from cancer or being prone to suffering from cancer in accordance with the present invention.

[0102] The herein provided method can be used to stratify/assess subjects according to the tumor/cancer grade. It can be helpful to assess whether a patient is suffering from Grade I, Grade II or Grade III tumor/cancer in order to decide which therapeutic intervention is warrented.

[0103] The definition of Grade I, Grade II and Grade III tumor is based on TNM classification recommended by the American joint Committee on Cancer (Goldstraw P. et al. (2007) J Thorac Oncol. 2(8):706-14; Beadsmoore C J and Screaton N J (2003) Eur J Radiol. 45(1):8-17; Mountain CF (1997) Chest. 111(6):1710-7.), which is incorporated herein by reference.

[0104] Ratios of the amount of said Em and said Ad isoform of GATA6 can be about 2.4 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from Grade I cancer or being prone to suffering from Grade I cancer in accordance with the present invention. Ratios of the amount of said Em and said Ad isoform of GATA6 can be about 3.4 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from Grade II cancer or being prone to suffering from Grade II cancer in accordance with the present invention. Ratios of the amount of said Em and said Ad isoform of GATA6 can be about 2.8 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from Grade III cancer or being prone to suffering from Grade III cancer in accordance with the present invention.

[0105] Again, preferred herein is lung cancer, in particular non-small cell lung cancer or small cell lung cancer. Particularly preferred is non-small cell lung cancer.

[0106] Threshold values/ratios of the amount of said Em and said Ad isoform of GATA6 indicating that a subject suffers from cancer or is prone to suffering from cancer can be about 0.6 or higher (in particular 1.0 or higher), if control sample(s) is/are exhaled breath condensate(s) from healthy individuals. For example, ratios of the amount of said Em and said Ad isoform of GATA6 can be about 1.5 (or higher) in samples (in particular and preferred in this context exhaled breath condensate(s)) from a subject assessed to suffer from cancer or being prone to suffering from cancer in accordance with the present invention.

[0107] Also here, lung cancer is preferred, in particular non-small cell lung cancer or small cell lung cancer. Particularly preferred is non-small cell lung cancer.

[0108] Threshold values/ratios of the amount of said Em and said Ad isoform of NKX2-1 indicating that a subject suffers from cancer or is prone to suffering from cancer can be about 0.5 or higher (in particular 1.0 or higher), if control sample(s) is/are healthy tissue(s) (obtained preferably in this context by biopsy) from diseased patients. Threshold values/ratios of the amount of said Em and said Ad isoform of NKX2-1 indicating that a subject suffers from cancer or is prone to suffering from cancer can be about 0.2 or 0.3 or higher (in particular 1.0 or higher), if control sample(s) is/are healthy tissue(s) (obtained preferably in this context by biopsy) from healthy individuals. For example, ratios of the amount of said Em and said Ad isoform of NKX2-1 can be about 2.0 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from cancer or being prone to suffering from cancer in accordance with the present invention.

[0109] The herein provided method can be used to stratify/assess subjects according to the tumor/cancer grade. It can be helpful to assess whether a patient is suffering from Grade I, Grade II or Grade III tumor/cancer in order to decide which therapeutic intervention is warrented.

[0110] Ratios of the amount of said Em and said Ad isoform of NKX2-1 can be about 1.9 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from Grade I cancer or being prone to suffering from Grade I cancer in accordance with the present invention. Ratios of the amount of said Em and said Ad isoform of NKX2-1 can be about 2.6 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from Grade II cancer or being prone to suffering from Grade II cancer in accordance with the present invention. Ratios of the amount of said Em and said Ad isoform of NKX2-1 can be about 3.8 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from Grade III cancer or being prone to suffering from Grade III cancer in accordance with the present invention.

[0111] Again, preferred herein is lung cancer, in particular non-small cell lung cancer or small cell lung cancer. Particularly preferred is non-small cell lung cancer.

[0112] Threshold values/ratios of the amount of said Em and said Ad isoform of NKX2-1 indicating that a subject suffers from cancer or is prone to suffering from cancer can be about 0.5 or higher (in particular 1.0 or higher), if control sample(s) is/are exhaled breath condensate(s) from healthy individuals. For example, ratios of the amount of said Em and said Ad isoform of NKX2-1 can be about 2.8 (or higher) in samples (in particular and preferred in this context exhaled breath condensate(s)) from a subject assessed to suffer from cancer or being prone to suffering from cancer in accordance with the present invention.

[0113] Also here, lung cancer is preferred, in particular non-small cell lung cancer or small cell lung cancer. Particularly preferred is non-small cell lung cancer.

[0114] The appended examples demonstrate that the herein provided methods can be reliably used for assessing whether a subject suffers from cancer, preferably lung cancer, such as non-small cell lung cancer or small cell lung cancer. Though most of the data provided herein relate to non-small cell lung cancer, FIG. 13B and Example 10 demonstrate that the herein provided methods allow also for a reliable assessment whether a subject suffers from small cell lung cancer.

[0115] For example, the small cell lung cancer sample assessed herein showed the following ratios:

Em/Ad for Gata6--Biopsy--2.9743;

Em/Ad for Gata6 EBC--3.12

Em/Ad for Nkx2.1--Biopsy--3.544;

Em/Ad for Nkx2.1 EBC--3.584

[0116] Thus, ratios of the amount of said Em and said Ad isoform of GATA6 of 1.0 or higher and/or ratios of the amount of said Em and said Ad isoform of NKX2-1 of 1.0 or higher indicate that a subject suffers from small cell lung cancer or is prone to suffering from small cell lung cancer sample.

[0117] For example, ratios of the amount of said Em and said Ad isoform of GATA6 can be about 3.0 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from small cell lung cancer or being prone to suffering from small cell lung cancer in accordance with the present invention.

[0118] For example, ratios of the amount of said Em and said Ad isoform of GATA6 can be about 3.1 (or higher) in samples (in particular and preferred in this context exhaled breath condensate(s)) from a subject assessed to suffer from small cell lung cancer or being prone to suffering from small cell lung cancer in accordance with the present invention.

[0119] For example, ratios of the amount of said Em and said Ad isoform of NKX2-1 can be about 3.5 (or higher) in samples (in particular and preferred in this context biopsies) from a subject assessed to suffer from small cell lung cancer or being prone to suffering from small cell lung cancer in accordance with the present invention.

[0120] For example, ratios of the amount of said Em and said Ad isoform of NKX2-1 can be about 3.6 (or higher) in samples (in particular and preferred in this context exhaled breath condensate(s)) from a subject assessed to suffer from small cell lung cancer or being prone to suffering from small cell lung cancer in accordance with the present invention.

[0121] As explained above, the ratio of the amount of said Em and said Ad isoform of GATA6 and/or the ratio of the amount of said Em and said Ad isoform of NKX2-1 is increased in samples from patients assessed to suffer from or assessed as being prone to suffering from cancer compared with a control (sample).

[0122] The present invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0123] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor, wherein said transcription factor is either GATA6 or NKX2-1 and wherein the two specific isoforms are either

[0124] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; or

[0125] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 6 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0126] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor; and

[0127] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0128] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is increased in comparison to a control (sample); or

[0129] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is increased in comparison to a control (sample).

[0130] The present invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0131] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor, wherein said transcription factors are GATA6 and NKX2-1 and wherein the two specific isoforms are

[0132] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; and

[0133] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 6 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0134] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor; and

[0135] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0136] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is increased in comparison to a control (sample); and

[0137] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is increased in comparison to a control (sample).

[0138] Also here, lung cancer is preferred, in particular non-small cell lung cancer or small cell lung cancer. Particularly preferred is non-small cell lung cancer.

[0139] The definitions and explanations provided herein in relation to the method of "assessing whether a subject suffers from cancer or is prone to suffering from cancer" apply, mutatis mutandis, in this context.

[0140] The term "specific transcription factor Ad isoform" according to the present application relates to specific isoforms of the transcription factors GATA6 (Uniprot-ID: Q92908; Gene-ID: 2627), NKX2-1 (Uniprot-ID: P43699; Gene-ID: 7080), FOXA2 (Uniprot-ID: Q9Y261; Gene-ID: 3170) and ID2 (Uniprot-ID: Q02363; Gene-ID:3398). If, for example, the amount of a specific transcription factor is measured on mRNA level, the specific transcription factor can be mRNA molecules (or transcript or splice variants). In this context, the transcription factors can be defined as

[0141] i) the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5;

[0142] ii) the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Ad isoform comprising the nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0143] iii) the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 7 or FOXA2 Ad isoform comprising the nucleic acid sequence with up to 74 additions, deletions or substitutions of SEQ ID NO: 3; or

[0144] iv) the ID2 Ad isoform consisting of the nucleic acid sequence of SEQ ID No: 8 or ID2 Ad isoform consisting of nucleic acid sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 8;

[0145] If, for example, the amount of a specific transcription factor is measure on protein level, the specific transcription factors can be proteins molecules. For example, they can be defined as

[0146] v) the GATA6 Ad isoform comprising the polypeptide sequence of SEQ ID No: 54 or the GATA6 Ad isoform polypeptide sequence with up to 23 additions, deletions or substitutions of SEQ ID NO: 54;

[0147] vi) the NKX2-1 Ad isoform comprising the polypeptide sequence of SEQ ID No: 55 or the NKX2-1 Ad isoform comprising the polypeptide sequence with up to 15 additions, deletions or substitutions of SEQ ID NO: 55;

[0148] vii) the FOXA2 Ad isoform comprising the polypeptide sequence of SEQ ID No: 56 or FOXA2 Ad isoform comprising the polypeptide sequence with up to 43 additions, deletions or substitutions of SEQ ID NO: 56; or

[0149] viii) the ID2 Ad isoform consisting of the polypeptide sequence of SEQ ID No: 57 or ID2 Ad isoform consisting of polypeptide sequence with up to 13 additions, deletions or substitutions of SEQ ID NO: 57;

[0150] The present invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0151] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor, wherein said transcription factor is either GATA6 or NKX2-1 and wherein the two specific isoforms are either:

[0152] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; or

[0153] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 6 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0154] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor

[0155] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0156] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; preferably higher than 0.6, 0.7, 0.8, 0.9 or 1; more preferably higher than 1.2, 1.4, 1.6, 1.8 or 2; even more preferably higher than 3, 4, 5, 6, 7, 8, 9 or 10;

[0157] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3 preferably higher than 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1; more preferably higher than 1.2, 1.4, 1.6, 1.8 or 2; even more preferably higher than 3, 4, 5, 6, 7, 8, 9 or 10;

[0158] The present invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0159] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor, wherein the transcription factor is selected from the group GATA6, NKX2-1, FOXA2 and ID2, and wherein the two specific isoforms are either:

[0160] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising the nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5;

[0161] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Ad isoform comprising the nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0162] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising the nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 7 or FOXA2 Ad isoform comprising the nucleic acid sequence with up to 74 additions, deletions or substitutions of SEQ ID NO: 3; or

[0163] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising the nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4; and the ID2 Ad isoform consisting of the nucleic acid sequence of SEQ ID No: 8 or ID2 Ad isoform consisting of nucleic acid sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 8;

[0164] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor

[0165] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0166] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; preferably higher than 0.6, 0.7, 0.8, 0.9 or 1; higher than 1.2, 1.4, 1.6, 1.8 or 2; higher than 3, 4, 5, 6, 7, 8, 9 or 10;

[0167] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3, preferably higher than 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1; higher than 1.2, 1.4, 1.6, 1.8 or 2; higher than 3, 4, 5, 6, 7, 8, 9 or 10;

[0168] iii) the transcription factor is FOXA2 and the ratio of the amount of said Em and said Ad isoform of FOXA2 is higher than 0.8; preferably higher than 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2; higher than 2.2, 2.4, 2.6, 2.8 or 3; higher than 4, 5, 6, 7, 8, 9, 10 or 15; or

[0169] iv) the transcription factor is ID2 and the ratio of the amount of said Em and said Ad isoform of ID2 is higher than 1; preferably higher than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2; higher than 2.2, 2.4, 2.6, 2.8 or 3; higher than 4, 5, 6, 7, 8, 9, 10 or 15.

[0170] It is known by the person skilled in the art that genes can contain single nucleotide polymorphisms. The specific transcription factor Em isoform sequences of the present invention encompass all naturally occurring sequences of the respective isoform independent of the number and nature of the SNPs in said sequence. To relate to currently known SNPs, the specific transcription factor Ad isoform sequences of the present invention are defined such that they contain up to 55 (in the case of GATA6), up to 38 (in the case of NKX2-1), up to 74 (in the case of FOXA2) or up to 30 (in the case of ID2) additions, deletions or substitutions of the nucleic acid sequences defined by SEQ ID NOs: 5, 6, 7 and 8, respectively, to also cover the respective Ad transcripts of carriers of different nucleotides at the respective SNPs. The SNPs of tables 2, 4, 6 and 8 may occur in the Ad isoforms of the present invention in any combination. For example, a (genetic) variant of the GATA6 Ad isoform to be used herein may comprise a nucleic acid sequence of SEQ ID NO:5, whereby the "C" residue at position 694 of SEQ ID NO:5 is substituted by "T". Further variants of the isoforms to be used herein are apparent from Tables 1 to 8 to the person skilled in the art.

[0171] The GATA6 Ad isoform according to the invention is the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID NO: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55; preferably up to 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 or 20; even more preferably up to 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2; or even furthermore preferably only 1 addition(s), deletion(s) or substitution(s) of SEQ ID NO: 5. The GATA6 Ad isoform can also be defined as the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID NO: 5 or the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID NO: 5 with additions, deletions or substitutions at any of positions 138; 228; 255; 262; 274; 365; 397; 415; 694; 1063; 1191; 1239; 1524; 1532; 1562; 1586; 1587; 1738; 1779; 1784; 1814; 1817; 1846; 1875; 1884; 1917; 1935; 1937; 1943; 1961; 1966; 2041; 2072; 2077; 2098; 2229; 2325; 2326; 2562; 2626; 2971; 3037; 3175; 3200; 3201; 3225; 3293; 3301; 3513; 3567; 3581; 3605; 3625; 3643 or 3670. The GATA6 Ad isoform according to the invention can also be defined as the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with at least 85% homology to SEQ ID No: 5, preferably up to 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% homology to SEQ ID No: 5; even more preferably up to 99% homology to SEQ ID No: 5.

[0172] The N10(2-1 Ad isoform according to the invention is the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID NO: 6 or the N10(2-1 Ad isoform comprising a nucleic acid sequence with up to 38; preferably up to 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10; even more preferably up to 9, 8, 7, 6, 5, 4, 3, or 2; or even furthermore preferably only 1 addition(s), deletion(s) or substitution(s) of SEQ ID NO: 6. The NKX2-1 Ad isoform can also be defined as the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID NO: 6 or the Nkx2-1 isoform Ad comprising the nucleic acid sequence of SEQ ID NO: 6 with additions, deletions or substitutions at any of positions 12; 125; 265; 270; 284; 286; 295; 331; 626; 630; 670; 795; 1014; 1150; 1189; 1293; 1303; 1312; 1334; 1397; 1478; 1479; 1478; 1485; 1486; 1488; 1512; 1518; 1523; 1593; 1595; 1676; 1738; 1761; 1762; 1779; 1944 or 2164. The NKX2-1 Ad isoform according to the invention can also be defined as the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 6 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with at least 90% homology to SEQ ID No: 6, preferably up to 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% homology to SEQ ID No: 6; even more preferably up to 99% homology to SEQ ID No: 6.

[0173] The FOXA2 Ad isoform according to the invention is the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID NO: 7 or the FOXA2 Ad isoform comprising a nucleic acid sequence with up to 74; preferably up to 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53 52, 51, 50, 49, 48 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 or 20; even more preferably up to 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2; or even furthermore preferably only 1 addition(s), deletion(s) or substitution(s) of SEQ ID NO: 7. The FOXA2 Ad isoform can also be defined as the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID NO: 7 or the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID NO: 7 with additions, deletions or substitutions at any of positions 5; 37; 65; 68; 70; 88; 128; 195; 276; 348; 355; 361; 366; 370; 391; 446; 468; 470; 481; 516; 551; 564; 571; 577; 597; 610; 628; 637; 646; 661; 760; 832; 1027; 1062; 1173; 1175; 1227; 1229; 1230; 1291; 1361; 1378; 1395; 1401; 1419; 1445; 1462; 1474; 1509; 1526; 1569; 1570; 1581; 1614; 1618; 1674; 1710; 1724; 1725; 1741; 1799; 1818; 1825; 1927; 1953; 1957; 2057; 2070; 2071; 2080; 2092; 2099; 2187 or 2375. The FOXA2 Ad isoform according to the invention can also be defined as the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 7 or the FOXA2 Ad isoform comprising a nucleic acid sequence with at least 93% homology to SEQ ID No: 7, preferably up to 92%, 93%, 94%, 95%, 96%, 97% or 98% homology to SEQ ID No: 7; even more preferably up to 99% homology to SEQ ID No: 7.

[0174] The ID2 Ad isoform according to the invention is the ID2 Ad isoform consisting the nucleic acid sequence of SEQ ID NO: 8 or the ID2 Ad isoform consisting of a nucleic acid sequence with up to 30; preferably up to 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10; even more preferably up to 9, 8, 7, 6, 5, 4, 3, or 2; or even furthermore preferably only 1 addition(s), deletion(s) or substitution(s) of SEQ ID NO: 8. The ID2 Ad isoform can also be defined as the ID2 Ad isoform consisting the nucleic acid sequence of SEQ ID NO: 8 or the ID2 Ad isoform consisting the nucleic acid sequence of SEQ ID NO: 8 with additions, deletions or substitutions at any of positions 93; 134; 148; 163; 176; 202; 225; 299; 338; 344; 424; 440; 483; 486; 544; 601; 604; 655; 696; 810; 815; 914; 1024; 1054; 1058; 1088; 1090; 1190; 1272 or 1289. The ID2 Ad isoform according to the invention can also be defined as the ID2 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 8 or the ID2 Ad isoform comprising a nucleic acid sequence with at least 51% homology to SEQ ID No: 8, preferably up to 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% homology to SEQ ID No: 8; even more preferably up to 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homology to SEQ ID No: 8.

[0175] The present invention relates to a method of treating a patient, said method comprising

[0176] a) selecting a cancer patient according to any of the above mentioned methods of assessing whether a subject suffers from cancer or is prone to suffering from cancer

[0177] b) administering to said cancer patient an effective amount of an anti-cancer agent.

[0178] The term "cancer patient" as used herein refers to a patient that is suspected to suffer from cancer or being prone to suffer from cancer. The cancer to be treated in accordance with the present invention can be a solid cancer or a liquid cancer. Non-limiting examples of cancers which can be treated according to the present invention are lung cancer, ovarian cancer, colorectal cancer, kidney cancer, bone cancer, bone marrow cancer, bladder cancer, prostate cancer, esophagus cancer, salivary gland cancer, pancreas cancer, liver cancer, head and neck cancer, CNS (especially brain) cancer, cervix cancer, cartilage cancer, colon cancer, genitourinary cancer, gastrointestinal tract cancer, pancreas cancer, synovium cancer, testis cancer, thymus cancer, thyroid cancer and uterine cancer.

[0179] Preferably, the cancer patient according to the present invention is a patient suffering from lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SLC). Particularly preferably, the patient suffers non-small cell lung cancer (NSCLC). Even more preferably, the cancer patient is a patient suffering from adenocarcinoma. The patient may also suffer from a squamous cell carcinoma or a large ell carcinoma. The adenocarcinoma can be a bronchoalveolar carcinoma.

[0180] The amount of the specific transcription factor isoform according to the invention can be measured for example by a polymerase chain reaction-based method, an in situ hybridization-based method, or a microarray. If the amount of the specific transcription factor isoform according to the invention is measured via a polymerase chain reaction-based method, it is preferably measured via a quantitative reverse transcriptase polymerase chain reaction.

[0181] The method of assessing whether a subject suffers from cancer or is prone to suffering from cancer according to the invention may comprise the contacting of a sample with primers, wherein said primers can be used for amplifying the respective specific transcription factor isoforms.

[0182] Primers for the polymerase chain reaction-based measurement of the amount of the specific transcription factor isoforms according to the invention may encompass the use of primers being selected from the Table 9.

TABLE-US-00014 TABLE 9 Examples of primer pairs for the amplification, detection and/or quantification of the amount of specific transcription factor isoforms Primers for Human (5' .fwdarw. 3') Gene Primers for Human (5' .fwdarw. 3') (For RNA from tissue sections) Gata6-Em Fwd SEQ ID NO 9: SEQ ID NO 10: CTCGGCTTCTCTCCGCGCCTG TTGACTGACGGCGGCTGGTG Gata6-Em Rev SEQ ID NO 11: SEQ ID NO 12: AGCTGAGGCGTCCCGCAGTTG CTCCCGCGCTGGAAAGGCTC Gata6-Ad Fwd SEQ ID NO 13: SEQ ID NO 14: GCGGTTTCGTTTTCGGGGAC AGGACCCAGACTGCTGCCCC Gata6-Ad Rev SEQ ID NO 15: SEQ ID NO 16: AAGGGATGCGAAGCGTAGGA CTGACCAGCCCGAACGCGAG Nkx2-1-Em SEQ ID NO 17: SEQ ID NO 18: Fwd AAACCTGGCGCCGGGCTAAA CAGCGAGGCTTCGCCTTCCC Nkx2-1-Em Rev SEQ ID NO 19: SEQ ID NO 20: GGAGAGGGGGAAGGCGAAGCC TCGACATGATTCGGCGGCGG Nkx2-1-Ad Fwd SEQ ID NO 21: SEQ ID NO 22: AGCGAAGCCCGATGTGGTCC TCCGGAGGCAGTGGGAAGGC Nk2-1-Ad Rev SEQ ID NO 23: SEQ ID NO 24: CCGCCCTCCATGCCCACTTTC GACATGATTCGGCGGCGGCT Foxa2-Var1 SEQ ID NO 25: SEQ ID NO 26: Fwd TGCCATGCACTCGGCTTCCAG CAGGGAGAGGGAGGGCGAGA Foxa2-Var1 Rev SEQ ID NO 27: SEQ ID NO 28: TCATGTTGCCCGAGCCGCTG CCCCCACCCCCACCCTCTTT Foxa2-Var2 SEQ ID NO 29: SEQ ID NO 30: Fwd CTGCTAGAGGGGCTGCTTGCG CGCTTCTCCCGAGGCCGTTC Foxa2-Var2 Rev SEQ ID NO 31: SEQ ID NO 32: ACGGCTCGTGCCCTTCCATC TAACTCGCCCGCTGCTGCTC Id2-Var1 Fwd SEQ ID NO 33: SEQ ID NO 34: AACCCCTGTGGACGACCCGA TGCGGATAAAAGCCGCCCCG Id2-Var1 Rev SEQ ID NO 35 SEQ ID NO 36: GCCCGGGTCTCTGGTGATGC AGCTAGCTGCGCTTGGCACC Id2-Var2 Fwd SEQ ID NO 37: SEQ ID NO 38: CTGCGGTGCTGAACTCGCCC CCCCCTGCGGTGCTGAACTC Id2-Var 2 Rev SEQ ID NO 39: SEQ ID NO 40: GACGAGCGGGCGCTTCCATT TAACTCGCCCGCTGCTGCTC

[0183] It lies within the scope of the invention to combine the measurement of several of the specific transcription factor Em isoforms of the present invention to allow assessing whether a subject suffers from cancer or is prone to suffering from cancer. In particular, the amount of two, three or up to all four of the specific transcription factor Em isoforms selected from i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Ern isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4 may be analyzed for assessing whether a subject suffers from cancer or is prone to suffering from cancer. Preferably, a combination of transcription factor Em isoforms analyzed for the assessment of whether a subject suffers from cancer or is prone to suffering from cancer according to the present invention includes the GATA6 Em isoform and the NKX2-1 Em isoform.

[0184] The method for assessing whether a subject suffers from cancer or is prone to suffering from cancer according to the present invention can be used for example for assessing whether a subject suffers from lung cancer or is prone to suffering from lung cancer. In particular, the method of the present invention allows assessing whether a subject suffers from adenocarcinoma or bronchoalveolar carcinoma or is prone to suffering from adenocarcinoma or bronchoalveolar carcinoma.

[0185] The diagnostic methods can be used, for example, in combination with (i.e. subsequently prior to or simultaneously with) other diagnostic techniques, like CT (short for computer tomography) and CXR (short for chest radiograph, colloquially called chest X-ray (CXR)).

[0186] The herein provided methods for the diagnosis of a patient group and the therapy of this selected patient group is particularly useful for high risk subjects/patients or patient groups, such as those that have a hereditary history and/or are exposed to tobacco smoke, environmental smoke, cooking fumes, indoor smoky coal emissions, asbestos, some metals (e.g. nickel, arsenic and cadmium), radon (particularly amongst miners) and ionizing radiation. These subjects/patients may particularly profit from an early diagnosis and, hence, treatment of the cancer in accordance with the present invention.

[0187] A method of treating a patient according to the present invention may comprise

[0188] a) obtaining a sample from a patient;

[0189] b) selecting a cancer patient according to any of the above mentioned methods of assessing whether a subject suffers from cancer or is prone to suffering from cancer;

[0190] c) administering to said cancer patient an effective amount of an anti-cancer agent.

[0191] The present invention also provides a method of treating a patient, said method comprising

[0192] a) selecting a cancer patient according to any of the above mentioned methods of assessing whether a subject suffers from cancer or is prone to suffering from cancer

[0193] b) administering to said cancer patient an effective amount of an anti-cancer agent, wherein the cancer agent is for example selected from the group of agents comprising Oxalaplatin, Gemcitabine (Gemzar), Paclitaxel (Taxol), Vincristine (Oncovin) and a composition for use in medicine comprising an inhibitor of

[0194] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising the nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0195] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0196] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and/or

[0197] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0198] The present invention relates to a pharmaceutical composition comprising an agent for the treatment or the prevention of cancer, wherein for the patient suffering from cancer has been determined by a method of the present invention and wherein the method of treatment comprises the step of determining whether or not the patient suffers from cancer. Preferably, the pharmaceutical composition according to the present invention comprises an agent for the treatment or the prevention of lung cancer, wherein for the patient lung cancer has been determined by a method of the present invention and wherein the method of treatment comprises the step of determining whether or not the patient suffers from lung cancer

[0199] The present invention provides a composition for use in medicine comprising an inhibitor of

[0200] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising the nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0201] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em iso form comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0202] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0203] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0204] It is surprisingly found that the Em isoforms of the transcription factors of the present invention have an oncogenic potential (see Examples 4, 6 and 7). Further, it is shown that their reduction leads to the prevention of the development of tumors and allows treating cancer (see example 7). Thus, the present invention relates to inhibitors of the Em isoforms of the transcription factors GATA6, NKX2-1, FOXA2 and ID2. In particular, the present invention relates to agents that allow reducing the amount of the Em isoform of the transcription factors GATA6, NKX2-1, FOXA2 and ID2. The present invention also relates to activators of the Ad isoform of the transcription factors GATA6, NKX2-1, FOXA2 and ID2. Examples of such activators are agents, which activate the promoter of the Ad isoform of the respective transcription factors.

[0205] The present invention also relates to a composition for use in medicine comprising an inhibitor of

[0206] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising the nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0207] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0208] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and/or

[0209] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0210] The inhibitors of

[0211] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising the nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0212] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0213] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0214] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4 according to the present invention can for example comprise siRNAs (small interfering RNAs) or shRNAs (small hairpin RNAs) targeting said specific transcription factor Em isoforms.

[0215] The person skilled in the art knows how to design siRNAs and shRNAs, which specifically target the specific transcription factor Em isoforms of the present invention. Examples of such specific siRNAs and shRNAs targeting the specific transcription factor Em isoforms of the present invention are depicted in Tables 10 and 11.

TABLE-US-00015 TABLE 10 Examples of siRNA sequences for the knockdown of Gata6 Em and Foxa2 Em Gata6 Target Sequence Sense strand siRNA Antisense strand siRNA AATCAGGAGCGCAGGCTGCAG (SEQ SEQ ID NO: 41 SEQ ID NO: 43 ID NO. 58) UCAGGAGCGCAGGCUGCAGtt CUGCAGCCUGCGCUCCUGAtt AAGAGGCGCCTCCTCTCTCCT (SEQ SEQ ID NO: 42 SEQ ID NO: 44 ID NO. 59) GAGGCGCCUCCUCUCUCCUtt AGGAGAGAGGAGGCGCCUCtt Foxa2 Target Sequence Sense strand siRNA Antisense strand siRNA AAACCGCCATGCACTCGGCTT (SEQ SEQ ID NO: 45 SEQ ID NO: 46 ID NO. 60) ACCGCCAUGCACUCGGCUUtt AAGCCGAGUGCAUGGCGGUtt

TABLE-US-00016 TABLE 11 Examples of shRNA sequences for the knockdown of Nkx2-1 Nkx2-1 shHairpin sequence (5'-3') SEQ ID NO: 47 CCGGCCCATGAAGAAGAAAGCAATTCTCGAGAATTGCTTTCTTCTTCATGGGTTTTTG SEQ ID NO: 48 GTACCGGGGGATCATCCTTGTAGATAAACTCGAGTTTATCTACAAGGATGATCCCTTTTTTG SEQ ID NO: 49 CCGGATTCGGAATCAGCTAGCAATTCTCGAGAATTGCTAGCTGATTCCGAATTTTTTG

[0216] The amount of the specific transcription factor isoform according to the present invention can be determined on the polypeptide level. Thus, the invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0217] a) measuring in a sample of said subject the amount of a specific transcription factor isoform as a polypeptide wherein said specific transcription isoform is either

[0218] i) the GATA6 Em isoform comprising the polypeptide sequence of SEQ ID No: 50 or the GATA6 Em isoform comprising the polypeptide sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 50; or

[0219] ii) the NKX2-1 Em isoform comprising the polypeptide sequence of SEQ ID No: 51 or the NKX2-1 Em isoform comprising the polypeptide sequence with up to 14 additions, deletions or substitutions of SEQ ID NO: 51;

[0220] b) comparing the amount of said specific transcription factor Em isoform with the amount of said specific transcription factor Em isoform in a control sample; and

[0221] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said specific transcription factor Em isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor Em isoform in the control sample.

[0222] The invention relates to a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0223] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor on the polypeptide level, wherein said transcription factor is either GATA6 or NKX2-1 and wherein the two specific isoforms are either

[0224] i) the GATA6 Em isoform comprising the polypeptide sequence of SEQ ID No: 50 or the GATA6 Em isoform comprising the polypeptide sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 50; and the GATA6 Ad isoform comprising the polypeptide sequence of SEQ ID No: 54 or the GATA6 Ad isoform polypeptide sequence with up to 23 additions, deletions or substitutions of SEQ ID NO: 54; or

[0225] ii) the NKX2-1 Em isoform comprising the polypeptide sequence of SEQ ID No: 51 or the NKX2-1 Em isoform comprising the polypeptide sequence with up to 14 additions, deletions or substitutions of SEQ ID NO: 51; and the NKX2-1 Ad isoform comprising the polypeptide sequence of SEQ ID No: 55 or the NKX2-1 Ad isoform comprising the polypeptide sequence with up to 15 additions, deletions or substitutions of SEQ ID NO: 55;

[0226] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor; and

[0227] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0228] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; or

[0229] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3.

[0230] The amount of the specific transcription factor isoforms according to the invention can be assessed on the polypeptide level using known quantitative methods for the assessment of polypeptide levels. For example, ELISA (Enzyme-linked Immunosorbent Assay)-based, gel-based, blot-based, mass spectrometry-based, or flow cytometry-based methods can be used for measuring the amount of the specific transcription factor isoforms on the polypeptide level according to the invention.

[0231] The method according of the present invention may further comprise measuring in a sample of a subject the amount of one or two further specific transcription factor isoform(s) on the polypeptide level selected from the group of specific transcription factor isoforms consisting of

[0232] i) the FOXA2 Em isoform comprising the polypeptide sequence of SEQ ID No: 52 or the FOXA2 Em isoform comprising polypeptide sequence with up to 43 additions, deletions or substitutions of SEQ ID NO: 52; and

[0233] ii) the ID2 Em isoform comprising the polypeptide sequence of SEQ ID No: 53 or the ID2 Em isoform comprising polypeptide sequence with up to 13 additions, deletions or substitutions of SEQ ID NO: 53;

[0234] and wherein for assessing that said subject suffers from cancer or is prone to suffering from cancer the amount of all analyzed specific transcription factor Em isoforms has to be increased in comparison to the amount of the analyzed specific transcription factor Em isoforms in the control sample.

[0235] In accordance with this invention, a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer is found, said method comprising the steps of

[0236] a) measuring in a sample of said subject the amount of a specific transcription factor isoform selected from the group of specific transcription factor isoforms consisting of

[0237] i) the GATA6 Em isoform comprising the polypeptide sequence of SEQ ID No: 50 or the GATA6 Em isoform comprising the polypeptide sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 50;

[0238] ii) the NKX2-1 Em isoform comprising the polypeptide sequence of SEQ ID No: 51 or the NKX2-1 Em isoform comprising the polypeptide sequence with up to 14 additions, deletions or substitutions of SEQ ID NO: 51;

[0239] iii) the FOXA2 Em isoform comprising the polypeptide sequence of SEQ ID No: 52 or the FOXA2 Em isoform comprising polypeptide sequence with up to 43 additions, deletions or substitutions of SEQ ID NO: 52; or

[0240] iv) the ID2 Em isoform comprising the polypeptide sequence of SEQ ID No: 53 or the ID2 Em isoform comprising polypeptide sequence with up to 13 additions, deletions or substitutions of SEQ ID NO: 53;

[0241] b) comparing the amount of said specific transcription factor isoform with the amount of said specific transcription factor isoform in a control sample;

[0242] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said specific transcription factor isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor isoform in the control sample.

[0243] The invention provides a method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0244] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor, wherein the transcription factor is selected from the group GATA6, NKX2-1, FOXA2 and ID2, and wherein the two specific isoforms are either:

[0245] i) the GATA6 Em isoform comprising the polypeptide sequence of SEQ ID No: 50 or the GATA6 Em isoform comprising the polypeptide sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 50; and the GATA6 Ad isoform comprising the polypeptide sequence of SEQ ID No: 54 or the GATA6 Ad isoform polypeptide sequence with up to 23 additions, deletions or substitutions of SEQ ID NO: 54;

[0246] ii) the NKX2-1 Em isoform comprising the polypeptide sequence of SEQ ID No: 51 or the NKX2-1 Em isoform comprising the polypeptide sequence with up to 14 additions, deletions or substitutions of SEQ ID NO: 51; and the NKX2-1 Ad isoform comprising the polypeptide sequence of SEQ ID No: 55 or the NKX2-1 Ad isoform comprising the polypeptide sequence with up to 15 additions, deletions or substitutions of SEQ ID NO: 55;

[0247] iii) the FOXA2 Em isoform comprising the polypeptide sequence of SEQ ID No: 52 or the FOXA2 Em isoform comprising the polypeptide sequence with up to 43 additions, deletions or substitutions of SEQ ID NO: 52; and the FOXA2 Ad isoform comprising the polypeptide sequence of SEQ ID No: 56 or FOXA2 Ad isoform comprising the polypeptide sequence with up to 43 additions, deletions or substitutions of SEQ ID NO: 56; or

[0248] iv) the ID2 Em isoform comprising the polypeptide sequence of SEQ ID No: 53 or the ID2 Em isoform comprising the polypeptide sequence with up to 13 additions, deletions or substitutions of SEQ ID NO: 53; and the ID2 Ad isoform consisting of the polypeptide sequence of SEQ ID No: 57 or ID2 Ad isoform consisting of polypeptide sequence with up to 13 additions, deletions or substitutions of SEQ ID NO: 57;

[0249] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor

[0250] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0251] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5;

[0252] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3;

[0253] iii) the transcription factor is FOXA2 and the ratio of the amount of said Em and said Ad isoform of FOXA2 is higher than 0.8; or the transcription factor is ID2 and the ratio of the amount of said Ern and said Ad isoform of ID2 is higher than 1.

[0254] The method according to the present invention may also comprise

[0255] a) measuring in a sample of a subject the amount of two specific transcription factor isoforms on protein level, wherein the transcription factor isoform are

[0256] i) the GATA6 Em isoform comprising the polypeptide sequence of SEQ ID No: 50 or the GATA6 Em isoform comprising the polypeptide sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 50; and

[0257] ii) the NKX2-1 Em isoform comprising the polypeptide sequence of SEQ ID No: 51 or the NKX2-1 Em isoform comprising the polypeptide sequence with up to 14 additions, deletions or substitutions of SEQ ID NO: 51;

[0258] b) comparing the amount of said specific transcription factor isoform with the amount of said specific transcription factor isoform in a control sample;

[0259] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of the GATA6 Em and the amount of the NKX2-1 Em isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor isoform in the control sample.

[0260] The method according to the present invention may allow assessing that a subject suffers from cancer or is prone to suffering from cancer if the amount of the analyzed specific transcription factor Em isoform(s) on polypeptide level is increased by at least 1.3-fold over control, at least 1.4-fold over control, at least 1.5-fold over control, at least 1.6-fold over control, at least 1.7-fold over control, at least 1.8-fold over control, at least 1.9-fold over control, at least 2-fold over control, at least 2.5 over control, at least 2.7 over control, at least 3-fold over control, at least 4-fold over control, at least 5-fold over control, wherein "over control" relates to the comparison of the amount of the analyzed specific transcription factor Em isoform(s) in the test/patient/subject sample to the amount of the analyzed specific transcription factor Em isoform(s) in a control sample.

[0261] The method according of the present invention may also comprise the step of measuring in a sample of a subject the amount of two specific isoforms of one or two further transcription factor(s) on the polypeptide level, wherein said one or two further transcription factor(s) are either Foxa2 and/or Id2 and wherein the two specific isoforms of said one or two further transcription factor(s) are:

[0262] i) the FOXA2 Em isoform comprising the polypeptide sequence of SEQ ID No: 52 or the FOXA2 Em isoform comprising the polypeptide sequence with up to 43 additions, deletions or substitutions of SEQ ID NO: 52; and the FOXA2 Ad isoform comprising the polypeptide sequence of SEQ ID No: 56 or FOXA2 Ad isoform comprising the polypeptide sequence with up to 43 additions, deletions or substitutions of SEQ ID NO: 56; or

[0263] ii) the ID2 Em isoform comprising the polypeptide sequence of SEQ ID No: 53 or the ID2 Em isoform comprising the polypeptide sequence with up to 13 additions, deletions or substitutions of SEQ ID NO: 53; and the ID2 Ad isoform consisting of the polypeptide sequence of SEQ ID No: 57 or ID2 Ad isoform consisting of polypeptide sequence with up to 13 additions, deletions or substitutions of SEQ ID NO: 57;

[0264] and wherein said subject is assessed as suffering from cancer or as being prone to suffer from cancer if

[0265] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; and/or

[0266] ii) the transcription factor is N10(2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3; and

[0267] iii) the transcription factor is FOXA2 and the ratio of the amount of said Em and said Ad isoform of FOXA2 is higher than 0.8; and/or

[0268] iv) the transcription factor is ID2 and the ratio of the amount of said Em and said Ad isoform of ID2 is higher than 1.

[0269] It is obvious to the person skilled in the art that the specific transcription factor isoforms of the present invention can show certain sequence varieties between different subjects of the same ancestry and in particular between subjects of different ancestry. Non-limiting examples of the polymorphisms of the cancer specific isoforms of the present invention are given in Tables 12 and 13.

TABLE-US-00017 TABLE 12 Examples of polymorphisms in the sequences of GATA6, Em and Ad isoforms in dependence of the ancestry of a subject (CEU: Utah residents with Northern and Western European ancestry from the CEPH collection; CHB: Han Chinese in Beijing, China; JPT: Japanese in Tokyo, Japan; YRI: Yoruban in Ibadan, Nigeria) S. Position in Position in Frequency Frequency No Region Gata6 Em Gata6 Ad Polymorphism Population of T of C 1 CCDS 1982 1917 T/C CEU 100% 0% JPT 100% 0% YRI 100% 0% S. Position in Position in Frequency Frequency No Region Gata6 Em Gata6 Ad Polymorphism Population of G of A 2 3'UTR 2137 2072 G/A CEU 56% 44% CHB 57% 43% JPT 65% 35% YRI 45% 55% S. Position in Position in Frequency Frequency No Region Gata6 Em Gata6 Ad Polymorphism Population of A of G 3 3'UTR 2142 2077 A/G CEU 97% 3% CHB 90% 10% JPT 100% 0% YRI 100% 0% S. Position in Position in Frequency Frequency No Region Gata6 Em Gata6 Ad Polymorphism Population of T of A 4 3'UTR 2391 2326 T/A CEU 100% 0% CHB 100% 0% JPT 100% 0% YRI 100% 0%

TABLE-US-00018 TABLE 13 Examples of polymorphisms in the sequences of FOXA2 variant 1 and 2 in dependence of the ancestry of a subject (ASW: African ancestry in Southwest USA; CEU: Utah residents with Northern and Western European ancestry from the CEPH collection; CHB: Han Chinese in Beijing, China; CHD: Chinese in Metropolitan Denver, Colorado; GIH: Gujarati Indians in Houston, Texas; JPT: Japanese in Tokyo, Japan; LWK: Luhya in Webuye, Kenya; MEX: Mexican ancestry in Los Angeles, California; MKK: Maasai in Kinyawa, Kenya; TSI: Tuscan in Italy; YRI: Yoruban in Ibadan, Nigeria) S. Position in Position in Frequency Frequency No Region Foxa2 Em Foxa2 Ad Polymorphism Population of T of C 1 CCDS 1408 1395 T/C CEU 100% 0% CHB 100% 0% JPT 100% 0% YRI 100% 0% S. Position in Position in Frequency Frequency No Region Foxa2 Em Foxa2 Ad Polymorphism Population of A of G 1 3'UTR 1627 1614 A/G ASW 38% 62% CEU 96% 4% CHB 84% 16% CHD 84% 16% JPT 77% 23% GIH 89% 11% LWK 27% 73% MEX 92% 8% MKK 40% 60% TSI 91% 9% YRI 20% 80%

[0270] Interestingly, it was found by the inventors that an increased expression of the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5 could be used for the diagnosis of non-cancer related lung disease, for example lung fibrosis (see Examples 8 and 9). Thus, the invention also relates to a method of assessing whether a subject suffers from fibrosis, in particular lung fibrosis, or is prone to suffering from fibrosis, in particular lung fibrosis, said method comprising the steps of

[0271] a) measuring in a sample of said subject the amount of a specific transcription factor isoform wherein said specific transcription isoform is either

[0272] i) the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5 or

[0273] b) comparing the amount of said specific GATA6 Ad isoform with the amount of said specific GATA6 Ad isoform in a control sample;

[0274] c) assessing that said subject suffers from lung fibrosis or is prone to suffering from lung fibrosis if the amount of said specific GATA6 Ad isoform in said sample from said subject is increased in comparison to the amount of said GATA6 Ad isoform isoform in the control sample.

[0275] As shown herein, it was surprisingly found that GATA6 Ad isoform is increased in comparison to the amount of the GATA6 Ad isoform in a control sample in fibrotic events, in particular in lung fibrosis. Accordingly, and increased amount of the GATA6 Ad isoform in a patient/subject sample as compared to a (healthy) control sample is indicative of the presence of lung fibrosis in said patient/subject.

[0276] The present invention provides a kit for use in any of the methods of the invention for assessing whether a subject suffers from cancer or is prone to suffering from cancer comprising reagents for measuring in a sample specifically the amount of one or several transcription factor isoforms selected from the group of specific transcription factor isoforms consisting of

[0277] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising the nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0278] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0279] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising the nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0280] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising the nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0281] The kit of the present invention may comprise primers and further reagents necessary for a qPCR analysis. The respective primers may be selected from the list in Table 9.

[0282] While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. It will be understood that changes and modifications may be made by those of ordinary skill within the scope and spirit of the following claims. In particular, the present invention covers further embodiments with any combination of features from different embodiments described above and below.

[0283] The invention also covers all further features shown in the figures individually although they may not have been described in the afore or following description. Also, single alternatives of the embodiments described in the figures and the description and single alternatives of features thereof can be disclaimed from the subject matter of the other aspect of the invention.

[0284] Furthermore, in the claims the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single unit may fulfill the functions of several features recited in the claims. The terms "essentially", "about", "approximately" and the like in connection with an attribute or a value particularly also define exactly the attribute or exactly the value, respectively. Any reference signs in the claims should not be construed as limiting the scope.

[0285] The present invention is also characterized by the following items:

[0286] 1. A method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0287] a) measuring in a sample of said subject the amount of a specific transcription factor isoform wherein said specific transcription isoform is either

[0288] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0289] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0290] b) comparing the amount of said specific transcription factor Em isoform with the amount of said specific transcription factor Em isoform in a control sample; and

[0291] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said specific transcription factor Em isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor Em isoform in the control sample.

[0292] 2. A method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0293] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor, wherein said transcription factor is either GATA6 or NKX2-1 and wherein the two specific isoforms are either

[0294] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; or

[0295] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 6 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0296] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor; and

[0297] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0298] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; or

[0299] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3.

[0300] 3. The method according to item 1 or 2, wherein the amount of said specific transcription factor isoform(s) is measured via a polymerase chain reaction-based method, an in situ hybridization-based method, or a microarray.

[0301] 4. The method according to item 3, wherein the amount of said specific transcription factor isoform(s) is measured via a polymerase chain reaction-based method and wherein said polymerase chain reaction-based method is a quantitative reverse transcriptase polymerase chain reaction.

[0302] 5. The method according to item 4, wherein the step of measuring in a sample of said subject the amount of a specific transcription factor comprises the contacting of the sample with primers, wherein said primers can be used for amplifying at least one of the specific transcription factor isoforms.

[0303] 6. The method according to item 5, wherein said primers are selected from the group of primers having a nucleic acid sequence as set forth in SEQ ID NOs 9 to 40.

[0304] 7. The method according to items 1 and 3 to 6, wherein

[0305] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and

[0306] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0307] are analyzed for assessing whether said subject suffers from cancer or is prone to suffering from cancer and wherein the amount of both said specific transcription factor Em isoforms has to be increased in comparison to the amount of said two specific transcription factor Em isoforms in the control sample for assessing that said subject suffers from cancer or is prone to suffering from cancer.

[0308] 8. The method according to items 1 and 3 to 7, wherein said step a) further comprises measuring in a sample of said subject the amount of one or two further specific transcription factor isoform(s) selected from the group of specific transcription factor isoforms consisting of

[0309] i) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and

[0310] ii) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4;

[0311] and wherein for assessing that said subject suffers from cancer or is prone to suffering from cancer the amount of all analyzed specific transcription factor Em isoforms has to be increased in comparison to the amount of the analyzed specific transcription factor Em isoforms in the control sample.

[0312] 9. The method according to items 1 and 3 to 8, wherein for assessing that said subject suffers from cancer or is prone to suffering from cancer the amount of said analyzed specific transcription factor Em isoform(s) has to be increased by at least 1.3-fold in comparison to the amount of the analyzed specific transcription factor Em isoform(s) in the control sample.

[0313] 10. The method according to items 2 to 6, wherein

[0314] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; and

[0315] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6

[0316] are analyzed for assessing whether said subject suffers from cancer or is prone to suffering from cancer and wherein it is assessed that said subject suffers from cancer if

[0317] i) the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; and

[0318] ii) the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3.

[0319] 11. The method according to items 2 to 6 and 10, wherein step a) further comprises measuring in a sample of said subject the amount of two specific isoforms of one or two further transcription factor(s), wherein said one or two further transcription factor(s) are either Foxa2 and/or Id2 and wherein the two specific isoforms of said one or two further transcription factor(s) are:

[0320] i) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising a nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 7 or FOXA2 Ad isoform comprising a nucleic acid sequence with up to 74 additions, deletions or substitutions of SEQ ID NO: 3; or

[0321] ii) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising a nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4; and the ID2 Ad isoform consisting of the nucleic acid sequence of SEQ ID No: 8 or ID2 Ad isoform consisting of nucleic acid sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 8;

[0322] and wherein said subject is assessed as suffering from cancer or as being prone to suffer from cancer if

[0323] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; and/or

[0324] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3; and

[0325] iii) the transcription factor is FOXA2 and the ratio of the amount of said Em and said Ad isoform of FOXA2 is higher than 0.8; and/or

[0326] iv) the transcription factor is ID2 and the ratio of the amount of said Em and said Ad isoform of ID2 is higher than 1.

[0327] 12. The method according to any of items 1, 2, or 7 to 10, wherein the amount of said specific transcription factor isoform(s) is measured on the polypeptide level.

[0328] 13. The method according to item 12, wherein the amount of said specific transcription factor isoform(s) is measured by an ELISA, a gel- or blot-based method, mass spectrometry, flow cytometry or FACS.

[0329] 14. The method according to items 1 to 13, wherein said cancer is a lung cancer.

[0330] 15. The method according to item 14, wherein said lung cancer is an adenocarcinoma or a bronchoalveolar carcinoma.

[0331] 16. The method according to items 1 to 15, wherein said sample comprises tumor cells.

[0332] 17. The method according to items 1 to 16, wherein said sample is a blood sample, a breath condensate sample, a bronchoalveolar lavage fluid sample, a mucus sample or a phlegm sample.

[0333] 18. The method according to items 1 to 17, wherein said subject is a human subject.

[0334] 19. The method of item 18, wherein said human subject is a subject having an increased risk for developing cancer.

[0335] a) selecting a cancer patient according to the method of any of items 1 to 19

[0336] b) administering to said cancer patient an effective amount of an anti-cancer agent and/or radiation therapy.

[0337] 21. The method of treating a patient according to item 20, wherein said anti-cancer agent is an inhibitor of

[0338] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0339] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0340] 22. The method of treating a patient according to item 20 or 21, wherein said cancer patient is a patient suffering from lung cancer.

[0341] 23. The method of treating a patient according to item 22, wherein said lung cancer is a lung adenocarcinoma or a bronchoalveolar carcinoma.

[0342] 24. A composition for use in medicine comprising an inhibitor of

[0343] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0344] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0345] 25. The composition for use in medicine of item 24, wherein said inhibitor comprises a siRNA or shRNA specifically targeting

[0346] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0347] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0348] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0349] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0350] 26. The composition for use in medicine of item 25, wherein said siRNA is selected from the group of siRNAs consisting of SEQ ID No: 41 to SEQ ID NO: 46.

[0351] 27. The composition for use in medicine of item 25, wherein said shRNA is selected from the group of shRNAs consisting of SEQ ID No: 47 to SEQ ID NO: 49.

[0352] 28. A composition for use in medicine comprising an inhibitor of

[0353] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and

[0354] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0355] 29. The composition according to item 28 further comprising an inhibitor of

[0356] i) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0357] ii) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4

[0358] 30. The composition for use in medicine of items 24 to 29, wherein said inhibitor further comprises protamine.

[0359] 31. The composition for use in medicine of items 24 to 29, wherein the inhibitor further comprises a fusion protein of protamine and an antigen-targeting polypeptide.

[0360] 32. The composition for use in medicine of item 31, wherein said antigen-targeting polypeptide is targeting a protein selected from the group of proteins consisting of ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11.

[0361] 33. The composition for use in medicine of item 31 or item 32, wherein said antigen-targeting polypeptide is a monoclonal antibody or a single chain variable fragment.



[0362] 34. The composition of items 24 to 33 for the use in the treatment of a lung disease.

[0363] 35. The composition of item 34 for the use in the treatment of a lung disease, wherein the lung disease is a lung cancer.

[0364] 36. The composition of item 35 for the use in the treatment of a lung cancer, wherein said lung cancer is an adenocarcinoma or a bronchoalveolar carcinoma.

[0365] 37. A kit for use in any of the methods according to items 1 to 23 comprising reagents for measuring in a sample specifically the amount of one or two transcription factor isoforms selected from the group of specific transcription factor isoforms consisting of

[0366] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and

[0367] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0368] 38. The kit according to item 37 further comprising reagents for measuring in a sample specifically the amount of one or two transcription factor isoforms selected from the group of specific transcription factor isoforms consisting of

[0369] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and

[0370] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0371] 39. The kit according to item 37 or 38 further comprising reagents for measuring in a sample specifically the amount of one or several further transcription factor isoform(s) selected from the group of specific transcription factor isoforms consisting of

[0372] i) the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5;

[0373] ii) the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Ad isoform comprising the nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0374] iii) the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 7 or FOXA2 Ad isoform comprising the nucleic acid sequence with up to 74 additions, deletions or substitutions of SEQ ID NO: 3; and

[0375] iv) the ID2 Ad isoform consisting of the nucleic acid sequence of SEQ ID No: 8 or ID2 Ad isoform consisting of nucleic acid sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 8;

[0376] 40. The kit of items 37 to 39 wherein said sample is a blood or breath condensate sample.

[0377] 41. The kit of items 37 to 40 wherein said sample is a sample from a human subject.

[0378] 42. The kit of item 41 wherein the kit comprises one or several primers selected from the group of primers comprising the nucleic acid sequence of SEQ IDs 9 to 40.

[0379] Furthermore, the present invention relates to the following items:

[0380] 1. A method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0381] a) measuring in a sample of said subject the amount of a specific transcription factor isoform wherein said specific transcription isoform is either

[0382] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0383] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0384] b) comparing the amount of said specific transcription factor Em isoform with the amount of said specific transcription factor Em isoform in a control sample; and

[0385] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said specific transcription factor Em isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor Em isoform in the control sample.

[0386] 2. A method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0387] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor, wherein said transcription factor is either GATA6 or NKX2-1 and wherein the two specific isoforms are either

[0388] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; or

[0389] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 6 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0390] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor; and

[0391] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0392] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5; or

[0393] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3.

[0394] 3. The method according to item 1 or 2, wherein the amount of said specific transcription factor isoforms) is measured via a quantitative reverse transcriptase polymerase chain reaction.

[0395] 4. The method according to item 3, wherein the step of measuring in a sample of said subject the amount of a specific transcription factor comprises the contacting of the sample with primers, wherein said primers can be used for amplifying at least one of the specific transcription factor isoforms and wherein said primers are selected from the group of primers having a nucleic acid sequence as set forth in SEQ ID NOs 9 to 40.

[0396] 5. The method according to to any one of items 1 and 3 to 4, wherein

[0397] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and

[0398] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0399] are analyzed for assessing whether said subject suffers from cancer or is prone to suffering from cancer and wherein the amount of both said specific transcription factor Em isoforms has to be increased in comparison to the amount of said two specific transcription factor Em isoforms in the control sample for assessing that said subject suffers from cancer or is prone to suffering from cancer.

[0400] 6. The method according to any one of items 1 and 3 to 5, wherein said step a) further comprises measuring in a sample of said subject the amount of one or two further specific transcription factor isoform(s) selected from the group of specific transcription factor isoforms consisting of

[0401] i) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising a nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and

[0402] ii) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising a nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4;

[0403] and wherein for assessing that said subject suffers from cancer or is prone to suffering from cancer the amount of all analyzed specific transcription factor Em isoforms has to be increased in comparison to the amount of the analyzed specific transcription factor Em isoforms in the control sample.

[0404] 7. The method according to any of items 1, 2, or 5 to 6, wherein the amount of said specific transcription factor isoform(s) is measured on the polypeptide level and wherein the amount of said specific transcription factor isoform(s) is measured by an ELISA, a gel- or blot-based method, mass spectrometry, flow cytometry or FACS.

[0405] 8. The method according to any one of items 1 to 7, wherein said cancer is a lung cancer.

[0406] 9. The method according to item 8, wherein said lung cancer is an adenocarcinoma or a bronchoalveolar carcinoma.

[0407] 10. The method according to any one of items 1 to 9, wherein said sample is a blood sample, a breath condensate sample, a bronchoalveolar lavage fluid sample, a mucus sample or a phlegm sample.

[0408] 11. The method according to any one of items 1 to 10, wherein said subject is a human subject.

[0409] 12. A composition for use in medicine comprising an inhibitor of

[0410] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0411] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0412] 13. The composition for use in medicine of item 12, wherein said inhibitor comprises an siRNA selected from the group of siRNAs consisting of SEQ ID No: 41 to SEQ ID NO: 46.

[0413] 14. The composition of item 12 or 13 for the use in the treatment of a lung cancer, wherein said lung cancer is an adenocarcinoma or a bronchoalveolar carcinoma.

[0414] 15. A kit for use in any of the methods according to items 1 to 11 comprising reagents for measuring in a sample specifically the amount of one or two transcription factor isoforms selected from the group of specific transcription factor isoforms consisting of

[0415] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and

[0416] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0417] The present invention is also characterized by the following items:

[0418] 1. A method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0419] a) measuring in a sample of said subject the amount of a specific transcription factor isoform wherein said specific transcription isoform is either

[0420] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0421] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0422] b) comparing the amount of said specific transcription factor Em isoform with the amount of said specific transcription factor Em isoform in a control sample; and

[0423] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said specific transcription factor Em isoform in said sample from said subject is increased in comparison to the amount of said specific transcription factor Em isoform in the control sample.

[0424] 2. A method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of

[0425] a) measuring in a sample of said subject the amount of two specific isoforms of a transcription factor, wherein said transcription factor is either GATA6 or NKX2-1 and wherein the two specific isoforms are either

[0426] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; or

[0427] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 6 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0428] b) building the ratio of the amount of said Em and said Ad isoform of said transcription factor; and

[0429] c) assessing that said subject suffers from cancer or is prone to suffering from cancer if

[0430] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5, in particular higher than 1.0, more particularly higher than 1.5; or

[0431] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3, in particular higher than 1.0, more particularly higher than 1.7.

[0432] 3. The method according to item 1 or 2, wherein the amount of said specific transcription factor isoform(s) is measured via a polymerase chain reaction-based method, an in situ hybridization-based method, or a microarray.

[0433] 4. The method according to item 3, wherein the amount of said specific transcription factor isoform(s) is measured via a polymerase chain reaction-based method and wherein said polymerase chain reaction-based method is a quantitative reverse transcriptase polymerase chain reaction.

[0434] 5. The method according to item 4, wherein the step of measuring in a sample of said subject the amount of a specific transcription factor comprises the contacting of the sample with primers, wherein said primers can be used for amplifying at least one of the specific transcription factor isoforms.

[0435] 6. The method according to item 5, wherein said primers are selected from the group of primers having a nucleic acid sequence as set forth in SEQ ID NOs 9 to 40.

[0436] 7. The method according to items 1 and 3 to 6, wherein

[0437] i) the GATA6 Ern isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and

[0438] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0439] are analyzed for assessing whether said subject suffers from cancer or is prone to suffering from cancer and wherein the amount of both said specific transcription factor Em isoforms has to be increased in comparison to the amount of said two specific transcription factor Em isoforms in the control sample for assessing that said subject suffers from cancer or is prone to suffering from cancer.

[0440] 8. The method according to items 1 and 3 to 7, wherein said step a) further comprises measuring in a sample of said subject the amount of one or two further specific transcription factor isoform(s) selected from the group of specific transcription factor isoforms consisting of

[0441] i) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and

[0442] ii) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4;

[0443] and wherein for assessing that said subject suffers from cancer or is prone to suffering from cancer the amount of all analyzed specific transcription factor Em isoforms has to be increased in comparison to the amount of the analyzed specific transcription factor Em isoforms in the control sample.

[0444] 9. The method according to items 1 and 3 to 8, wherein for assessing that said subject suffers from cancer or is prone to suffering from cancer the amount of said analyzed specific transcription factor Em isoform(s) has to be increased by at least 1.3-fold in comparison to the amount of the analyzed specific transcription factor Em isoform(s) in the control sample.

[0445] 10. The method according to items 2 to 6, wherein

[0446] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; and

[0447] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; and the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Ad isoform comprising a nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6

[0448] are analyzed for assessing whether said subject suffers from cancer or is prone to suffering from cancer and wherein it is assessed that said subject suffers from cancer if

[0449] i) the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5, in particular higher than 1.0, more particularly higher than 1.5; and

[0450] ii) the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3 in particular higher than 1.0, more particularly higher than 1.7.

[0451] 11. The method according to items 2 to 6 and 10, wherein step a) further comprises measuring in a sample of said subject the amount of two specific isoforms of one or two further transcription factor(s), wherein said one or two further transcription factor(s) are either Foxa2 and/or Id2 and wherein the two specific isoforms of said one or two further transcription factor(s) are:

[0452] i) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising a nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 7 or FOXA2 Ad isoform comprising a nucleic acid sequence with up to 74 additions, deletions or substitutions of SEQ ID NO: 3; or

[0453] ii) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising a nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4; and the ID2 Ad isoform consisting of the nucleic acid sequence of SEQ ID No: 8 or ID2 Ad isoform consisting of nucleic acid sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 8;

[0454] and wherein said subject is assessed as suffering from cancer or as being prone to suffer from cancer if

[0455] i) the transcription factor is GATA6 and the ratio of the amount of said Em and said Ad isoform of GATA6 is higher than 0.5, in particular higher than 1.0, more particularly higher than 1.5; and/or

[0456] ii) the transcription factor is NKX2-1 and the ratio of the amount of said Em and said Ad isoform of NKX2-1 is higher than 0.3, in particular higher than 1.0, more particularly higher than 1.7; and

[0457] iii) the transcription factor is FOXA2 and the ratio of the amount of said Em and said Ad isoform of FOXA2 is higher than 0.8; and/or

[0458] iv) the transcription factor is ID2 and the ratio of the amount of said Em and said Ad isoform of ID2 is higher than 1.

[0459] 12. The method according to items 1 to 11, wherein said sample comprises tumor cells.

[0460] 13. The method according to items 1 to 12, wherein said sample is a breath condensate sample.

[0461] 14. The method according to items 1 to 12, wherein said sample is a biopsy sample.

[0462] 15. The method according to items 1 to 12, wherein said sample is a breath condensate sample, a biopsy sample, a blood sample, or a bronchoalveolar lavage fluid sample.

[0463] 16. The method according to any of items 1, 2, or 7 to 10, wherein the amount of said specific transcription factor isoform(s) is measured on the polypeptide level.

[0464] 17. The method according to item 16, wherein the amount of said specific transcription factor isoform(s) is measured by an ELISA, a gel- or blot-based method, mass spectrometry, flow cytometry or FACS.

[0465] 18. The method according to item 16 or 17, wherein said sample comprises tumor cells.

[0466] 19. The method according to any one of items 16 to 18, wherein said sample is a breath condensate sample.

[0467] 20. The method according to any one of items 16 to 18, wherein said sample is a biopsy sample.

[0468] 21. The method according to any one of items 16 to 18, wherein said sample is a breath condensate sample, a biopsy sample, a blood sample, a bronchoalveolar lavage fluid sample, a mucus sample or a phlegm sample.

[0469] 22. The method according to items 1 to 21, wherein said cancer is a lung cancer.

[0470] 23. The method according to item 22, wherein said lung cancer is non-small cell lung cancer (NSCLC).

[0471] 24. The method according to item 23, wherein said NSCLC is an adenocarcinoma, a squamous cell carcinoma or a large cell carcinoma.

[0472] 25. The method according to item 23, wherein said adenocarcinoma is a bronchoalveolar carcinoma.

[0473] 26. The method according to item 23, wherein said adenocarcinoma is a bronchoalveolar carcinoma, an acinar adenocarcinoma, a papillary adenocarcinoma, a solid adenocarcinoma with mucin production, a adenocarcinoma with mixed subtypes, a variant adenocarcinomas, including well differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, or clear cell adenocarcinoma.

[0474] 27. The method according to item 22, wherein said lung cancer is small cell lung cancer.

[0475] 28. The method according to any one of items 1 to 27, wherein said subject is a human subject.

[0476] 29. The method of item 28, wherein said human subject is a subject having an increased risk for developing cancer.

[0477] 30. A method of treating a patient, said method comprising

[0478] a) selecting a cancer patient according to the method of any of items 1 to 29

[0479] b) administering to said cancer patient an effective amount of an anti-cancer agent and/or radiation therapy.

[0480] 31. The method of treating a patient according to item 30, wherein said anti-cancer agent is an inhibitor of

[0481] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Ern isoform nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0482] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0483] 32. The method of treating a patient according to item 30 or 31, wherein said cancer patient is a patient suffering from lung cancer.

[0484] 33. The method according to item 32, wherein said lung cancer is non-small cell lung cancer (NSCLC).

[0485] 34. The method according to item 33, wherein said NSCLC is an adenocarcinoma, a squamous cell carcinoma or a large cell carcinoma.

[0486] 35. The method according to item 33, wherein said adenocarcinoma is a bronchoalveolar carcinoma.

[0487] 36. The method according to item 33, wherein said adenocarcinoma is a bronchoalveolar carcinoma, an acinar adenocarcinoma, a papillary adenocarcinoma, a solid adenocarcinoma with mucin production, a adenocarcinoma with mixed subtypes, a variant adenocarcinomas, including well differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, or clear cell adenocarcinoma.

[0488] 37. The method according to item 32, wherein said lung cancer is small cell lung cancer.

[0489] 38. A composition for use in medicine comprising an inhibitor of

[0490] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or

[0491] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; or

[0492] the method of treating a patient according to any one of items 30 to 37, wherein said anti-cancer agent comprises or is a composition for use in medicine comprising an inhibitor of

[0493] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or



[0494] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2

[0495] 39. The composition for use in medicine of item 38, or the method of treating a patient according to any one of items 30 to 38, wherein said inhibitor comprises a siRNA or shRNA specifically targeting

[0496] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0497] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0498] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0499] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0500] 40. The composition for use in medicine of item 39, or the method of treating a patient according to item 39, wherein said siRNA is selected from the group of siRNAs consisting of SEQ ID No: 41 to SEQ ID NO: 46.

[0501] 41. The composition for use in medicine of item 39, or the method of treating a patient according to item 39, wherein said shRNA is selected from the group of shRNAs consisting of SEQ ID No: 47 to SEQ ID NO: 49.

[0502] 42. A composition for use in medicine comprising an inhibitor of

[0503] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and

[0504] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0505] or the method of treating a patient according to any one of items 30 to 37, wherein said anti-cancer agent comprises or is a composition for use in medicine comprising an inhibitor of

[0506] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and

[0507] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0508] 43. The composition according to item 42, or the method of treating a patient according to item 42, further comprising an inhibitor of

[0509] i) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0510] ii) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4

[0511] 44. The composition for use in medicine of items 38 to 43, or the method of treating a patient according to any one of items 38 to 43, wherein said inhibitor further comprises protamine.

[0512] 45. The composition for use in medicine of items 38 to 43, or the method of treating a patient according to any one of items 38 to 43, wherein the inhibitor further comprises a fusion protein of protamine and an antigen-targeting polypeptide.

[0513] 46. The composition for use in medicine of item 45, or the method of treating a patient according to item 45, wherein said antigen-targeting polypeptide is targeting a protein selected from the group of proteins consisting of ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11.

[0514] 47. The composition for use in medicine of item 45 or item 46, or the method of treating a patient according to item 45 or 46, wherein said antigen-targeting polypeptide is a monoclonal antibody or a single chain variable fragment.

[0515] 48. The composition of any one of items 38 to 47, or the method of treating a patient according to any one of items 38 to 47, for the use in the treatment of a lung disease.

[0516] 49. The composition of item 48, or the method of treating a patient according to item 48 for the use in the treatment of a lung disease, wherein the lung disease is a lung cancer.

[0517] 50. The composition of item 49 for the use in the treatment of a lung cancer--or the method of treating a patient according to item 49, wherein said lung cancer is non-small cell lung cancer (NSCLC).

[0518] 51. The composition of item 50 for the use in the treatment of a lung cancer, or the method of treating a patient according to item 50, wherein said NSCLC is an adenocarcinoma, a squamous cell carcinoma or a large cell carcinoma.

[0519] 52. The composition of item 51 for the use in the treatment of a lung cancer, or the method of treating a patient according to item 51, wherein said adenocarcinoma is a bronchoalveolar carcinoma.

[0520] 53. The composition of item 51 for the use in the treatment of a lung cancer, or the method of treating a patient according to item 51, wherein said adenocarcinoma is a bronchoalveolar carcinoma, an acinar adenocarcinoma, a papillary adenocarcinoma, a solid adenocarcinoma with mucin production, a adenocarcinoma with mixed subtypes, a variant adenocarcinomas, including well differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, or clear cell adenocarcinoma.

[0521] 54. The composition of item 49 for the use in the treatment of a lung cancer, or the method of treating a patient according to item 49, wherein said lung cancer is small cell lung cancer.

[0522] 55. A kit for use in any of the methods according to items 1 to 54 comprising reagents for measuring in a sample specifically the amount of one or two transcription factor isoforms selected from the group of specific transcription factor isoforms consisting of

[0523] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and

[0524] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

[0525] 56. The kit according to item 55 further comprising reagents for measuring in a sample specifically the amount of one or two transcription factor isoforms selected from the group of specific transcription factor isoforms consisting of

[0526] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and

[0527] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0528] 57. The kit according to item 54 or 55 further comprising reagents for measuring in a sample specifically the amount of one or several further transcription factor isoform(s) selected from the group of specific transcription factor isoforms consisting of

[0529] i) the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5;

[0530] ii) the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Ad isoform comprising the nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6;

[0531] iii) the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 7 or FOXA2 Ad isoform comprising the nucleic acid sequence with up to 74 additions, deletions or substitutions of SEQ ID NO: 3; and

[0532] iv) the ID2 Ad isoform consisting of the nucleic acid sequence of SEQ ID No: 8 or ID2 Ad isoform consisting of nucleic acid sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 8;

[0533] 58. The kit of any one of items 54 to 57, wherein said sample comprises tumor cells.

[0534] 59. The kit of item 58, wherein said sample is a breath condensate sample.

[0535] 60. The kit of item 58, wherein said sample is a biopsy sample.

[0536] 61. The kit of item 58, wherein said sample is a breath condensate sample, a biopsy sample, a blood sample, a bronchoalveolar lavage fluid sample, a mucus sample or a phlegm sample.

[0537] 62. The kit of any one of items 58 to 61, wherein said sample is a sample from a human subject.

[0538] 63. The kit of item 62, wherein the kit comprises one or several primers selected from the group of primers comprising the nucleic acid sequence of SEQ IDs 9 to 40.

[0539] The proteins to be targeted in accordance with the above and mentioned in item 32 above can be selected from the group of proteins consisting of ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11. The proteins ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11 are preferably human. The proteins are known in the art and their respective amino acid sequences and nucleic acid sequences encoding the proteins can be retrieved from the corresponding databases, like Uniprot or NCBI. The following table provides an overview of human proteins ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11, showing the gene symbol as used above, the gene name and the accession numbers. By using this information a person skilled in the art is readily in the position to retrieve the sequence of any one of the human proteins ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11. These proteins are also described further below in more detail and also exemplary nucleotide and amino acid sequences thereof are provided herein.

TABLE-US-00019 Human Gene Uniprot NCBI Gene NCBI (Transcript, Symbol Gene Name ID ID Protein) ITGB2 Integrin beta-2 P05107 3689 NM_000211.3, NP_000202.2 PTGIS prostaglandin I2 Q16647 5740 NM_000961.3, (prostacyclin) NP 000952.1 synthase BASP1 brain abundant, P80723 10409 NM_001271606.1, membrane attached NP_001258535.1 signal protein 1 DES desmin P17661 1674 NM_001927.3, NP_001918.3 ITGA2 integrin, alpha 2 P17301 3673 NM_002203.3, (CD49B, alpha 2 NP_002194.2 subunit of VLA-2 receptor) CTSS cathepsin S P25774 1520 NM_001199739.1, NP_001186668.1 (isoform 2) NM_004079.4, NP_004070.3 (isoform 1) PTPRC protein tyrosine Q6PJK7 5788 NM_001267798.1, phosphatase, NP_001254727.1 (isoform 5) receptor type, C NM_002838.4, NP_002829.3 (isoform 1) NM_080921.3, NP_563578.2 (isoform 2) ANPEP aminopeptidase N P15144 290 NM_001150.2, precursor NP_001141.2 FILIP1L filamin A interacting Q4L180 11259 NM_182909.2, protein 1-like NP_878913.2 (isoform 1) NM_014890.2, NP_055705.2 (isoform 2) NM_001042459.1, NP_001035924.1 (isoform 3) MGLL monoglyceride Q99685 23945 NM_011844.4, lipase NP_035974.1 (isoform b) NM_001166251.1, NP_001159723.1 (isoform a) OSMR oncostatin M Q99650 9180 NM_001168355.1, receptor NP_001161827.1 (isoform 2) NM_003999.2, NP_003990.1 (isoform 1) ITGB6 integrin, beta 6 P18564 3694 NM_000888.3, NP_000879.2 AGPAT4 1-acylglycerol-3- Q9NRZ5 56895 NM_020133.2, phosphate O- NP_064518.1 acyltransferase 4 ASS1 argininosuccinate P00966 445 NM_000050.4, synthetase 1 NP_000041.2 CSPG4 chondroitin sulfate Q6UVK1 1464 NM_001897.4, proteoglycan 4 NP_001888.2 CDH11 cadherin 11, type 2, P55287 1009 NM_001797.2, OB-cadherin NP_001788.2 (osteoblast)

[0540] The following table provides an overview of murine proteins ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11, showing the gene symbol as used above, the gene name and the accession numbers. By using this information a person skilled in the art is readily in the position to retrieve the sequence of any one of the murine proteins ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11.

TABLE-US-00020 Mouse Gene NCBI Gene Symbol Gene Name Uniprot ID NCBI Itgb2 Integrin beta-2 P11835 16414 NM_008404.4, NP_032430.2 Ptgis prostaglandin I2 Q8BXC0 19223 NM_008968.3, (prostacyclin) NP_032994.1 synthase Basp1 brain abundant, Q91XV3 70350 NM_027395.2, membrane attached NP_081671.1 signal protein 1 Des desmin P31001 13346 NM_010043.1, NP_034173.1 Itga2 integrin, alpha 2 Q62469 16398 NM_008396.2, (CD49B, alpha 2 NP_032422.2 subunit of VLA-2 receptor) Ctss cathepsin S Q3U5K1 13040 NM_021281.2, NP_067256.3 NM_001267695.1, NP_001254624.1 Ptprc protein tyrosine P06800 19264 NM_001111316.2, phosphatase, NP_001104786.2 (isoform 1) receptor type, C NM_001268286.1, NP_001255215.1 NM_011210.4, NP_035340.3 (isoform 2) Anpep aminopeptidase N P97449 16790 NM_008486.2, precursor NP_032512.2 Filip1l filamin A interacting Q6P6LO 78749 NM_001040397.4, protein 1-like NP_001035487.2 (isoform 1) NM_001177871.1, NP_001171342.1 (isoform 2) Mgll monoglyceride 035678 11343 NM_007283.6, lipase NP_009214.1 (isoform 1) NM_001256585.1, NP_001243514.1 (isoform 3) NM_001003794.2, NP_001003794.1 (isoform 2) Osmr oncostatin M 070458 18414 NM_011019.3, receptor NP_035149.2 Itgb6 integrin, beta 6 Q9Z0T9 16420 NM_001159564.1, NP_001153036.1 Agpta4 1-acylglycerol-3- Q8K4X7 68262 NM_026644.2, phosphate O- NP 080920.2 acyltransferase 4 Ass1 argininosuccinate P16460 11898 NM_007494.3, synthetase 1 NP_031520.1 Cspg4 chondroitin sulfate Q8VHY0 121021 NM_139001.2, proteoglycan 4 NP_620570.2 Cdh11 cadherin 11, type 2, P55288 12552 NM_009866.4, OB-cadherin NP_033996.4 (osteoblast)

[0541] Herein above, markers, in particular GATA6 Em isoform and NKX2-1 Em isoform, for the diagnosis of cancer, particularly lung cancer, have been provided and described. These markers are highly expressed in cancer and are therefore useful as targets in the therapy of cancer. The following provide nucleic acid delivery systems that can be used in the therapy of these cancers or as research tools, inter alia, targeting GATA6 Em isoform and NKX2-1 Em isoform. Accordingly, the present invention relates also to a nucleic acid delivery system, in particular, an alveolar type II cell directed nucleic acid delivery system for the treatment of lung diseases. Provided is a nucleic acid delivery system for the delivery of nucleic acids specifically into an alveolar type II epithelial cell (ATII cells), wherein said system comprises a polypeptide binding to a specific surface marker of ATII cells, wherein said specific surface marker is ITGB2 or ITGB6. Moreover, the present invention relates to the use of the nucleic acid delivery system in the treatment of a lung disease.

[0542] The lung is a complex organ consisting of different epithelial and mesenchymal cell lineages organized in a proximal-distal manner, with several specialized cell types that form the functional gas exchange interface required for postnatal respiration (FIG. 19, [21639799, 20531299]). The lung shows slow homeostatic turnover but rapid repair after injury, and tissue-resident lung-endogenous progenitor cell niches located in specific regions along the proximal-distal axis of the airways are thought to be responsible for both processes (Rawlins and Hogan, 2006). ATII cells represent one of these regional progenitor cell populations and are located in the alveoli. ATII cells are responsible for regeneration of alveolar epithelium during homeostatic turnover and in response to injury [PMID: 4812806, 163758, 12922980, 21079581]. ATII cells have been related to a diversity of lung diseases including lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), emphysema and cystic fibrosis [PMID: 22411819, 23134111, 19934355, 16888288, 19335897]. Thus, characterization of the regulatory mechanisms controlling the proper balance between expansion and differentiation of ATII cells will have a profound impact on our understanding and treatment of lung disease. However, detailed characterization of ATII cells has been challenging since the most specific known cellular marker for these cells (surfactant associated protein C, SFTPC or SP-C) is a secreted molecule making difficult the enrichment of a homogenous population of these cells. Furthermore, a lack of reliable cell markers of ATII cells hampers the specific targeting of said cells using siRNAs or alternative agents. Thus, there is a great need to identify specific ATII cell markers to provide means and methods to target ATII cells specifically. Accordingly, the technical problem underlying the present invention is the provision of means and methods to target ATII cells specifically.

[0543] The technical problem is solved by provision of the embodiments herein, inter alia, in the items below.

[0544] 1. A nucleic acid delivery system for the delivery of nucleic acids specifically into an alveolar type-II epithelial cell, wherein said system comprises a polypeptide binding to a specific surface marker of alveolar type-II epithelial cells, wherein said specific surface marker is Itgb2 or Itgb6.

[0545] 2. The nucleic acid delivery system according to item 1, wherein said polypeptide is a monoclonal antibody or a single chain variable fragment.

[0546] 3. The nucleic acid delivery system according to item 1 or 2, wherein said polypeptide is fused to a nucleic acid binding molecule.

[0547] 4. The nucleic acid delivery system according to item 3, wherein said nucleic acid binding molecule is protamine or a polypeptide having at least 90% identity with protamine and having nucleic acid binding activity.

[0548] 5. The nucleic acid delivery system according to any one of items 1 to 4, wherein said system comprises a nucleic acid, such as an siRNA or shRNA.

[0549] 6. The nucleic acid delivery system according to item 5, wherein said siRNA is specifically targeting an mRNA being upregulated in a lung disease, like lung cancer, such as adenocarcinoma or a bronchoalveolar carcinoma.

[0550] 7. The nucleic acid delivery system according to item 5 or 6, wherein said siRNA is targeting

[0551] i) the GATA6 Em isoformcomprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoformcomprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0552] ii) the NKX2-1 Em isoformcomprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoformcomprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0553] iii) the FOXA2 Em isoformcomprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoformcomprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0554] iv) the ID2 Em isoformcomprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoformcomprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4;

[0555] 8. The nucleic acid delivery system according to any one of items 1 to 7, wherein said surface marker Itgb2 has the amino acid sequence as shown in SEQ ID NO. 110, and wherein said surface marker Itgb6 has the amino acid sequence as shown in SEQ ID NO. 150.

[0556] 9. Use of the nucleic acid delivery systems of any one of items 1 to 8 for the transfection of specifically alveolar type-II epithelial cells.

[0557] 10. A composition comprising (an) siRNA(s) targeting

[0558] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0559] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0560] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0561] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4;

[0562] and a fusion protein of protamine and an Itgb2-, or Itgb6--targeting monoclonal antibody or single chain variable fragment.

[0563] 11. A composition for use in medicine comprising the nucleic acid delivery system of any one of items 1 to 8 or the composition of item 10.

[0564] 12. The composition according to item 11 for the use in the treatment of a lung disease.

[0565] 13. The composition according to item 11 for the use in the treatment of lung cancer.

[0566] 14. The composition according to item 11 for the use in the treatment of lung adenocarcinoma or lung bronchoalveolar carcinoma.

[0567] 15. A nucleic acid delivery system for the delivery of nucleic acids into an alveolar type-II epithelial cell according to any of items 1 to 8, wherein the nucleic acid delivery system is a non-viral nucleic acid delivery system; or the composition according to any of items 10 to 14, wherein the composition is characterized by being a substantially non-viral composition.

[0568] Furthermore, the present invention relates to the following items:

[0569] 1. A nucleic acid delivery system for the delivery of nucleic acids specifically into an alveolar type-II epithelial cell, wherein said system comprises a polypeptide binding to a specific surface marker of alveolar type-II epithelial cells, wherein said specific surface marker is Itgb2 or Itgb6.

[0570] 2. The nucleic acid delivery system according to item 1, wherein said polypeptide is a monoclonal antibody or a single chain variable fragment.

[0571] 3. The nucleic acid delivery system according to items 1 or 2, wherein said polypeptide is fused to a nucleic acid binding molecule.

[0572] 4. The nucleic acid delivery system according to item 3, wherein said nucleic acid binding molecule is protamine or a polypeptide having at least 70%, 75%, 80%, 85% or at least 90%, 95%, 96%, 97%, 98% or at least 99% identity with protamine and having nucleic acid binding activity.

[0573] 5. The nucleic acid delivery system according to items 1 to 4, wherein said system comprises a nucleic acid, such as an siRNA or shRNA.

[0574] 6. The nucleic acid delivery system according to item 5, wherein said siRNA is specifically targeting an mRNA being upregulated in a lung disease.

[0575] 7. The nucleic acid delivery system according to item 6, wherein said lung disease is lung cancer.

[0576] 8. The nucleic acid delivery system according to item 7, wherein said lung cancer is an adenocarcinoma or a bronchoalveolar cacrinoma.

[0577] 9. The nucleic acid delivery system according to item 7 or 8, wherein said mRNA being upregulated in a lung disease is upregulated in lung cancer.

[0578] 10. The nucleic acid delivery system according to items 5 to 9, wherein said siRNA is targeting

[0579] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0580] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0581] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0582] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4;

[0583] 11. A composition comprising (an) siRNA(s) targeting

[0584] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0585] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0586] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0587] iv) the ID2 Em isoform Em comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform Em comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4;

[0588] and a fusion protein of protamine and an Itgb2-, or Itgb6--targeting monoclonal antibody or single chain variable fragment.

[0589] 12. A kit for the delivery of a nucleic acid into an alveolar type-II epithelial cell comprising any of the nucleic acid delivery systems of items 1 to 10 or the composition of item 11.

[0590] 13. Use of the nucleic acid delivery systems of items 1 to 10 for the transfection of specifically alveolar type-II epithelial cells.

[0591] 14. A composition for use in medicine comprising any of the nucleic acid delivery systems of items 1 to 10 or the composition of item 11.

[0592] 15. The composition according to item 14 for the use in the treatment of a lung disease.

[0593] 16. The composition according to item 14 for the use in the treatment of lung cancer.

[0594] 17. The composition according to item 14 for the use in the treatment of lung adenocarcinoma or lung bronchoalveolar carcinoma.

[0595] 18. A nucleic acid delivery system for the delivery of nucleic acids into an alveolar type-II epithelial cell according to any of items 1 to 10, wherein the nucleic acid delivery system is a non-viral nucleic acid delivery system.

[0596] 19. The composition according to any of items 11 or 14 to 17, wherein the composition is characterized by being a substantially non-viral composition.

[0597] 20. A method of treating a subject suffering from cancer or a subject with an increased risk of suffering from cancer comprising the step of administering to said subject the nucleic acid delivery system according to items 1 to 10 or 18.

[0598] 21. The method of item 20, wherein the subject is a human subject.

[0599] 22. The method of item 20, wherein said cancer is a lung cancer.

[0600] 23. The method of item 22, wherein said lung cancer is an adenocarcinoma or a bronchoalveolar carcinoma.

[0601] The present invention relates to a nucleic acid delivery system for the delivery of nucleic acids specifically into an alveolar type-II epithelial cell (ATII cells), wherein said system comprises a polypeptide binding to a specific surface marker of alveolar type-II epithelial cell (ATII cells), wherein said specific surface marker is ITGB2 or ITGB6.

[0602] Furthermore, the present invention relates to a nucleic acid delivery system for the delivery of nucleic acids specifically into an alveolar type-II epithelial cell (ATII cell), wherein said system comprises a polypeptide binding to a specific surface marker of alveolar type-II epithelial cell (ATII cells), wherein said specific surface marker is selected from the group consisting of ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11.

[0603] The terms "alveolar type II cell", "alveolar type II epithelial cell", "alveolar type-II epithelial cell", "AT-II cell", "ATII cell" and the like can be used interchangeably herein.

[0604] Metabolic labeling of living organisms with stable isotopes has become a powerful tool for global protein quantitation. The SILAC (stable isotope labeling with amino acids in cell culture) approach is based on the incorporation of nonradioactive-labeled isotopic forms of amino acids into cellular proteins [PMID:12118079]. The effective SILAC labeling of immortalized cells and single-cell organisms (e.g., yeast and bacteria) was recently extended to more complex organisms, including worms, flies, and even rodents [PMID:18662549]. The administration of a .sup.13C.sub.6-lysine (Lys6--heavy) containing diet for one mouse generation leads to a complete exchange of the natural isotope .sup.12C.sub.6-lysine (Lys0--light). Here we used the lung of the fully labeled SILAC mice as a heavy "spike-in" standard into nonlabeled samples of murine ATII or MLE-12 cells (mouse lung epithelial cell line) in combination with high-performance mass spectrometry to analyze fractions of membrane proteins. By a comparison of the membrane protein fractions of ATII cells, MLE-12 cells and whole adult lung derived from the SILAC mouse, we were able to identify membrane proteins that are enriched in ATII cells. A comparison of the results obtained by the proteomic approach with an Affymetrix microarray based expression analysis of ATII cells led us to the identification of 16 membrane proteins that are present and highly expressed in ATII cells; see FIG. 22. These 16 membrane proteins are ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11. Exemplary amino acid sequences and nucleic acid sequences encoding same are shown in SEQ ID NO. 108 to 126 and 128 to 159.

[0605] The 16 membrane proteins described above constitute surface markers of ATII cells that will be recognized by the nucleic acid delivery system of the present invention thereby allowing ATII cell specific targeting. Upon recognition, it is believed that the above described surface proteins of ATII cells will facilitate the internalization of the nucleic acid delivery system of the present invention thereby mediating ATII cell specific delivery. The potential of nucleic acids delivery systems into specific cells using antibodies recognizing cell surface proteins has been previously demonstrated (Schneider (2012) Molecular Therapy-Nucleic Acids. 1, e46; Dou (2012) Journal of Controlled Release. 16, 875-883; Song (2005) NATURE BIOTECHNOLOGY 23(6), 709-717).

[0606] It is envisaged herein that the nucleic acid delivery systems can be administered by using an aerosol that will be inhalated thereby ensuring ATII cell specific targeting. The aerosol contains the nucleic acid delivery provided herein.

[0607] The herein provided nucleic acid delivery systems are not only useful as a research tool to further characterize ATII cells. The nucleic acid delivery systems can also be used in medical intervention in diseases associated with ATII cells. For example, ATII cells have been related to a diversity of lung diseases including lung cancer (like lung adenocarcinoma), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), emphysema and cystic fibrosis [PMID: 22411819, 23134111, 19934355, 16888288, 19335897]. Thus, the present invention allows the targeting of the ATII cells to provide means for the treatment of lung diseases (including lung cancer (like lung adenocarcinoma), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), emphysema and cystic fibrosis) that arise from or are associated with ATII cells. For example, antibodies against any of the 16 membrane proteins that were identified as ATII cell specific can be used in context of the herein provided nucleic acid delivery system. A combination of the nucleic acid delivery system of the present invention with known as well as newly identified specific agents will help to prevent and to treat a diversity of lung diseases, to which ATII cells have been or will be related, including but not limited to lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), emphysema and cystic fibrosis.

[0608] Recently, it was shown that ATII cells are the cells of origin of lung adenocarcinoma (Xu et al 2012, PNAS, word wide web at pnas.org/cgi/doi/10.1073/pnas.1112499109). In addition, data are provided herein (see Example 12 and FIGS. 25 and 26) which support that lung adenocarcinoma originates from ATII cells.

[0609] Lung cancer is a typical model cancer with a very high prevalence. Lung cancer is the most frequent cause of cancer related deaths worldwide. There are two major classes of lung cancer, non small cell lung cancer (contributing to 85% of all lung cancers) and small cell lung cancer (the remaining 15%). Lung cancer cells show an enhanced expression of transcription factors that are present during embryonic development in the endoderm as GATA6 (GATA Binding Factor 6), NKX2-1 (NK2 homeobox 1, also known as Ttf-1, Thyroid transcription factor-1), FOXA2 (Forkhead box protein A2), and ID2 (Inhibitor of DNA binding 2) (Guo M et al., (2004) Clin Cancer Res. 10(23): 7917-24; Kendall J et al., (2007) Proc Natl Acad Sci USA. 104(42): 16663-8; Tang Y et al., (2011) Cell Res. 21(2): 316-26; Rollin J et al., (2009) PLoS One. 4(1): e4158). It was recently demonstrated that lung adenocarcinoma initiates from clonal expansion of cells expressing high levels of Nkx2-1 and progress to a more aggressive state with low expression of Nkx2-1 (see Winslow (2011) Nature 473(7345): 101-104). GATA6 has been shown to be abundantly expressed in malignant mesotheliomas, and to a small extent, in metastatic adenocarcinomas (see Lindholm (2009) Journal of Clinical Pathology 62(4): 339-344). In addition, GATA6 regulates tumorigenesis related genes, such as KRAS, an oncogene activated by point mutations (see Gorshkove (2005) Biochemistry (Mosc):70: 1180-1184).

[0610] GATA6, FOXA2 and NKX2-1 are crucial for early lung development. Genetic analyses with knockout animals demonstrated their role in lung endoderm differentiation and post natal repair and homeostasis. Nkx2-1, Gata6 and Foxa2 are expressed in respiratory epithelial cells throughout lung morphogenesis. They all have been shown to bind and trans-activate many lung specific promoters, including SftpA-, SftpB-, SftpC- and Scgb1a1-promoters (Bruno M D et al., (1995) 270(12): 6531-6; Margana R K and Boggaram V. (1997) J Biol Chem. 272(5): 3083-90). Mice harboring a Nkx2-1 null mutation show severe attenuation of lung airway branching. In addition, the lung epithelial cells present in these mice lack expression of putative targets like SftpC (Minoo Petal., (1999) Dev Biol. 209(1): 60-71). Conditional deletion of Gata6 in the lung endoderm demonstrated its central role in lung endoderm gene expression, proliferation and branching morphogensis. (Keijzer R et al., (2001) Development 128(4): 503-11). A loss of Foxa2 in the lung can be compensated by Foxa1. However, a loss of both Foxa1/2 also dramatically inhibits endoderm differentiation and branching morphogenesis. (Wan H et al., (2005) J Biol Chem. 280(14): 13809-16). Foxa2 has also been shown to be essential for the transition to breathing air at birth (Wan H et al., (2004) Proc Natl Acad Sci USA. 101(40): 14449-54).

[0611] It was demonstrated by the disclosure of a patent application that will be submitted back-to-back with the present application that GATA6, NKX2-1, FOXA2 and ID2 share a common gene structure, with two promoters driving the expression of two distinct transcripts. It is surprisingly found that though different isoforms exist only one is oncogenic and is indicative of the presence/development of cancer (see Examples 2 and 3). The embryonic GATA6 and NKX2-1 "Em" transcripts as defined herein are found to be detectable in high levels in human lung cancer cell lines and patient lung cancer biopsies (see Examples 2 and 3). Remarkably, these cancer specific isoforms are oncogenic and forced overexpression in cell lines as well as in mice results in a tumorigenic phenotype (see Examples 4, 6 and 7). This is illustrated by the finding that mice develop adenocarcinoma as early as 5 weeks after transfection with one of those specific embryonic "Em" isoforms. Further, it is surprisingly found that these specific "Em" isoforms can be detected in the blood of mice that are induced for tumor formation, showing their usability as early diagnostic markers for cancer, in particular lung cancer (see Example 3). In addition, overexpression of hyperactive KRAS G12D mutant increases the expression of embryonic Gata6 and Nkx2-1 (FIG. 9), supporting the involvement of the embryonic isoforms in KRAS induced malignant transformation. Furthermore, siRNA mediated loss-of-function of Gata6 Em reduces the number and the size of lung tumors after tail vein injection of LLC1 cells (FIG. 8), demonstrating the therapeutic potential of targeting the embryonic isoforms. In a normal, healthy ATII cell, the embryonic isoforms should be expressed at very low level. Only after transformation of a normal cell into a cancer cell the expression of the embryonic isoforms increases dramatically.

[0612] Therefore, it is plausible that the nucleic acid delivery system provided herein can be used to treat ATII relates lung diseases, like lung adenocarcinoma, for example via an ATII cell directed loss-of-function of the embryonic isoforms of GATA6, NKX2-1, FOXA2 and/or ID2.

[0613] Furthermore, it was confirmed that integrin beta 2 and 6 (ITGB2 and ITGB6) are indeed present in ATII cells. Integrins are heterodimeric cell adhesion molecules that are formed by specific non-covalent associations of an alpha and a beta subunit [22819514]. In general each integrin subunit has a large extracellular region, a single pass transmembrane domain and a short cytoplasmic tail [PMID: 21421922]. Integrins mediate cell-cell and cell-ECM (extracellular matrix) interaction and transmit signals across the plasma membrane in both directions between their extracellular ligand binding adhesion sites and their cytoplasmic domain [PMID: 12297042, 22458844], thereby linking the cytoskeleton to several signal transduction pathways [21900405, 18441324, 15863032, 15554942, 15053919]. Surprisingly, a close analysis of the membrane protein fraction of ATII cells showed an enrichment of proteins that are involved in WNT signaling. Therefore WNT signaling was anlayzed in the lung of Itgb2.sup.-/- mice [8700894]. Enhanced expression and increased protein levels of WNT targets were found in the lung of Itgb2.sup.-/- mice. It was found that Itgb2 seems to be required for a negative regulation of WNT signaling in the adult lung. Moreover, ectopic expression of Itgb2 in MLE-12 cells counteracted the lithium chloride (LiCl) induced enhancement of WNT signaling. It is shown herein that ITGB2 and ITGB6 are cell surface markers for a subpopulation of ATII cells. Proteins that are involved in WNT signaling are enriched in the membrane of ATII cells, showing an important role of this pathway. Furthermore, Itgb2 is required for a negative regulation of WNT signaling in the lung.

[0614] Integrins have been involved in lung development, lung epithelial cell differentiation and epithelial repair after lung injury [PMID:12242717; 18725542; 12843406, 16169900, 20363851]. The epithelial cells of the airways express multiple members of the integrin family. Although the multiple integrins on airway epithelial cells may have overlapping ligand binding specificities thereby supporting adhesion to the same molecules of the extracellular matrix (ECM), the functional roles of each integrin that has been examined in detail are quite distinct. Several integrins are able to activate latent transforming growth factor beta 1 (TGFB1) located in the ECM thereby showing a critical role of ECM and integrins in regulating TGFB signaling [PMID 21900405, 23046811]. Integrins play a role in fibroblast growth factor (FGF) signaling through cross-talk with FGF receptors [18441324; 15863032].

[0615] A regulation of WNT signaling by cell-cell and cell-ECM adhesion has been suggested to be mediated by integrin outside-in signaling [PMID:15554942; 15053919]. Although the majority of recent studies in embryonic stem cells and organ progenitor cells have focused on the role of growth factors, such as TGFB, FGF and WNT, relatively little is known about the role of ECM-integrin signaling. Recent data provide evidence that ECM-integrin signaling promotes differentiation of human embryonic stem cells toward definitive endoderm [PMID 23154389], an early embryonic cell population fated to give rise to specific organs such as the lung, liver, pancreas, stomach, and intestine. In the mouse adult lung, a subpopulation of alveolar epithelial cells expressing Itga6 and Itgb4 has been reported to have regenerative potential after lung injury making it a strong candidate as progenitor cells during alveolar epithelium repair [21701069; 21701072]. The data provided herein confirmed that integrin beta 2 and 6 (ITGB2 and ITGB6) are indeed present in ATII cells.

[0616] Further characterization of these cells after sorting and enrichment of a homogenous cell population could have a profound impact on our understanding on the regulatory mechanisms controlling the proper balance between expansion and differentiation of ATII cells. In addition, it will be relevant for clinical applications to determine the regenerative potential of these ITGB2- and ITGB6-positive cells using lung injury models. The herein described surface markers of ATII cells (ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11) can be used in accordance with the present invention to sort and/or enrich ATII cells. Accordingly, a cell population enriched in ATII cells is provided herein.

[0617] ATII cells have been related to a diversity of lung diseases including lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), emphysema and cystic fibrosis [PMID: 22411819, 23134111, 19934355, 16888288, 19335897]. On the other hand, integrins have been related to different processes in the lung like regulation of lung inflammation, macrophage protease expression, pulmonary fibrosis, the pulmonary edema that follows acute lung injury and malignant transformation [PMID: 12843406, 23046811, 18378634, 14527926, 22802286]. Thus our data suggest that Itgb2 and Itgb6 are attractive as diagnostic and therapeutic targets for intervention in a number of common lung disorders (like lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), emphysema and cystic fibrosis, lung inflammation, macrophage protease expression, pulmonary fibrosis, the pulmonary edema that follows acute lung injury and malignant transformation. Indeed, significant efforts have been directed towards the development of advanced molecular tools for an integrin-mediated drug delivery in cancer and cardiovascular diseases with peptide-functionalized nanoparticles [22612699].

[0618] The present invention relates to a nucleic acid delivery system for the delivery of nucleic acids specifically into an alveolar type-II epithelial cell (ATII cell), wherein said system comprises a polypeptide binding to a specific surface marker of alveolar type-II epithelial cell (ATII cells), wherein said specific surface marker is selected from the group consisting of ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11.

[0619] The present invention relates to a nucleic acid delivery system for the delivery of nucleic acids specifically into an alveolar type-II epithelial cell (ATII cell), wherein said system comprises a polypeptide binding to a specific surface marker of alveolar type-II epithelial cell (ATII cells), wherein said specific surface marker is ITGB2 or ITGB6.

[0620] In accordance with the above, the present invention provides a nucleic acid delivery system for the delivery of nucleic acids into an alveolar type-II epithelial cell (ATII cell), wherein said system comprises a polypeptide binding to a specific surface marker of alveolar type-II epithelial cell (ATII cells). Preferably, the nucleic acid delivery system is for the delivery of nucleic acids specifically into an alveolar type-II epithelial cell (ATII cell).

[0621] A "nucleic acid delivery system" according to the present invention can be any system capable of introducing or transferring a nucleic acid into a cell. Suitable systems taking advantage of surface markers are described in the art, such as (Schneider (2012) loc. cit.; Dou (2012) loc. cit., or Song (2005) loc. cit. (see also PMID: 12067443 PMID 9862854 PMID: 16146351 PMID: 16606824 PMID: 16778167 PMID: 16823371 PMID: 11156528 PMID: 15908939 PMID: 21902630) which are incorporated herein by reference in their entirety.

[0622] The term "specific surface marker of alveolar type-II epithelial cell (ATII cells)" as used herein refers to a membrane protein. The membrane protein is primarily found at the surface of alveolar type-II epithelial cells (ATII cells). The "specific surface marker of alveolar type-II epithelial cell (ATII cells)" is therefore characteristic or specific for alveolar type-II epithelial cell (ATII cells). For example, other lung cell types do not have such a "specific surface marker of alveolar type-II epithelial cell (ATII cells)" (e.g. other lung cell types do not have such a "specific surface marker of alveolar type-II epithelial cell (ATII cells)" in detectable amounts). Other lung cell types than alveolar type-II epithelial cell (ATII cells) can, for example, have significantly less "specific surface marker of alveolar type-II epithelial cell (ATII cells)" than alveolar type-II epithelial cell (ATII cells).

[0623] Exemplary "specific surface markers of alveolar type-II epithelial cell (ATII cells)" of the present invention are ITGB2, ITGB6, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, AGPAT4, ASS1, CSPG4, and CDH11. Preferred specific surface markers are ITGB2 and ITGB6. Exemplary amino acid sequences of the surface markers and nucleic acid sequences encoding these surface markers are shown in SEQ ID NO:s 108-126 and 128 to 159. Also the use of variants of these surface markers (like variants with SNP polymorphisms or other genetic variants, like mutants) is envisaged herein without deferring from the gist of the present invention. Furthermore, also membrane proteins having a certain level of identity (like at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) to any of these membrane proteins as shown in the above SEQ ID NO.s is envisaged in accordance with the present invention.

[0624] The "nucleic acid delivery system" according to the present invention comprises a polypeptide binding to a specific surface marker of alveolar type-II epithelial cell (ATII cells) as described herein. The "nucleic acid delivery system" according to the present invention can be used as a transfection system for the targeted transfection of alveolar type-II epithelial cell (ATII cells). Said polypeptide can induce internalization of the surface marker(s), thereby allowing or facilitating or enhancing the transport/delivery of (a) nucleic acid(s) into the alveolar type-II epithelial cell(s) (ATII cell(s)) (s). Alternatively, the polypeptide binds to the specific surface marker without inducing its internalization. The delivery of the nucleic acids can be achieved by taking advantage of the naturally occurring internalization procedure of the surface markers. It is believed that the entire surface marker-polypeptide-complex (including e.g. nucleic acids bound to the polypeptide either directly or indirectly) is internalized and that thereby the nucleic acid is delivered into the ATII cell. It is envisaged that the nucleic acids to be delivered into the ATII cells are bound either directly or indirectly to the polypeptide. Indirect binding can involve the use of a nucleic acid binding molecule like protamine, histones, high mobility group proteins, a cell-permeant RNA-binding protein, a HIV-1 TAT peptid, or a polypeptide sharing at least 60% identity with one of those polypeptides, at least 65%, 70%, 75%, 80%, 85%, preferably at least 90%, 95%, 96%, 97%, 98% or 99% and having nucleic acid binding capability. A "nucleic acid binding molecule" according to the present invention can be protamine. A "nucleic acid binding molecule" according to the present invention can be dioxigenin or nano particles.

[0625] A "polypeptide binding to a specific surface marker of alveolar type-II epithelial cell (ATII cells)" according to the present invention can be any polypeptide (e.g. haptens or antibodies and the like) which shows binding capacity to a "specific surface marker" of an alveolar type-II epithelial cell (ATII cells). In particular, such a polypeptide can be an antibody or a fragment of an antibody, like for example a Fab fragment an F(ab)' fragment of an antibody, or a F(ab).sub.2-fragment. The antibody can be a full antibody (immunoglobulin), a murine antibody, a chimeric antibody, a humanized antibody, a human antibody, a deimmunized antibody, a single-chain antibody, a CDR-grafted antibody, a bivalent antibody-construct, a synthetic antibody, a bispecific single chain antibody or a cross-cloned antibody. A "polypeptide binding to a specific surface marker of alveolar type-II epithelial cell (ATII cells)" according to the present invention can be a monoclonal antibody or a single chain variable fragment.

[0626] A person skilled in the art is readily in the position to generate antibodies binding to a specific surface maker. Polyclonal or monoclonal antibodies or other antibodies (derived therefrom) can be routinely prepared using, inter alia, standard immunization protocols; see Ed Harlow, David Lane, (December 1988), Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory; or Ed Harlow, David Lane, (December 1998), Portable Protocols (Using Antibodies): A Laboratory Manual 2nd edition, Cold Spring Harbor Laboratory.

[0627] For example, immunization may involve the intraperitoneal or subcutaneous administration of the surface marker (and/or fragments, isoforms, homologues and so on) as defined herein to a mammal (e.g. rodents such as mice, rats, hamsters and the like). Preferably, fragments of the surface marker are used, wherein the fragment preferably comprises the extracellular domain of the surface marker (or a part thereof). For example, a fragment, e.g. of the extracellular domain, of the surface marker ITGB2 (preferably ITGB2 shown in SEQ ID NO: 110) may be used. For example, a fragment, e.g. of the extracellular domain, of the surface marker ITGB6 (preferably ITGB6 shown in SEQ ID NO: 150) may be used.

[0628] The fragment can consist of five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or sixteen or more of the entire surface marker, particularly of the extraceullar domain thereof. Corresponding fragments (peptides) may be prepared by enzymatic hydrolysis or by chemical synthesis.

[0629] For example, antibodies recognizing the surface marker may be affinity purified. ELISA is commonly used for screening sera and/or assaying affinity column fractions. Western Blots can be used to demonstrate that the antibody can detect the actual protein of interest and to evaluate whether the antibody only recognizes the protein of interest, or if it cross-reacts with other proteins.

[0630] A person skilled in the art is in the position to apply and to adapt the teaching of these documents for the generation and validation of antibodies specifically binding to or specifically recognizing the polypeptides as defined herein in context of the present invention.

[0631] "Alveolar type-II epithelial cell (ATII cells)" and their characteristics are well known [PMID: 4812806; PMID: 163758; PMID: 21079581; PMID: 62893; PMID: 12922980; PMID: 9151120; PMID: 8770063; PMID: 7917310] An "alveolar type-II epithelial cell (ATII cells)" according to the present invention is an "alveolar type-II epithelial cell (ATII cells)" having at least one surface marker of the group consisting of ITGB2, ITGB6, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11. An "alveolar type-II epithelial cell (ATII cells)" according to the present invention can have at least the surface marker ITGB2 and/or ITGB6. The one or more surface marker can be enriched on the cell surface of an "alveolar type-II epithelial cell (ATII cells)" according to the present invention. The one or more surface marker can be enriched on the cell surface of an "alveolar type-II epithelial cell (ATII cells)" according to the present invention compared to other lung cell lines, e.g. in MLE-12 cells.

[0632] An exemplary nucleic delivery system for use in the present invention, wherein the nucleic acid is directly (via a digoxigenin label) bound to a polypeptide is described in Schneider (2012) loc. cit. This delivery system can be used in context of the present invention: A bispecific antibody (e.g. a bispecific monoclonal antibody or bispecific single chain variable fragment or bispecific single chain antibody) can be used, wherein a first variable domain is capable of binding to a surface marker and a second variable domain is capable of binding to digoxigenin. The nucleic acids (like siRNAs and the like) can be labeled with digoxigenin e.g. at its 3' ends. The bispecific antibody binds to both the surface marker and the digoxigenin labeled nucleic acid and thereby effects delivery of the siRNA into the ATII cells.

[0633] The "polypeptide binding to a specific surface marker of alveolar type-II epithelial cell (ATII cells)" according to the present invention can be fused to or otherwise bound to a nucleic acid binding molecule. For example, the nucleic acid(s) to be delivered is (are) bound to or associated with the binding molecule(s) and the binding molecule(s) is(are), in turn, bound by the polypeptide(s). Upon binding of the polypeptide(s) to the surface marker(s), the nucleic acid(s) is(are) delivered into the ATII cell(s).

[0634] A "nucleic acid binding molecule" according to the present invention can be any molecule which is capable of binding nucleic acids, like a polypeptide. A "nucleic acid binding molecule" according to the present invention can be a polypeptide selected from the group consisting of protamine, histones, high mobility group proteins, a cell-permeant RNA-binding protein, a HIV-1 TAT peptid, or a polypeptide sharing at least 60% identity with one of those polypeptides, at least 65%, 70%, 75%, 80%, 85%, preferably at least 90%, 95%, 96%, 97%, 98% or 99% and having nucleic acid binding capability. A "nucleic acid binding molecule" according to the present invention can be a protamine. A "nucleic acid binding molecule" according to the present invention can be dioxigenin or nano particles.

[0635] An exemplary nucleic acid delivery system that takes advantage of a nucleic acid binding molecule is described in Song (2012), loc. cit. or Dou (2012) loc. cit. These delivery systems can be used in accordance with the present invention. For example, a nucleic acid sequence encoding a nucleic acid binding molecule (like protamine and the like) can be fused in frame to a e.g. a sequence encoding the C-terminus of a polypeptide binding to a specific surface marker (e.g. the C-terminus of the heavy chain of an antibody). Expression can be performed in appropriate host systems (like eukaryotic host cells, e.g. CHO cells). Because the nucleic acid (e.g. siRNA) binds to the binding molecule fused to the polypeptide, the nucleic acid can be delivered to the ATII cell upon binding of the polypeptide-binding molecule-nucleic acid complex to the surface marker.

[0636] A "nucleic acid" according to the present invention can be any nucleic acid. If for example, it is aimed to overexpress a gene in a alveolar type-II epithelial cell (ATII cells) according to the present invention, the nucleic acid may be a nucleic acid encoding said polypeptide linked to regulatory elements for the expression and/or translation of said polypeptide. If, for example, the aim is to reduce or abandon the expression of a gene product in a alveolar type-II epithelial cell (ATII cells) according to the present invention, the nucleic acid may be an antisense DNA or RNA molecule or be an siRNA molecule specifically targeting the gene of which the product should be reduced in its expression. The nucleic acid may also encode an antisense RNA molecule or a shRNA molecule.

[0637] The nucleic acid delivery system to be used herein comprises a nucleic acid molecule to be delivered, such as the afore-mentioned DNA or RNA molecules, like siRNA, shRNA, miRNA (or DNA molecules encoding same) and so forth. Also modified forms of these molecules to improve characteristic of these molecules as stability and or specificity are envisaged herein.

[0638] The nucleic acid delivery system according to the present invention may comprise an siRNA. This siRNA is preferably an siRNA specifically targeting an mRNA being upregulated in a lung disease. The nucleic acid delivery system according to the present invention may comprise an shRNA. This shRNA is preferably an shRNA specifically targeting an mRNA being upregulated in a lung disease.

[0639] A "lung disease" according to the present invention can be any lung disease. Preferably, it is a "lung disease" which is associated with malfunction or dissregulation of ATII cells. Examples of such diseases are lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), emphysema and cystic fibrosis [PMID: 22411819, 23134111, 19934355, 16888288, 19335897].

[0640] A "lung cancer" according to the present invention can be any "lung cancer". Preferably, it is a "lung cancer" which is associated with or derived from alveolar type-II epithelial cells (ATII cells). Examples of such "lung cancers" are adenocarcinoma or bronchoalveolar carcinoma. According to a preferred embodiment of the present invention, "lung cancer" is "lung adenocarcinoma".

[0641] The nucleic acid system of the present invention can be used to treat lung cancer, for example, when it comprises an siRNA specifically targeting an mRNA being upregulated in lung cancer. Examples of such mRNAs being upregulated in lung cancer are

[0642] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0643] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0644] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0645] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

[0646] Thus, the siRNAs according to the present invention may be siRNAs targeting said mRNAs being upregulated in lung cancer.

[0647] The present invention relates to a composition comprising (an) siRNA(s) targeting

[0648] i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1;

[0649] ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising the nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2;

[0650] iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; or

[0651] iv) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4; and a fusion protein of a nucleic acid binding molecule (like the polypeptides described herein, such as protamine) and an surface marker (e.g. Itgb2- or Itgb6-)-targeting antibody (e.g. monoclonal antibody or single chain variable fragment).

[0652] Genes can contain single nucleotide polymorphisms (SNPs). The specific transcription factor Em isoform sequences of the present invention encompass (genetic) variants thereof, for example, variants having SNPs. Without deferring from the gist of the present invention, all naturally occurring sequences of the respective isoform independent of the number and nature of the SNPs in said sequence can be used herein. To relate to currently known SNPs, the transcription factor Em isoforms of the present invention are defined such that they contain up to 55 (in the case of GATA6), up to 39 (in the case of NKX2-1), up to 68 (in the case of FOXA2) or up to 34 (in the case of ID2) additions, deletions or substitutions of the nucleic acid sequences defined by SEQ ID NOs: 1, 2, 3 and 4, respectively. Thus, respective Em transcripts of carriers of different nucleotides at the respective SNPs are covered by the present application.

[0653] These "specific transcription factor Em isoform" (like GATA6 Em isoform, NKX2-1 Em isoform, FOXA2 Em isoform and ID2 Em isoform) have been described herein above in detail. These definitions and explanations apply, mutatis mutandis, in this context.

[0654] The person skilled in the art knows how to design siRNAs and shRNAs which specifically target the specific transcription factor Em isoforms of the present invention. Examples of such specific siRNAs and shRNAs targeting the specific transcription factor Em isoforms of the present invention are depicted in Tables 6 and 7.

TABLE-US-00021 TABLE 10 Examples of siRNA sequences for the knockdown of Gata6 Em and Foxa2 Em Gata6 Target Sequence Sense strand siRNA Antisense strand siRNA SEQ ID NO: 58 SEQ ID NO: 41 SEQ ID NO: 43 AATCAGGAGCGCAGGCTGCAG UCAGGAGCGCAGGCUGCAGtt CUGCAGCCUGCGCUCCUGAtt SEQ ID NO: 59 SEQ ID NO: 42 SEQ ID NO: 44 AAGAGGCGCCTCCTCTCTCCT GAGGCGCCUCCUCUCUCCUtt AGGAGAGAGGAGGCGCCUCtt Foxa2 Target Sequence Sense strand siRNA Antisense strand siRNA SEQ ID NO: 60 SEQ ID NO: 45 SEQ ID NO: 46 AAACCGCCATGCACTCGGCTT ACCGCCAUGCACUCGGCUUtt AAGCCGAGUGCAUGGCGGUtt

TABLE-US-00022 TABLE 11 Examples of DNA sequences encoding hairpin sequences from which shRNA sequences are cleaved that can be used for the knockdown of Nkx2-1 Nkx2-1 shHairpin sequence (5'-3') SEQ ID NO: 47 CCGGCCCATGAAGAAGAAAGCAATTCTCGAGAATTGCTTTCTTCTTCATGGGTTTTTG SEQ ID NO: 48 GTACCGGGGGATCATCCTTGTAGATAAACTCGAGTTTATCTACAAGGATGATCCCTTTTTTG SEQ ID NO: 49 CCGGATTCGGAATCAGCTAGCAATTCTCGAGAATTGCTAGCTGATTCCGAATTTTTTG

[0655] The use of corresponding shRNA molecules is envisaged herein (i.e. the shRNA molecules are cleaved from hairpin sequences which are identical to the above DNA sequences of Table 11 with the exception that the "T" residues are replaced by "U" residues).

[0656] The siRNA to be used herein can comprise a nucleic acid molecule comprising at least ten contiguous bases of a sequence as shown in the sequence of SEQ ID NOs 41, 43, 42, 44, 45 or 46. It is to be understood that an siRNA molecule consists of an antisense and a sense strand. For example, an siRNA targeting a GATA6 Em isoform can consist of a nucleic acid molecule comprising at least ten contiguous bases of a sequence as shown in the sequence of SEQ ID NOs 41, and a nucleic acid molecule comprising at least ten contiguous bases of a sequence as shown in the sequence 43. For example, an siRNA targeting a GATA6 Em isoform can consist of a nucleic acid molecule comprising at least ten contiguous bases of a sequence as shown in the sequence of SEQ ID NOs 42, and a nucleic acid molecule comprising at least ten contiguous bases of a sequence as shown in the sequence 44. For example, an siRNA targeting a FOXA2 Em isoform can consist of a nucleic acid molecule comprising at least ten contiguous bases of a sequence as shown in the sequence of SEQ ID NOs 45, and a nucleic acid molecule comprising at least ten contiguous bases of a sequence as shown in the sequence 46.

[0657] Up to 10% of the contiguous bases of the above-mentioned nucleic acid-molecule can be non-complementary. The nucleic acid molecule may further comprise at least one base at the 5' end and/or at least one base at the 3' end. The siRNA to be used herein can consist of a molecule as shown in SEQ ID No. 41 and 43; SEQ ID NO. 42 and 44; or SEQ ID NO. 45 and 46.

[0658] The present invention relates to a kit for the delivery of a nucleic acid into an alveolar type-II epithelial cell comprising any the nucleic acid delivery system. The kit according to the present invention is a kit which contains all the components which are necessary to deliver nucleic acids into alveolar type-II epithelial cells. In particular, the kit may contain a fusion protein of a nucleic acid binding protein and a polypeptide specifically binding to a specific surface marker of alveolar type-II epithelial cells. As an example, the kit may comprise a fusion protein of protamine and a monoclonal antibody or a single chain variable fragment, wherein the antibody or the single chain variable fragment specifically binds to a cell surface marker of alveolar type-II epithelial cells, wherein this cell surface marker of alveolar type-II epithelial cells is preferably selected from the group of proteins consisting of ITGB2, ITGB6, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, AGPAT4, ASS1, CSPG4, and CDH11.

[0659] The present invention relates to the use of the nucleic acid delivery system of the present invention for the transfection of alveolar type-II epithelial cells. In other words, the present invention provides a method for delivering nucleic acid molecules (such as DNA molecules or RNA molecules (e.g. siRNA) into ATII cells, wherein the nucleic acid is bound directly or indirectly (e.g. via a nucleic binding molecule) to a polypeptides binding to a specific surface marker of ATII cells. The nucleic acid delivery system may be used to deliver nucleic acid molecules into healthy or diseased ATII cells (e.g. tumor or cancer cells). The use or method may be employed in vitro, for example as a research tool to deliver nucleic acid molecules into healthy ATII cells.

[0660] The present invention relates to a composition for use in medicine comprising any of the nucleic acid delivery systems or the compositions of the present invention. The composition can be for use in the treatment of a lung disease, like lung cancer. Said lung cancer can be a lung adenocarcinoma or a lung bronchoalveolar carcinoma.

[0661] The present invention relates to a nucleic acid delivery system for the delivery of nucleic acids specifically into an alveolar type-II epithelial cell, wherein said system comprises a polypeptide binding to a specific surface marker of alveolar type-II epithelial cells. Preferably, the nucleic acid system according to the present invention is a non-viral nucleic acid delivery system. In the context of the present invention, the term "non-viral" defines the nucleic acid delivery system as not using viruses for the delivery of the nucleic acid. This does not necessary imply that no viral particles can be detected in the nucleic acid delivery system but only that they are not of functional relevance for the delivery of the nucleic acid of the present invention.

[0662] The present invention relates to a method of treating a subject suffering from a lung disease, like lung cancer, or a subject with an increased risk of suffering from a lung disease, like lung cancer, comprising the step of administering to said subject the nucleic acid delivery system of the present invention. Preferably, said cancer is lung cancer. Even more preferably, said lung cancer is adenocarcinoma or a lung bronchoalveolar carcinoma. The subject according to the present invention is preferably a human.

[0663] The method of treating a subject suffering from cancer or a subject with an increased risk of suffering from cancer may comprise the step of contacting an alveolar type-II epithelial cell of said subject with a nucleic acid delivery system of the present invention.

[0664] The following relates to pharmaceutical compositions which may comprise the nucleic acid delivery system and compositions described and defined herein above.

[0665] The pharmaceutical composition will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient, the site of delivery of the pharmaceutical composition, the method of administration, the scheduling of administration, and other factors known to practitioners. The "effective amount" of the nucleic acid delivery system or the pharmaceutical composition for purposes herein is thus determined by such considerations.

[0666] The skilled person knows that the effective amount of pharmaceutical composition administered to an individual will, inter alia, depend on the nature of the compound. For example, if said compound is a an nucleic acid molecule the total pharmaceutically effective amount of pharmaceutical composition administered parenterally per dose will be in the range of about 1 .mu.g/kg/day to 100 mg/kg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg/kg/day, and most preferably for humans between about 0.01 and 1 mg/kg/day. The presently recommended dose for nucleic acid molecules lies in a range of between 8 and 80 mg per/kg/day. However, this dose may be further decreased subject to therapeutic discretion, in particular if concomittantly certain lipids are applied or if the nucleic acid molecule is subject to certain chemical modifications. If given continuously, the pharmaceutical composition is typically administered at a dose rate of about in/kg/hour to about 40 .mu.g/kg/hour, either by 1-4 injections per day or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution may also be employed. The length of treatment needed to observe changes and the interval following treatment for responses to occur appears to vary depending on the desired effect. The particular amounts may be determined by conventional tests which are well known to the person skilled in the art.

[0667] Pharmaceutical compositions of the invention may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), bucally, or as an oral or nasal spray. Preferably the pharmaceutical compositions of the invention are administered as a spray. The term "pharmaceutical composition" and "composition for use in medicine" and the like can be used interchangeably herein. It is envisaged and preferred herein that the nucleic acid delivery systems and compositions comprising same can be administered by using a spray (like an oral or nasal spry). For example, they can be administered in form of an aerosol that will be inhalated thereby ensuring ATII cell specific targeting. The aerosol contains the nucleic acid delivery provided herein.

[0668] Pharmaceutical compositions of the invention preferably comprise a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

[0669] The pharmaceutical composition is also suitably administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or mirocapsules. Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22:547-556 (1983)), poly (2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167-277 (1981), and R. Langer, Chem. Tech. 12:98-105 (1982)), ethylene vinyl acetate (R. Langer et al., Id.) or poly-D-(-)-3-hydroxybutyric acid (EP 133,988). Sustained release pharmaceutical composition also include liposomally entrapped compound. Liposomes containing the pharmaceutical composition are prepared by methods known per se: DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal therapy.

[0670] For parenteral administration, the pharmaceutical composition is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.

[0671] Generally, the formulations are prepared by contacting the components of the pharmaceutical composition uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes. The carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) (poly)peptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, manose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and/or nonionic surfactants such as polysorbates, poloxamers, or PEG.

[0672] The components of the pharmaceutical composition to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutic components of the pharmaceutical composition generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0673] The components of the pharmaceutical composition ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-ml vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous solution, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized compound(s) using bacteriostatic Water-for-Injection.

[0674] The nucleic acid molecules may be delivered as follows: for example, the nucleic acid molecules can be injected directly into a cell, such as by microinjection. Alternatively, the molecules can be contacted with a cell, preferably aided by a delivery system as provided herein. Further useful delivery systems include, for example, liposomes and charged lipids. Liposomes typically encapsulate oligonucleotide molecules within their aqueous center. Charged lipids generally form lipid-oligonucleotide molecule complexes as a result of opposing charges. Yet, the delivery by internalization via the herein provided and defined surface markers is preferred herein.

[0675] These liposomes-oligonucleotide molecule complexes or lipid-oligonucleotide molecule complexes are usually internalized in cells by endocytosis. The liposomes or charged lipids generally comprise helper lipids which disrupt the endosomal membrane and release the oligonucleotide molecules.

[0676] Other methods for introducing nucleic acid molecules into a cell include use of delivery vehicles, such as dendrimers, biodegradable polymers, polymers of amino acids, polymers of sugars, and oligonucleotide-binding nanoparticles. In addition, pluoronic gel as a depot reservoir can be used to deliver the anti-microRNA oligonucleotide molecules over a prolonged period. The above methods are described in, for example, Hughes et al., Drug Discovery Today 6, 303-315 (2001); Liang et al. Eur. J. Biochem. 269 5753-5758 (2002); and Becker et al., In Antisense Technology in the Central Nervous System (Leslie, R. A., Hunter, A. J. & Robertson, H. A., eds), pp. 147-157, Oxford University Press.

[0677] Targeting of nucleic acid molecules to a particular cell can be performed by any method known to those skilled in the art. For example, nucleic acid molecules can be conjugated to an antibody or ligand specifically recognized by receptors on the cell.

[0678] The terms "treatment", "treating" and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing fibrosis or symptom thereof and/or may be therapeutic in terms of partially or completely curing a lung disease and/or adverse effect attributed to a lung disease. The term "treatment" as used herein covers any treatment of a disease in a subject and includes: (a) preventing a lung disease from occurring in a subject which may be predisposed to a lung disease; (b) inhibiting a lung disease, i.e. arresting its development; or (c) relieving lung disease, i.e. causing regression of a lung disease.

[0679] The nucleic acid molecule can be introduced into the mammal by any method known to those in the art. For example, the above described methods for introducing the nucleic acid molecule into a cell can also be used for introducing the molecules into a mammal.

[0680] It is envisaged herein that the above described and defined nucleic acid molecules can also be applied in combination with conventional therapies. For example, one or more additional pharpharmaceutical agents can be used. Non-limiting examples of additional pharmaceutical agents are diuretics (e.g. sprionolactone, eplerenone, furosemide), inotropes (e.g. dobutamine, milrinone), digoxin, vasodilators, angiotensin II converting enzyme (ACE) inhibitors (e.g. are captopril, enalapril, lisinopril, benazepril, quinapril, fosinopril, and ramipril), angiotensin II receptor blockers (ARB) (e.g. candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, eprosartan), calcium channel blockers, isosorbide dinitrate, hydralazine, nitrates (e.g. isosorbide mononitrate, isosorbide dinitrate), hydralazine, beta-blockers (e.g. carvedilol, metoprolol), and natriuretic peptides (e.g. nesiritide).

[0681] An additional pharmaceutical agent may also enhance the body's immune system, and may, therefore, include low-dose cyclophosphamide, thymostimulin, vitamins and nutritional supplements (e.g., antioxidants, including vitamins A, C, E, beta-carotene, zinc, selenium, glutathione, coenzyme Q-10 and echinacea), and vaccines, e.g., the immunostimulating complex (ISCOM), which comprises a vaccine formulation that combines a multimeric presentation of antigen and an adjuvant.

[0682] The additional therapy can also be selected to treat or ameliorate a side effect of one or more pharmaceutical compositions of the present invention. Such side effects include, without limitation, injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, and myopathies. For example, increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality. For example, increased bilirubin may indicate liver toxicity or liver function abnormality.

[0683] Moreover, one or more pharmaceutical compositions of the present invention and one or more other pharmaceutical agents can be administered at the same time. The one or more pharmaceutical compositions of the present invention and one or more other pharmaceutical agents can also be prepared together in a single formulation.

[0684] While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. It will be understood that changes and modifications may be made by those of ordinary skill within the scope and spirit of the items and claims provided herein. In particular, the present invention covers further embodiments with any combination of features from different embodiments described above and below.

[0685] The invention also covers all further features shown in the figures individually although they may not have been described in the afore or following description. Also, single alternatives of the embodiments described in the figures and the description and single alternatives of features thereof can be disclaimed from the subject matter of the other aspect of the invention.

[0686] Furthermore, in the claims the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single unit may fulfill the functions of several features recited in the claims. The terms "essentially", "about", "approximately" and the like in connection with an attribute or a value particularly also define exactly the attribute or exactly the value, respectively. Any reference signs in the claims should not be construed as limiting the scope.

[0687] As used herein, the terms "comprising" and "including" or grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof. This term encompasses the terms "consisting of" and "consisting essentially of." Thus, the terms "comprising"/"including"/"having" mean that any further component (or likewise features, integers, steps and the like) can be present.

[0688] The term "consisting of" means that no further component (or likewise features, integers, steps and the like) can be present.

[0689] The term "consisting essentially of" or grammatical variants thereof when used herein are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof but only if the additional features, integers, steps, components or groups thereof do not materially alter the basic and novel characteristics of the claimed composition, device or method.

[0690] Thus, the term "consisting essentially or means that specific further components (or likewise features, integers, steps and the like) can be present, namely those not materially affecting the essential characteristics of" the composition, device or method. In other words, the term "consisting essentially of" (which can be interchangeably used herein with the term "comprising substantially"), allows the presence of other components in the composition, device or method in addition to the mandatory components (or likewise features, integers, steps and the like), provided that the essential characteristics of the device or method are not materially affected by the presence of other components.

[0691] As used herein the term "about" refers to .+-.10%.

[0692] The present invention is also illustrated by the following figures. The figures show:

[0693] FIG. 1: Lung relevant genes share similar structure.

[0694] (A) In silico analysis of the indicated genes shows an identical arrangement with two promoters (hatched boxes), surrounded by CpG islands (), driving the expression of two distinct transcripts (exons as black boxes, shown in right panel; coding region in white). Gata6, GATA Binding Factor 6; Nkx2-1, also known as Ttf1, Thyroid transcription factor 1; Foxa2, Foxhead box protein A2; 1d2, Inhibitor of DNA binding 2; Em, Embryonic; Ad, Adult; Var1, Variant 1; Var2, Variant 2. (B) The two transcript isoforms are differentially regulated during embryonic lung development and show complementary expression. Expression of both isoforms of each gene was analyzed by quantitative reverse transcriptase (q-RT) PCR in embryonic lungs isolated at different days post coitum (dpc; 11, 12, 13 and 14). Data are represented as mean+/- standard error mean (s.e.m.), n=5

[0695] FIG. 2: High expression of embryonic isoforms in human lung cancer samples as well as their detection in mouse blood at early stage of tumor initiation supports the potential of the Em-isoforms as markers for early lung cancer diagnosis.

[0696] (A) Em-isoforms are predominantly expressed in human lung cancer cell lines. Isoform specific expression analysis of the indicated genes by qRT-PCR in human lung adenocarcinoma (A549, A427) and bronchoalveolar carcinoma (H322) cell lines. Data are represented as mean+/-standard error mean (s.e.m.), n=5 (B) Em-isoforms are highly expressed in human lung cancer tissue. Isoform specific expression was monitored by qRT-PCR after total RNA isolation from human lung tumor and normal lung cryosections. Data are represented as in A. (C) Embryonic transcripts of the indicated genes were detected in blood of mice at early stage of tumor initiation. Isoforom specific expression analysis of the indicated genes by qRT-PCR in blood isolated from mouse hearts. Data are represented as in A.

[0697] FIG. 3: Embryonic isoforms mediate oncogenic transformation in cell lines.

[0698] (A) MLE-12 cells transfected with Gata6 Em or Nkx2-1 Em are highly proliferative. Cells were analyzed by immunofluorescence microscopy after immunostaining with MKI67- or MYC-specific antibodies. Draq5, nuclear staining. Scale bars, 20 .mu.m. (B) Enhanced cell migration in MLE-12 cells transfected with Gata6 Em and Nkx2-1 Em. Scratch was made in 100% confluent monolayer culture 24 hours after transfection. Cells were observed by bright field microscopy every 6 hours after making the scratch, till the scratch was filled. Scale bar, 200 .mu.m. (C) Increased colony formation in MLE-12 cells stable transfected with Gata6 Em. Control (Ctrl) and Gata6 Em stable transfected cells were plated at a density of 500 cells per well. Cells were cultured till colonies were observed (2 weeks), fixed in 4% Paraformaldehyde, stained by Haematoxylin and colonies counted. Data are represented as mean+/-standard error mean (s.e.m.), n=3. (D) MLE-12 cells stable transfected with Gata6 Em undergo epithelial mesenchymal transition (EMT). Analysis of EMT by expression analysis of Snail homolog 1 (Snail), alpha smooth muscle actin (Acta2) and POU domain class 5 transcription factor 1 (Pou5f1) was monitored by qRT-PCR after total RNA isolation from MLE-12 cells stable transfected with Gata6 Em. Data are represented as in FIG. 1B.

[0699] FIG. 4: Embryonic isoforms are oncogenic

[0700] (A) Forced expression of Em-isoforms in adult lung induced hyperplasia. Haematoxylin and Eosin staining on sections of mice lungs in vivo transfected with control (Ctrl), isoform specific expression constructs (Em or Ad, Gata6 or Nkx2-1). Scale bars, 50 .mu.m. (B) Isoform specific in vivo overexpression of Gata6 and Nkx2-1 was performed as in A. Isoform specific expression analysis by qRT-PCR was performed on total lung RNA 5 weeks after transfection. Data are represented as in FIG. 1B

[0701] FIG. 5: Gata6 Em-isoform induces adenocarcinomas in adult lung

[0702] (A) Gata6 Em GOF specifically increased expression of markers for cancer. Expression analysis of the indicated genes by qRT-PCR after in vivo transfection of adult lung with the indicated constructs. Cdkn1, Cyclin dependent kinase 1 (proliferation marker); Vegf, Vascular endothelial growth factor; Plgf, Placental growth factor (angiogenesis markers); Pdpk1, 3-phosphoinositide dependent protein kinase 1 (metabolic/migration marker) and Hif2, Hypoxia inducible factor 2 (Hypoxia marker). Data are represented as mean+/-standard error mean (s.e.m.), n=5. (B-D) Atypical hyperplasia observed in adult lungs after overexpression of Em isoforms consists of small clusters of dedifferentiated `stem` cells which are epithelial and are positive for lung adenocarcinoma diagnostic markers. Sections of treated lungs were analyzed by confocal microscopy after immunostaining with POU5F1, Pan-cytokeratin (KRT), NapsinA (NAPSA) and tumor protein 63 (TRP63)-specific antibodies. DAPI, nuclear staining. Scale bars, 50 .mu.m.

[0703] FIG. 6: Efficency of siRNA mediated knockdown of Gata6 Em and Nkx2-1 Em

[0704] (A) Isoform specific siRNAs can be used to exclusively target the Embryonic isoform transcripts. Expression analysis of both isoforms of Gata6 and Nkx2-1 in MLE-12 cells 48 hours after transfection with indicated siRNA or shDNA plasmids. Additional siRNA/shRNA sequences tested are listed (B). Data are represented as in FIG. 1B.

[0705] FIG. 7: Targeted knock down of Gata6 Em decreases tumor metastasis

[0706] (A) Schematic representation of experiment design. Lewis Lung Carcinoma (LLC) cells were injected into the mouse tail vein at a density of 1 million cells. Three days after injection, control (siCtrl) or Gata6 Em specific (siGata6) siRNA was administered orotracheally. Lungs were harvested 21 days after injection and tumor foci were monitored. (B and C) Knockdown of Gata6 Em reduces lung tumor metastasis. (B) Images of lungs treated as in A. Arrows indicate tumor nodules. Scale bars, 1 mm. (C) Haematoxylin Eosin staining of mice lungs treated as in A. Scale bars, 100 .mu.m.

[0707] FIG. 8: Gata6 Ad is specifically expressed in lung fibrosis

[0708] (A) Schematic representation of experiment design. Mice were treated with 2.5 U/kg body weight of Bleomycin. The lungs were harvested for RNA isolation and histology 21 days after treatment. (B) Bleomycin treatment induced lung fibrosis. Masson's Trichrome staining of mouse lungs 21 days after Bleomycin treatment. Scale bar, 2 mm (upper panel) 50 .mu.m (lower panel). (C) Gata6 Ad expression increased specifically in fibrotic lungs. Expression of both isoforms of Gata6 was monitored by qRT-PCR 21 days after Bleomycin treatment. Data are represented as mean+/-standard error mean (s.e.m.), n=3

[0709] FIG. 9: Oncogenic Kras mutant G12D specifically induced the expression of the embryonic isoforms of Gata6 and Nkx2-1

[0710] MLE-12 cells were transfected with control (Ctrl) or KrasG12D plasmid DNA. Expression of isoform specific transcripts was monitored by qRT-PCR 48 hours after transfection. Data are represented as mean+/-standard error mean (s.e.m.), n=3

[0711] FIG. 10: Gata6 Em expression is epigenetically regulated.

[0712] (A) Specific induction of Gata6 Em after DNA demethlyation. Passive DNA demethylation was induced in MLE-12 cells by 5'Azadeoxycytidine (Aza) treatment. Isoform specific expression of Gata6 was analysed by qRT-PCR 48 hours after AZA treatment. (B) Aza treatment induces Gata6 Em promoter demethylation. MLE-12 cells were treated as in A. DNA methylation was analyzed by Methylation Sensitive (MS) PCR 48 hours after Aza treatment. (C) Active histone marks accumulated in Gata6 Em promoter after Aza treatment. MLE-12 cells were treated as in A. Chromatin Immunoprecipitation (ChIP) was performed 48 hours after Aza treatment with antibodies against H3K4me2-me3, H3K9Ac, WDR5 and p300. Enrichment was monitored by qPCR after DNA purification. Data are represented as mean+/-standard error mean (s.e.m.), n=3 (A-C)

[0713] FIG. 11: Alignment of the Em and the Ad isoform of GATA6, NKX2-1, FOXA2 and

[0714] ID2 Sequence alignment of Em and Ad isoforms of GATA6, NKX2-1, FOXA2 and ID2 was performed for both, mouse (Mus musculus) and human (Homo sapiens) sequences. Nucleotide sequences were obtained from NCBI or from its public mRNA database Aceview. Protein sequences were obtained from Uniprot or NCBI. The sequences were aligned pair-wise using Needleman-Wunsch Algorithm for global alignment (with free and gaps). The settings used for generating these alignments were: Cost Matrix: 65% similarity (5.0/-4.0); Gap open penalty: 14; Gap extension penalty: 0. All alignments were performed with Geneious (Geneious version R6 created by Biomatters. Available from www.geneious.com).

[0715] FIG. 12: Two distinct isoforms of GATA6 and NKX2-1.

[0716] (A) Schematic representation of the gene structure of human GATA6 and NKX2-1. In silico analysis of the indicated genes (upper panel) shows an identical arrangement with two promoters (grey boxes) driving the expression of two distinct transcripts (exons as black boxes; coding region in white, lower panel). GATA6, GATA Binding Factor 6; NKX2-1, also known as Ttf1, Thyroid transcription factor 1; Em, Embryonic; Ad, Adult. (B) The two transcript isoforms are differentially regulated during lung cancer and show complementary expression. Isoform specific gene expression analysis was performed for both genes by quantitative reverse transcriptase polymerase chain reaction (q-RT PCR) in healthy donor lungs (Ctrl) and lung cancer cell lines, A549, A427 (Adenocarcinoma) and H322 (Bronchoalveolar carcinoma). Rel nor exp, relative expression normalized to TUBA1A. Error bars, standard error mean (s.e.m.), n=5. (C) The two transcript isoforms encode two distinct proteins. Expression of both isoforms at the protein level was analyzed by western blot in A549 cell lines using antibodies against indicated proteins. TUBA1A, Tubulin, alpha 1a. (D) High expression of Em isoform of Gata6 and Nkx2.1 in lung cancer. Isoform specific expression analysis was performed in healthy mouse lungs (Ctrl) and lung tumors that developed in mice after tail vein injection of Lewis lung carcinoma (LLC1) cell lines (Tum1, 2), n=5 mice each and Tum1, 2 represent tumors from two different mice. Data are represented as in (B).

[0717] FIG. 13: High expression of Em isoform in human lung cancer tissues.

[0718] (A) Isoform specific expression of GATA6 and NKX2-1 was monitored by qRT-PCR after total RNA isolation from human lung tumor and normal lung formalin fixed paraffin embedded (FFPE) sections. The Em/Ad ratio for both genes is plotted. Samples are normalized to TUB1A1. Each point represents one sample, horizontal line in the middle represents the mean and the error bars represent the standard error mean (s.e.m). n=20 Healthy, n=39 Tumor. P values after one-way ANOVA. (B) Unadjusted Receiver-Operating-Characteristics (ROC) Curves for GATA6 and NKX2-1. Sensitivity and 1 minus specificity (ROC curves) are shown for different values for Em/Ad ratio of GATA6 and NKX2-1. (C and D) High Em/Ad ratio is conserved among ethnic groups (C) and gender (D). CHB, Han Chinese in Beijing; CEU, Utah residents with ancestry from northern and western Europe; MXL, Mexican ancestry in Los Angeles. n=10 Healthy, 28 Tumor (CHB); n=7 Healthy, 3 Tumor (CEU); n=3 Healthy, 14 Tumor (MXL); n=5 Healthy, 15 Tumor (Male) and n=2 Healthy and 16 Tumor (Female); Data are represented as in (A). The filled triangles in (C) (MXL) represent NSCLC tumor samples. The empty triangle in (C) (MXL) represents a small cell lung cancer sample. (E) Expression of Em isoform correlates with tumor grade. Ratio of Em/Ad isoform was monitored in lung cancer biopsies of Grade I, II and III. n=10 Healthy, n=12 Grade I, n=14 Grade II and 2 Grade III. Samples were staged according to the TNM Classification recommended by the American Joint Committee on Cancer. Data are represented as in (A).

[0719] FIG. 14: Noninvasive lung cancer diagnosis using Exhaled breath condensate (EBC).

[0720] (A) Exhaled breath condensate (EBC) as a promising source of biomarkers for lung diseases. Water vapour is rapidly diffused from the airway lining fluid (both bronchial and alveolar) into the expiratory flow. Droplet formation (nonvolatile biomarkers) takes place in the airway lining fluid, while respiratory gases (volatile biomarkers) are from both the airspaces and the airways. Adapted from Effros et al. (2012) Am J Respir Crit Care Med. 185(8): 803-804) (B) RTube is more suitable for RNA isolation as compared to TurboDECCS. Two main EBC collection devices were compared for the total RNA yield (y-axis, ng) obtained using the QIAGEN RNeasy Micro column using 500 .mu.l EBC as starting material. Data are represented as mean.+-.s.e.m, n=6. (C) 500 .mu.l of EBC is optimal for RNA isolation. Total RNA isolation with the RNeasy Micro kit was compared using 200, 350, 500 and 1000 .mu.l starting EBC volume. Data are represented as in (B), n=3.

[0721] FIG. 15: EBC based lung cancer diagnosis correlates with classical methods.

[0722] Representative pictures of (A) chest X-ray and (B) low-dose helical computed tomography (CT) scans for patients with lung cancer. (C) Immunohistochemistry analysis for adjacent normal (upper panel) and tumor (lower panel) from a lung cancer patient sample with the indicated antibodies. PAN-KRT, Pan Cytokeratin; NKX2-1, also known as TTF1, Thyroid transcription factor 1; DAPI, nucleus. Scale bar, 10 .mu.m. (D) Expression analysis of known tumor suppressor and oncogenes in EBCs of healthy donors and tumor patients. CDKNA2, also known as P16, cyclin-dependent kinase inhibitor 2A; TP53, tumor protein p53; MYC, v-myc avian myelocytomatosis viral oncogene homolog. Data are represented as in FIG. 13.

[0723] FIG. 16: Specific PCR amplification of both isoforms of GATA6. (A) Amplification efficiency for each primer pair was calculated using serial dilutions of the cDNA template. Primer efficiency was assessed by plotting the cycle threshold values (Ct, y-axis) against the logarithm (base 10) of the fold dilution (log (Quantity), x-axis). Primer efficiency was calculated using the slope of the linear function. Data points represent mean Ct values of triplicates. (B) Dissociation curve analysis of the PCR products was performed by constantly monitoring the flurorescence with increasing temperatures from 60.degree. C. to 95.degree. C. Melt curves were generated by plotting the negative first derivative of the fluorescence (-d/dT (Fluorescence) 520 nm) versus temperature (degree Celsius, .degree. C.). (C) Specific PCR amplification was also demonstrated by agarose gel electrophoresis. PCR products after quantitative RT-PCR were analyzed by agarose gel electrophoresis. +, specific PCR reaction using EBC template; -, no RT control; M, 100 bp DNA ladder. (D) Sequencing of the PCR products of GATA6 Em and Ad demonstrates specific PCR amplification of both isoforms using EBC as template. Five clones for each primer pair (GATA6 Em and Ad) were sequenced and aligned to the reference sequence (top row, yellow highlighted). Sequence similarities are represented as dots.

[0724] FIG. 17: Specific PCR amplification of both isoforms of NKX2-1.

[0725] (A) Amplification efficiency for each primer pair was calculated using serial dilutions of the cDNA template. Primer efficiency was assessed by plotting the cycle threshold values (Ct, y-axis) against the logarithm (base 10) of the fold dilution (log (Quantity), x-axis). Primer efficiency was calculated using the slope of the linear function. Data points represent mean Ct values of triplicates. (B) Dissociation curve analysis of the PCR products was performed by constantly monitoring the flurorescence with increasing temperatures from 60.degree. C. to 95.degree. C. Melt curves were generated by plotting the negative first derivative of the fluorescence (-d/dT (Fluorescence) 520 nm) versus temperature (degree Celsius, .degree. C.). (C) Specific PCR amplification was also demonstrated by agarose gel electrophoresis. PCR products after quantitative RT-PCR were analyzed by agarose gel electrophoresis. +, specific PCR reaction using EBC template; -, no RT control; M, 100 bp DNA ladder. (D) Sequencing of the PCR products of NKX2-1 Em and Ad demonstrates specific PCR amplification of both isoforms using EBC as template. Five clones for each primer pair (NKX2-1 Em and Ad) were sequenced and aligned to the reference sequence (top row, yellow highlighted). Sequence similarities are represented as dots.

[0726] FIG. 18--Loss-of-function (LOF) of embryonic Gata6 counteracts lung tumor formation.

[0727] (A) SiRNA mediated Gata6 depletion is isoform-specific and efficient. MLE-12 cells were transiently transfected with control siRNA (Ctrl) or siRNA specific against Guta6 embryonic (Em) or adult (Ad) isoforms. Isoform specific Gata6 expression analysis was performed by qRT-PCR. Rel nor exp Gata6, relative expression of Gata6 normalized to Tuba1a, n=3, Asterix, P values after one-way ANOVA, ***P<0.001; **P<0.01; *P<0.05. (B) Gata6 Em specific LOF results in reduced migration of MLE-12 cells. MLE-12 cells were transfected as in A. Transfected cells were grown till a confluent monolayer was formed and a scratch (dashed lines) was made in the center (0 hr). The closure of the scratch or wound healing by the growth of a confluent monolayer of cells was monitored 24 hr later. siCtrl, control siRNA; siGata6 Em and siGata6 Ad, embryonic and adult isoform specific siRNAs. (C) Orotracheal administration of siRNA results in Gata6 Em specific loss of function in adult mouse lung. Lungs of mice that were orotrachealy administered with siCtrl and siGata6 Em were harvested for total lung RNA isolation. Isoform specific expression analysis was performed by qRT-PCR. Data are represented as in A. (D) Macroscopic tumor analysis revealed significant reduction of tumor formation in mice treated with siGata6 Em. Lungs were isolated from mice injected with LLC1 cells and treated with siCtrl or siGata6 as in C. Macroscopic surface tumors (Surface tum, arrows) were counted and percentage tumor reduction was analyzed. Scale bar, 1 mm; n=5; P values as in A.

[0728] FIG. 19. Schematic representation of the lung structure.

[0729] The lung consists of different structural regions organized along a proximal-distal axis. Each of these regions is characterized by specialized cell types of epithelial or mesenchymal origin (listed in the square). Different tissue-resident lung-endogenous progenitor cells (underlined in the list) are located in specific regions along the proximal-distal axis of the airways. They are responsible for homeostatic turnover and repair after injury. Alveolar type II (ATII) cells represent one of these regional progenitor cell populations and are located in the alveoli. Sm. Mus., smooth muscle cells; Clarav, variant Clara cells; PNEC, pulmonary neuroendocrine cells; BASC, bronchioalveolar stem cells; AT I, alveolar type I cells.

[0730] FIG. 20.

[0731] (A) Schematic representation of experimental procedure. Spike-in based relative quantification of ATII versus MLE-12 cells using (13)C6-lysine labeled lung (Lys-6 labeled, heavy labeled lung) as standard. (B) Quality analysis of membrane protein isolation. Distribution of Gene Ontology cellular component (GOCC) terms based analysis of identified proteins after mass spectrometric measurement. (C) Calculation of direct abundance ratio between MLE-12 and ATII cells (MLE-12/ATII). (D) (Top) Histogram of spike-in SILAC-ratios (log 2) between heavy labeled lung and ATII (right) or MLE-12 (left) cells. (Bottom) Histogram of direct ratio between MLE-12 versus ATII cells (MLE-12/ATII, log 2, left) and the direct ratio plotted against intensity (log 10, right).

[0732] FIG. 21.

[0733] (A) Table of selected proteins enriched in ATII cells. (B) MS spectra of ITGB2 specific SILAC-pairs derived from ATII or MLE-12 cells mixed with labeled heavy lung. H, heavy, L, light; N., number; n.d., not determined; m/z, xyz

[0734] FIG. 22. Identification of potential ATII cell specific membrane proteins.

[0735] (A) Scatter plot between membrane protein abundance ratio (MLE-12/ATII) and gene expression ratio (MLE-12/ATII). Proteins enriched in the membrane of ATII cells are indicated in the marked section and listed in the table (B). Prot Abud, protein abundance; Gene Exp, gene expression.

[0736] FIG. 23. Integrin beta 2 and 6 are membrane proteins of a sub-population of alveolar type II cells.

[0737] (A) Itgb2 and Itgb6 are specifically expressed in ATII cells. Expression of the indicated genes was analyzed in different cell lines and in adult lung by qRT-PCR. Gene expression was normalized after Gapdh. Data are represented as mean.+-.s.e.m. (n=6). (B) ITGB2 and ITGB6 are ATII cells specific proteins. Protein extracts of different cell lines, adult lung and spleen were analyzed by western blot using antibodies specific for the indicated proteins. CD14 and CD45 were used as controls for blood cells specific antigens. LMNB1, Lamin B1, loading control. (C) A sub-population of alveolar type II cells is positive for ITGB2 or ITGB6. Cell suspensions of adult lung were analyzed by flow cytometry after single (top and middle) or double (bottom) immunostaining using SFTPC- and either ITGB2- or ITGB6-specific antibodies. The numbers indicate the percentage of positive stained cells in the relevant quadrants. (D) SFTPC and ITGB2 or ITGB6 co-localized in alveolar type II cells. Confocal microscopy of isolated alveolar type II cells (left) and adult lung sections (middle and right) after double immunostaining using SFTPC- and either ITGB2- or ITGB6-specific antibodies. Nuclear staining with Draq5. Squares show regions presented at higher magnification on the right. Scale bars, 20 um.

[0738] FIG. 24. Integrin beta 2 antagonizes WNT signaling pathway.

[0739] (A) WNT signaling pathway related proteins are enriched in the membrane of ATII cells. Schematic representation of Gene Ontology biological process (GOBP) terms based analysis of identified proteins after mass spectrometric measurement using the GORILLA online-tool (Eden, BMC Bioinformatics, 2009). The color represents the frequency of ATII enriched membrane proteins involved in the indicated biological processes (red, high; orange, middle; white, low). (B) Itgb2 knockout (Itgb2-/-) increased activated-beta-catenin immunostaining (ABC) in adult lung. Sections of adult lung of wild type (WT) and Itgb2-/- mice were analyzed by confocal microscopy after immunostaining using ABC specific antibodies. Nuclear staining with Draq5. Scale bars, 20 .mu.m. (C) Quantification of ABC positive cells in adult lung of WT and Itgb2-/-mice after immunostaining as in B. Axis of ordinates show percentage of ABC positive cells relative to total counted cells. Data are represented as mean.+-.s.e.m, (n=3). Asterisks, P values after one-way ANOVA, ***P<0.001; **P<0.01; *P<0.05 (D) Itgb2 knockout enhanced expression of canonical WNT pathway markers. Expression analysis of the indicated genes by qRT-PCR in adult lung of WT and Itgb2-/- mice. Data are represented as mean.+-.s.e.m. (n=3). Asterisks as in C. (E) Itgb2 knockout increased in adult lung the level of proteins encoded by genes that are targets of WNT signaling. Lung protein extracts from WT or Itgb2-/- mice were analyzed by western blot using antibodies specific for the indicated proteins. (F) Itgb2 gain-of-function antagonized the positive effect of lithium chloride (LiCl) on expression of canonical Wnt targets. Expression analysis of the indicated genes by qRT-PCR in MLE-12 cells that were untreated (UTr) or treated (Tr) with LiCl and transfected with either control (-) or mouse Itgb2 expression plasmid as indicated. Data are represented as mean.+-.s.e.m. (n=3). Asterisks as in C.

[0740] FIG. 25:

[0741] (A) Schematic representation of experiment design. Sftpc-rtTA/TetOP-Cre//TK-LoxP-LacZ-LoxP-GFP triple transgenic mice were treated with Control (Ctrl) or Gata6 Em expression vectors as in FIG. 10. 3 days after the first treatment, doxycycline was administered via water. After 7 weeks, lungs were isolated and single cell homogenate was made and following negative selection for blood cells using CD16, CD45/32 antibodies, a pupe population of lung epithelial cells was obtained. These cells were cultured in low attachment dishes in serum free conditions, supplemented with basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and heparin. (B) Diagrammatic representation of the transgenic mice. Surfactant protein C (SftpC) promoter drives the expression of rtTA which in the presence of doxyclycine binds to the Tet operator (Tet OP) and activates downstream expression of Cre recombinase (Cre). Cre recombinase is essential for homologous recombination at the LoxP sites, resulting in the deletion of the LacZ gene, and the expression of EGFP in SftpC expressing cells.

[0742] FIG. 26: Gata6 Em Induced hyperplasia originates from SFTPC positive cells.

[0743] Isolated primary cultures of Gata6 Em treated lungs form clusters of cells within 10 days of culture as compared to Ctrl treated lungs (Left panel). These clusters of cells express EGFP. Following subsequent dissociation and replacing, these clusters were able to maintain in culture for 4 passages and continuously expressed EGFP (Right panel). Scale 200m.

[0744] A number of documents including patent applications, manufacturer's manuals and scientific publications are cited herein. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0745] The present invention is additionally described by way of the following illustrative non-limiting examples that provide a better understanding of the present invention and of its many advantages. The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques used in the present invention to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1: Materials and Methods

In Silico Analysis of Gene Structure

[0746] Genomic sequences for lung relevant genes (Gata6, Nkx2-1, Foxa2 and Id2) were obtained from the NCBI Gene database. Sequences analysed for promoter identification and CpG island analysis included up to 5 kb upstream of the transcription start site. Promoters were predicted using WWW Promoter Scan online tool using the PROSCAN Version 1.7 Suite of programs (see Prestridge (1995) Journal of Molecular Biology 249: 923-932). Promoters chosen for further analysis had a score greater than 60 based on transcription factor binding sites and RNA Pol II eukaryotic promoter sequences. The EMBL online tool, CpG Plot (http://www.ebi.ac.uk/Tools/emboss/cpgplot/) was used to identify CpG islands surrounding the identified or known promoter sequences. The CpG islands were identified as regions containing more than 50% CG content over a minimum region of 200 bp. Promoter predictions were then compared to mRNA sequences for these genes obtained from Aceview (Thierry-Mieg (2006) Genome Biology 7 (Suppl 1):s12) which provides a comprehensive and non-redundant sequence representation of all human and mouse mRNA sequences (mRNAs from GenBank or RefSeq, and single pass cDNA sequences from dbEST and Trace). Isoforms that were identified based on mRNA sequences corresponding to predicted promoters with CpG islands at their 5' end were taken for further analysis.

TABLE-US-00023 TABLE 1 Accession Numbers Gene Mouse Human Gata6, GATA6 NC_000084.6 NC 000018.9 (11052510 . . . 11085635) (19749404 . . . 19782491) Nkx2-1, NKX2-1 NC_000078.6 NC_000014.8 (56531935 . . . 56536908, (36985602 . . . 36989430, complement) complement) Foxa2, FOXA2 NC_000068.7 NC_000020.10 (148042878 . . . 148046969, (22561642 . . . 22566101, complement) complement) Id2, ID2 NC_000078.6 NC_000002.11 (25093799 . . . 25096092, (8822113 . . . 8824583) complement)

DNA Constructs

[0747] Expression plasmid for Gata6 Em was purchased from Origene (MR222974) in vector pCMV6-Entry containing a Myc and DDK tag. The Gata6 Ad was PCR amplified using the embryonic isoform as template and sub cloned into pcDNA3.1 Myc His B (Invitrogen). The Nkx2-1 Em was purchased from Addgene (Plasmid 15540) and subcloned into pCS2-Myc. The Nkx2-1 Ad was PCR amplified and cloned into pcDNA3.1 Myc His A (Invitrogen).

Cell Culture

[0748] Cell lines used in this study were A549 (CCL-185), A427 (HTB-53), H322 and MLE-12 (CRL-2110). Cell lines were cultured in medium and conditions recommended by the American Type Culture Collection (ATCC). Cells were used for the preparation of RNA (QIAGEN RNeasy plus mini kit).

[0749] MLE-12 cells were transfected using Lipofectamine 2000 (Invitrogen) with the expression vectors for Gata6 Em and Nkx2-1 Em in a ratio of 1:2 DNA:Lipofectamine. The cells were washed and the medium was changed on the following day. For the generation of stable transfected cells, 48 hours after transfection, the cells were plated at clonal density and selection medium supplemented with 1 mg/ml G418 (Sigma) was added. Cells were maintained in selection medium for subsequent passages.

In Vitro Scratch Assay

[0750] The in vitro scratch assay was performed as previously described (Liang C C et al., (2007) Nat Protoc. 2007; 2(2): 329-33). Briefly, MLE-12 cells were transfected with Gata6 Em, Nkx2-1 Em and Control plasmids as above. The cells were grown at 37.degree. C. till they reached 100% confluence to form a monolayer. A p200 pipet tip was used to create a scratch of the cell monolayer. The plate was then washed to remove the floating cells and the medium was replaced. The cells were then observed after every 6 hours to check migration.

Colony Formation Assay

[0751] For the clonogenecity assay, control and Gata6 Em stable transfected cells were trypsinized with 0.005% trypsin and counted. Cells were plated at a density of 500 and 1000 cells/well of a 12 well plate in medium supplemented with 1 mg/ml G418 (Sigma-Aldrich). The total number of colonies was counted after 2 weeks following Haematoxylin staining.

RNA Isolation and Expression Analysis

[0752] Timed pregnant (C57B16 WT) mice were sacrificed on post coitum days 11.5, 12.5, 13.5 and 14.5. Lungs were dissected from these embryos, as previously described. Total RNA was isolated from 5 lungs for each stage using the RNeasy plus mini kit (Qiagen). Human lung tumor tissues were obtained as cryoblocks. Six sections of 10 .mu.m were used for total RNA isolation with the RNeasy plus micro kit (Qiagen). The High Capacity cDNA Reverse Transcription kit (Applied Biosystem) was used for cDNA synthesis according to manufacturer's instructions. The PCR results were normalized with respect to the housekeeping gene Gapdh. Quantitative real time PCR reactions were performed using SYBR.RTM. Green on the Step One plus Real-time PCR system (Applied Biosystem).

Table 2: Primer Sequences

TABLE-US-00024

[0753] Primers for Human Primers for Mouse Primers for Human (5' .fwdarw. 3') (For RNA from Gene (5' .fwdarw. 3') (5' .fwdarw. 3') tissue sections) HPRT Fwd TGACCTTGATTTATTTTG TTTGCTTTCCTTGGTCAG CATACC (SEQ ID NO. 61) GCAGT (SEQ ID NO. 62) HPRT Rev CGAGCAAGACGTTCAGTC CGTGGGGTCCTTTTCACC CT(SEQ ID NO. 63) AGCA (SEQ ID NO. 64) Gapdh Fwd TGAGTATGTCGTGGAGT GCAAATTCCATGGCACCG GGCCCGATTTCTCCTCCG CTAC (SEQ ID NO. 65) T (SEQ ID NO. 66) GGT (SEQ ID NO. 67) Gapdh Rev TGGACTGTGGTCATGAG TCGCCCCACTTGATTTTGG GGTGACCAGGCGCCCAAT CC (SEQ ID NO. 68) (SEQ ID NO. 69) ACG (SEQ ID NO. 70) Gata6-Em GCTAGCGCTGTTTGTTT SEQ ID NO 9: SEQ ID NO 10: Fwd AGGGCTCG (SEQ ID NO. CTCGGCTTCTCTCCGCGCC TTGACTGACGGCGGCTGG 71) TG TG Gata6-Em GCCCCGAAACGCTTCGG SEQ ID NO 11: SEQ ID NO 12: Rev CAG (SEQ ID NO. 72) AGCTGAGGCGTCCCGCAG CTCCCGCGCTGGAAAGGC TTG TC Gata6-Ad TTTGGGGTGGCCTCGGC SEQ ID NO 13: SEQ ID NO 14: Fwd TCT (SEQ ID NO. 73) GCGGTTTCGTTTTCGGGG AGGACCCAGACTGCTGCC AC CC Gata6-Ad CCAGGCCAACCGCACAC SEQ ID NO 15: SEQ ID NO 16: Rev CTT (SEQ ID NO. 74) AAGGGATGCGAAGCGTAG CTGACCAGCCCGAACGCG GA AG Nkx2-1-Em GCGGCCATGCAGCAGCA SEQ ID NO 17: SEQ ID NO 18: Fwd C (SEQ ID NO. 75) AAACCTGGCGCCGGGCTA CAGCGAGGCTTCGCCTTC AA CC Nkx2-1-Em CCATGTTCTTGCTCACG SEQ ID NO 19: SEQ ID NO 20: Rev TCC (SEQ ID NO. 76) GGAGAGGGGGAAGGCGAA TCGACATGATTCGGCGGC GCC GG Nkx2-1-Ad ACTCTTTTGGTGGTGAC SEQ ID NO 21: SEQ ID NO 21: Fwd TGGG (SEQ ID NO. 77) AGCGAAGCCCGATGTGGT TCCGGAGGCAGTGGGAAG CC GC Nk2-1-Ad CTCATGTTGCCCAGGTT SEQ ID NO 22: SEQ ID NO 23: Rev GCC (SEQ ID NO. 78) CCGCCCTCCATGCCCACTT GACATGATTCGGCGGCGG TC CT Foxa2-Var1 ACCGCCATGCACTCGGC SEQ ID NO 24: SEQ ID NO 25: Fwd TTC (SEQ ID NO. 79) TGCCATGCACTCGGCTTCC CAGGGAGAGGGAGGGCG AG AGA Foxa2-Var1 GGCTCATTCCAGCGCCC SEQ ID NO 26: SEQ ID NO 27: Rev ACA (SEQ ID NO. 80) TCATGTTGCCCGAGCCGCT CCCCCACCCCCACCCTCT G TT Foxa2-Var2 GGCACTGCGCTTCACTC SEQ ID NO 28: SEQ ID NO 29: Fwd CCC (SEQ ID NO. 81) CTGCTAGAGGGGCTGCTT CGCTTCTCCCGAGGCCGT GCG TC Foxa2-Var2 GGCTCATTCCAGCGCCC SEQ ID NO 30: SEQ ID NO 31: Rev ACA (SEQ ID NO. 82) ACGGCTCGTGCCCTTCCAT TAACTCGCCCGCTGCTGC C TC Id2-Var1 CTGAACCGAGCCTGGTG SEQ ID NO 32: SEQ ID NO 33: Fwd CCG (SEQ ID NO. 83) AACCCCTGTGGACGACCCG TGCGGATAAAAGCCGCCC A CG Id2-Var1 Rev GCTCCGGGAGATGCCCA SEQ ID NO 34 SEQ ID NO 35: AGC (SEQ ID NO. 84) GCCCGGGTCTCTGGTGAT AGCTAGCTGCGCTTGGCA GC CC Id2-Var2 GGGTGCTGAAAGATTCC SEQ ID NO 36: SEQ ID NO 37: Fwd AAACCTCG (SEQ ID NO. CTGCGGTGCTGAACTCGCC CCCCCTGCGGTGCTGAAC 85) C TC Id2-Var 2 TGTGCCCTTCAGTGTAG SEQ ID NO 38: SEQ ID NO 39: Rev GTGGCA (SEQ ID NO. GACGAGCGGGCGCTTCCA TAACTCGCCCGCTGCTGC 86) TT TC Snai1 Fwd CCGAAGCCACACGCTGC CTT (SEQ ID NO. 87) Snai1 Rev AGCACGGTTGCAGTGGG AGC (SEQ ID NO. 88) Acta2 Fwd GCTGGTGATGATGCTC CCA (SEQ ID NO. 89) Acta2 Rev GCCCATTCCAACCATT ACTCC (SEQ ID NO. 90) Pou5f1 Fwd TGTGGACCTCAGGTTGG ACT (SEQ ID NO. 91) Pou5f1 Rev CTTCTGCAGGGCTTTCA TGTC (SEQ ID NO. 92)

Animal Experiments

[0754] Five to 6 weeks old C57BL6 mice were used throughout this study. Animals were housed under controlled temperature and lighting [12/12-hour light/dark cycle], fed with commercial animal feed and water ad libitum. All experiments were performed according to the institutional guidelines that comply with national and international regulations. The mice were administered orotracheally control (pBLSK, Ctrl) or plasmids specific to isoforms (Em, Embryonic or Ad, Adult) of Gata6 and Nkx2-1 prepared in PEI transfection reagent (Sigma-Aldrich, 408727) at 50 .mu.g/kg body weight of the mouse, three times (Day 0, 3, 7). Lungs were harvested at 5, 7 and 12 weeks after administration of plasmid, for RNA (QIAGEN Rneasy Mini Kit) and protein isolation and histology. For histology, the lungs were fixed overnight in 1% Paraformaldehyde (PFA) followed by overnight incubation in PBS. The lungs were dehydrated over a graded series of alcohol changes and embedded in paraffin. In addition, blood was isolated from the mice by cardiac puncture and processed immediately for RNA isolation (QIAGEN Rneasy Mini Kit). A minimum of 200 .mu.l of blood was taken for RNA isolation.

Histology and Haematoxylin Staining

[0755] Paraffin embedded lung tissues were analysed by Haematoxylin and Eosin staining. 4 .mu.m sections were prepared and standard staining protocols were followed.

[0756] For colony formation assay, cells were fixed in 4% Paraformaldehyde (PFA) for 20 minutes followed by three washes with Phophate buffered saline (PBS) for 5 minutes. The cells were then incubated in haemaxylin for 20 minutes, followed by two washes in PBS for 5 minutes.

Immunochemistry

[0757] For paraffin embedded mouse lung tissue, sections of 4 .mu.m were prepared on a microtome (Leica Germany). Antigen retrieval was performed by boiling in 10 mM Citrate Buffer followed by incubation at sub boiling temperatures for 10 minutes. Antibody staining was performed following standard procedures. All incubations and washes were done with 1.times.TBS/0.1% Tween-20 (1.times.TBST). Non-specific binding was blocked by incubating in 5% donkey serum in TBST for 60 minutes. The sections were then incubated with primary and secondary antibodies for 60 min followed by nuclear staining. Antibodies were specific to Pan-cytokeratin (Dako, Code Z0622, 1:200 dilution), Napsin A (Abcam, ab9868; 1:100 dilution) and TRP63 (Cell Signaling Techn., 4984; 1:150 dilution). For cell lines, MLE-12 cells were cultured on coverslips and transfected with Control, Gata6 Em and Nkx2-1 Em plasmids. Cells were fixed 48 hours after transfection with 1% PFA for 20 minutes and washed 3 times, for 5 minutes, with 1.times.PBS. Antibody staining was performed as above. Antibodies were specific to MKI67 (Abcam, ab15580; 1:200 dilution) and MYC (Abcam, ab9132, 1:500 dilution)

Example 2: In Silico Analysis of Gata6. Nkx2-1. Foxa2 and Id2

[0758] In silico analysis of lung important genes revealed a common structure of Gata6, Nkx2-1, Foxa2 and Id2 (FIG. 1A, left). Promoter analysis showed the presence of two promoters, one 5' of the first exon and the other in the first intron. Further analysis showed that each of the predicted promoters was surrounded by CpG islands (greater than 200 bp, with more than 50% CG), suggesting that these in fact are functional promoters and that they might be epigenetically regulated. Expression analysis showed that each gene gave rise to two distinct transcripts driven by different promoters. (FIG. 1A, right). In silico analysis of the same genes in humans demonstrated a similar structure as in mice, which clearly highlights that the identified gene structure was maintained during evolution and is conserved among species, reflecting its relevance. Isoform specific expression analysis was carried out during the pseudoglandular stage of mouse lung development (E11-14, FIG. 1B). Expression of both isoforms of the same gene was complementary with one isoform mainly expressed at early stages (E11, 12) while the other at later stages (E13, 14). In the adult lung mainly the transcript that is expressed at late stages of embryonic development can be detected (data not show). Our data suggest that the expression of both transcripts is developmentally regulated with an Em-isoform expressed at early stages of embryonic lung development and an Ad-isoform expressed at late stages of embryonic lung development and in the adult lung.

Example 3: Expression of Specific Gata6, Nkx2-1, Foxa2 and Id2 Isoforms in Cancer Cell Lines, Biopsy Samples and Blood

[0759] Isoform specific expression analysis was carried out in human lung adenocarcinoma (A549, A427) and human bronchoalveolar carcinoma (H322) cell lines (FIG. 2A). The expression of the Em-isoform of each one of the genes analyzed was higher in all three cell lines tested, suggesting that the Em-isoforms are relevant during lung cancer formation. To confirm this hypothesis, human lung biopsies from healthy donors and lung tumor patients were analyzed (FIG. 2B). Consistent with the expression analysis in cell culture, the embryonic transcript of each one of the genes analyzed was enriched in the biopsies of lung tumor when compared to the healthy tissue. To confirm the diagnostic potential of the Em-isoforms of the genes analyzed here, it was attempted to detect these isoforms in the blood of genetic mouse models of lung cancer at early stage of cancer formation as well as in blood of lung cancer patients. Preliminary results after hyperplasia induced by in vivo gain-of-function (GOF; see example 6, FIG. 4) showed that transcripts of Gata6 Em and Nkx2-1 Em can be detected in the blood of mice after forced expression of Gata6 Em (FIG. 2C, middle) whereas only Gata6 Em transcript can be detected in the blood of mice after forced expression of Nkx2-1 Em (right).

Example 4: Analysis of the Oncogenic Potential of Gata6 Em or Nkx2-1 Em (I)

[0760] To analyze the potential role of the Em-isoforms in oncogenic transformation, the primary characteristics of cancer cells, enhanced proliferation and migration, were analyzed after transient transfection of Gata6 Em or Nkx2-1 Em in Mouse Lung Epithelial-12 (MLE) cells. Immunostaining of transient transfected MLE-12 cells using antibodies specific for cell proliferation markers MKI67 and MYC (FIG. 3A) showed enhanced cell proliferation after transfection of Gata6 Em or Nkx2-1 Em when compared to the control transfected cells (Ctrl). In addition, migration was assessed by standard in vitro scratch assay (FIG. 3B). The Em-isoforms transfected MLE-12 cells were able to close the scratch faster (after 24 h) than control transfected cells (Ctrl; 48 h) demonstrating enhanced cell migration. To assess clonogenicity, other characteristic of cancer cells, control (Ctrl) and Gata6 Em stable transfected MLE-12 cells were plated at clonal density and colonies were counted after 2 weeks (FIG. 3C). The ability to form colonies increased more than four times in cells expressing Gata6 Em when compared to control transfected cells, clearly supporting the oncogenic potential of this Em-isoform.

Example 5: Analysis of the of the Role of Gata6 Em in Metastasis

[0761] Epithelial-mesenchymal transition (EMT) is a process characterized by loss of cell adhesion and increased cell motility. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. However, initiation of metastasis involves invasion, which has many phenotypic similarities to EMT, including a loss of cell-cell adhesion and an increase in cell mobility. Recent evidence suggests that EMT results in formation of cells with stem cell like properties (see Mani (2008) Cell 133(4): 704-715). Such cells are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. In control (Ctrl) and Gata6 Em stable transfected MLE-12 cells, EMT was monitored by expression analysis of Snail homolog 1 (Snail) and alpha smooth muscle actin (Acta2) (FIG. 3D, top), whereas `sternness` was monitored by expression analysis of the stem cell marker POU domain class 5 transcription factor 1 (Pou5f1, also known as Oct4; FIG. 3D, bottom). Gata6 Em increased the expression of all three markers indicating EMT and a potential role of this Em-isoform in metastasis.

Example 6: Analysis of the Oncogenic Potential of Gata6 Em or Nkx2-1 Em (II)

[0762] To confirm the oncogenic potential of the Em-isoforms, isoform specific in vivo GOF was carried out in wild type C57/B16 mice (FIG. 4). The mice were induced by orotracheal administration of a transfection mix containing Polyethylenimine (PEI, transfection reagent) and either a control plasmid (Ctrl) or plasmids for specific expression of each isoform (embryonic, Em or adult, Ad) of Nkx2-1 or Gata6. Isoform specific GOF was monitored by qRT-PCR (FIG. 4B). As early as 5 weeks after transfection, histological analysis of the lungs by Haematoxylin and Eosin staining revealed atypical hyperplasia exclusively in Em-isoform treated lungs while the Ad-isoform treated lungs were apparently normal, demonstrating the oncogenic potential of the Gata6 Em and Nkx2-1 Em (FIG. 4A).

[0763] To further characterize the phenotype induced after forced expression of the Em-isoforms in the adult lung, the expression of markers for all four hallmarks of cancer was analyzed: proliferation, angiogenesis, migration and hypoxic growth (FIG. 5A). Forced expression of Gata6 Em isoform in adult lung led to increased expression of Cdkn1 (Cyclin dependent kinase, proliferation marker); Vegf (Vascular endothelial growth factor) and Plgf (Placental growth factor, angiogenesis markers); Pdpk1 (3-phosphoinositide dependent protein kinase 1, migration/metabolic marker) and Hif2 (Hypoxia inducible factor 2, hypoxic marker), supporting the oncogenic potential of the Em-isoform in this in vivo model. To assess the formation of cancer stem cells in vivo, immunostaining using POU5F1 specific antibody on sections of Gata6 Em treated lungs was performed (FIG. 5B). Small clusters of POU5F1 positive cells were observed within regions of the lung with atypical hyperplasia after Gata6 Em in vivo GOF supporting the formation of high tumorigenic dedifferentiated cells. Furthermore, immunohistochemistry using Pan-cytokeratin (KRT) specific antibody on sections of Gata6 Em treated lungs (FIG. 5C) showed the presence of cytokeratin filaments, which are markers for both major classes of epithelial lung tumors, i.e. squamous cell carcinoma and adenocarcinoma. Clinical diagnosis of lung adenocarcinoma includes positive staining for NKX2-1 and Napsin A (NAPSA) (Bishop J A et al., (2010) Hum Pathol. 41(1): 20-5) as well as cytoplasmatic staining for tumor protein 63 (TRP63) (see Kalhor (2006) Modern Pathology 19: 1117-1123). Immunohistochemistry on sections of Gata6 Em treated lungs (FIG. 5D) demonstrated strong staining for NAPSA as well as for cytoplasmic TRP63 in the regions of hyperplasia, indicating that these regions correlate well with adenocarinomas of the lung.

[0764] Enhanced colony formation and Pou5f1 expression in cell lines transfected with Gata6 Em as well as clusters of POU5F1 positive cells within tumors resulting from forced overexpression of Gata6 Ern in the adult lung show the formation of cancer stem cells. Targeting these cancer stem cells by cell-specific knockdown of the embryonic/cancer specific isoform of the genes analyzed here provides a therapeutic strategy to prevent frequent tumor relapse.

Example 7: Analysis of the Oncogenic Potential of Gata6 Em or Nkx2-1 Em (III)

[0765] To exploit the use of the Em isoform in cancer therapeutics, isoform specific knockdown was carried out (FIG. 6A). MLE-12 cells were transfected with different siRNAs against Gata6 Em or Ad (top) or shDNA plasmids against Nkx2-1 Em or Ad (bottom). The best siRNAs or shDNAs by showing the maximum knockdown with the least off target effects were selected (FIG. 6B) for further use in vivo.

[0766] In order to demonstrate the therapeutic property of blocking the embryonic isoform, isoform specific knockdown was carried out in a highly aggressive tumor metastasis model. Lewis lung carcinoma (LLC1) cells were injected into the mouse tail vein. These cells would seed into the lung and form local tumors within 10-21 days. Three days after injection, the mice were treated with either a control (siCtrl) or Gata6 Em specific siRNAs (siGata6 Em) by orotracheal administration. The lungs were examined for both number and size tumor foci 21 days after injection (FIG. 7B-C). It was observed that after treatment with siGata6 Em tumor formation was dramatically reduced as compared to the siCtrl treatment. These results supported the therapeutic potential of targeting the Em isoform in lung cancer.

Example 8: Material and Methods of In Vivo Lung Fibrosis Model

[0767] Adult C57BL/6N mice (Charles River Laboratories) were used throughout this study. Animals were housed under controlled temperature and lighting [12/12-hour light/dark cycle], fed with commercial animal feed and water ad libitum. All experiments were performed according to the institutional guidelines that comply with national and international regulations. Bleomycin sulphate (2.5 U/Kg; Hexal AG, Germany) or sterile saline was administered as orotracheal instillation method as described earlier.

[0768] At day 21 after bleomycin instillation, mice were anaesthetised with 30-60 mg/kg ketamine (Pfizer, Germany) and 5-10 mg/kg, xylazine (Bayer, Germany). In anaesthetised mice, the thorax was opened and lung was then perfused with 1.times.PBS. The lung was either frozen for mRNA isolation or perfusion-fixed with 4% paraformaldehyde for 15 min with a pressure of 20 cm H.sub.2O for immunohistology

Example 9: Gata6 Ad Expression Increases Dramatically after Lung Fibrosis Induction by Bleomycin Treatment

[0769] Interestingly it was found in an in vivo model of lung fibrosis (FIG. 8B) that the expression of Gata6 Ad increased dramatically after induction of lung fibrosis by Bleomycin treatment when compared with the control treated mice (FIG. 8C), suggesting that increased expression of the adult isoform could be used for the diagnosis of lung fibrosis.

Example 10: Embryonic Isoforms of GATA6 and NKX2-1 in Lung Cancer Diagnosis

Materials and Methods

Study Population

[0770] All patients were studied according to a protocol approved by the local institutional research ethics committee. Transbronchial biopsy specimens were obtained from the 45 patients who had primary lung tumors in the last five years. Inclusion criteria included primary lung tumor samples including lung adenocarcinoma (Grades 1,2,3), lung squamous cell carcinoma (Grades 1,2,3) and lung small cell carcinoma (Grades 1,2,3). All tumors were graded according to the Bloom-Richardson and the TNM grading system recommended by the American Joint Committee on Cancer. In addition, from 13 patients adjacent normal tissues were also obtained. Secondary lung tumors and lung cancer samples older than 5 years were excluded.

[0771] All cases were reviewed by an expert panel of pulmonologists and oncologists according to the current diagnostic criteria for morphological features and immunophenotypes. Specifically, for immunohistochemistry, reactivity to NKX2-1, Cytokeratins (specifically CK5/6/7/8) and MKI67 was evaluated. In addition, for some samples, genetic analysis for EGFR mutations was also performed.

TABLE-US-00025 TABLE 1 Classification of cases Original No. Of Pathological No. Of No. Of No. Of diagnosis Cases Diagnosis* Cases Gender Cases Gender Cases Non Small Cell 50 Adenocarcinoma 47 Female 19 Male 70 Lung Cancer Squamous Cell 1 Female 1 Male 0 Carcinoma Large Cell 1 Female 0 Male 1 Carcinoma AdenoSquamous 1 Female 1 Male 0 Carcinoma Small Cell 1 Small cell lung 1 Female 1 Male 0 Lung Cancer cancer *Pathological diagnosis is according to the current diagnostic criteria for morphology, immunohistochemistry and genetic findings.

TABLE-US-00026 SUPPLEMENT TABLE 1 Clinical characteristics of patients with lung cancer Clinical Characteristic % Patients Age <50 8.8 50-70 46.6% >70 35.5% Gender Male 46.6% Female 53.3% Ethnic group CEU 6.6% CHB 62.2% MXL 31.1% Stage* I-II 50.9% III-IV 49.0% Recurrent disease 6.6% Treatment ongoing at biopsy 6.5% collection *Stage of tumor according to the Bloom Richardson and TNM staging criteria. Percentages may not round up to 100% because of rounding.

Exhaled Breath Condensate (EDC) Collection

[0772] From 10 samples that were currently undergoing diagnostic evaluation for lung cancer, EBC collection was also performed just prior to biopsy collection. Further, healthy EBC was also collected from donor individuals. All participants provided written informed consent.

[0773] EBC collection was performed using the RTube (Respiratory Research) as described online (http://www.respiratoryresearch.com/products-rtube-how.htm). Briefly, the aluminum cooling sleeve was cooled to -20.degree. C. and the disposable, sterile RTube was placed in the cooling sleeve. The apparatus was the covered by the insulating cover provided. All donors used a nose clamp to avoid nasal contaminants and breathing was only through the mouthpiece. The collection device consists of a one way valve that directs the air to the collection chamber where vapors, aerosols and moisture in the breath are condensed. Exhaled breath was collected for 10 min for each donor. After this, the mouthpiece was removed and a plunger was used to collect the EBCs. The RTube was placed on top of the standard plunger and slowly pushed down until the RTube reached the bottom of the plunger. Exhaled breath condensates were collected with a pipette and 500 .mu.l aliquots were prepared. EBCs were stored at -80.degree. C. until further use. As a precaution to avoid contaminants from the mouth, subjects were asked to refrain from eating, drinking (except water) and smoking up to 3 hours before EBC collection and were asked to rinse their mouth with fresh water just prior to collection.

Cell Culture and Mouse Experiments

[0774] Cell lines used in this study were A549 (CCL-185), A427 (HTB-53), H322 (CRL-5806) and LLC1 (CRL-1642). Cell lines were cultured in medium and conditions recommended by the American Type Culture Collection (ATCC). Cells were used for the preparation of RNA (QIAGEN RNeasy plus mini kit) and protein extracts.

[0775] Five to 6 weeks old C57BL6 mice were used throughout this study. Animals were housed under controlled temperature and lighting [12/12-hour light/dark cycle], fed with commercial animal feed and water ad libitum. All experiments were performed according to the institutional guidelines that comply with national and international regulations. For LLC1 cell injection, a cell suspension of 1 million cells/100 .mu.l of medium was prepared. 100 .mu.l of cell suspension was injected into the tail vein of each mouse. The development of tumors was observed after 21 days and lung tumors were harvested for RNA isolation.

RNA Isolation, cDNA Synthesis and Gene Expression Analysis

[0776] Total RNA was isolated from cell lines using the RNeasy Mini kit (Qiagen). Human lung tumor biopsies were obtained as formalin fixed paraffin embedded (FFPE) tissues. 80 .mu.m of tissue in sections of 10 .mu.m was cut and total RNA was isolated using the RecoverAll.TM. Total Nucleic Acid Isolation Kit for FFPE (Ambion). For exhaled breath condensates, 500 .mu.l of EBC was used for RNA isolation using the RNeasy Micro Kit (Qiagen) following manufacturer's instructions. cDNA was synthesized from total RNA using the High Capacity cDNA Reverse Transcription kit (Applied Biosystem) according to manufacturer's instructions. The cDNA was 6 fold diluted and 3.5 .mu.l of the diluted cDNA was used for SYBR green based expression analysis for EBCs and 1 .mu.l for cDNA from cell lines, mice and tumor biopsies (Applied biosystems, power SYBR green). Briefly, lx concentration of the SYBR green master mix was used with 250 nM each forward and reverse primer. The PCR results were normalized with respect to the housekeeping gene TUBA1A. Quantitative real time PCR reactions were performed using SYBR.RTM. Green on the Step One plus Real-time PCR system (Applied Biosystems) using the primers specified in the supplementary table 2.

TABLE-US-00027 SUPPLEMENT TABLE 2 Primer sequences used for the analysis of GATA6 and NKX2-1. Estimation of Receiver-operating-characteristic (ROC) curves Primer Sequence for tissue, Gene Primer Sequence for cell lines (5'-3') EBC (5'-3') Gata6 Em CTCGGCTTCTCTCCGCGCCTG TTGACTGACGGCGGCTGGTG Fwd Gata6 Em AGCTGAGGCGTCCCGCAGTTG CTCCCGCGCTGGAAAGGCTC Rev Gata6 Ad GCGGTTTCGTTTTCGGGGAC AGGACCCAGACTGCTGCCCC Fwd Gata6 Ad AAGGGATGCGAAGCGTAGGA CTGACCAGCCCGAACGCGAG Rev Nkx2-1 AAACCTGGCGCCGGGCTAAA CAGCGAGGCTTCGCCTTCCC Em Fwd Nkx2-1 GGAGAGGGGGAAGGCGAAGCC TCGACATGATTCGGCGGCGG Em Rev Nkx2-1 Ad AGCGAAGCCCGATGTGGTCC TCCGGAGGCAGTGGGAAGGC Fwd Nk2-1 Ad CCGCCCTCCATGCCCACTITC GACATGATTCGGCGGCGGCT Rev

[0777] Receiver-operating-characteristic (ROC) curves were estimated for the 59 biopsies. Em/Ad ratios were categorized into five groups, in order to adequately separate the points on the ROC curve. (For GATA6, the range was <0.5; 0.5-0.8; 0.8-1.1; 1.1-2; and >2 while for NKX2-1, <0.4; 0.4-0.8; 0.8-1.2; 1.2-2; >2.)

[0778] ROC curve analysis was performed using the web based calculator for ROC curves, ROC Analysis (Eng J. ROC analysis: web-based calculator for ROC curves. Baltimore: Johns Hopkins University [updated 2014 Mar. 19; cited Apr. 25, 2014]. Available from: http://www.jrocfit.org.). The area under the empirical ROC curve was calculated by the trapezoid (nonparametric) method.

Statistical Analysis

[0779] Samples were analyzed at least in triplicates and cell line and mouse experiments experiments were performed three times. Statistical analyses were performed using Excel Solver. The data are represented as mean.+-.Standard Error (mean.+-.s.e.m) and for human samples, each point on the graph represents an individual sample while the horizontal line represents the median.+-.Standard Error (median.+-.s.e.m.). One-way analysis of variance (ANOVA) was used to determine the levels of difference between the groups and P values for significance.

[0780] Lung cancer is the leading cause of cancer related deaths worldwide, accounting for an estimated 1.6 million deaths out of 1.8 million cases in 2012 (Globacon 2012). The incidence pattern of lung cancer closely parallels the mortality rate because of persistently low patient survival. There are two major classes of lung cancer, non-small cell lung cancer (NSCLC, representing 85% of all lung cancers) and small cell lung cancer (SCLC, the remaining 15%) (Herbst R S et al., (2008) N Engl J Med 359(13): 1367-80). Depending on the histological characteristics, NSCLC is further divided into three major subtypes; squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Adenocarcinoma is the most common form and has approximately 40% prevalence, followed by squamous cell and large cell carcinoma that have 25% and 10% prevalence respectively (Hoffman P C et al., (2000) Lancet 355(9202): 479-85).

[0781] Clinical manifestations of lung cancer are diverse and patients are mostly asymptomatic at early stages. Symptoms, even when present, are non-specific and mimic more common benign etiologies, including persistent cough, dyspnea, hoarseness, chest pain, weight loss and fatigue (Hyde L and Hyde Cl, (1974) Chest 65(3): 299-306). Traditional diagnostic strategies for lung cancer include imaging tests, including chest X-rays, histological analysis, including sputum cytology, and tissue biopsies (Strauss G M and Dominioni L, (2013) J Surg Oncol 108(5): 294-300; D'Urso V et al., (2013) J Cell Physiol 228(5): 945-51; Travis W D et al., (2013) Arch Pathol Lab Med 137(5): 668-84). Most of these tests are performed only after the development of symptoms, frequently at advanced stages of the disease when patient prognosis is poor as shown by a low five-year patient survival of 1-5% (Herbst R S et al., (2008) N Engl J Med 359(13): 1367-80). Strikingly, patient survival increases to almost 52% if lung cancer is diagnosed early (Herbst R S et al., (2008) N Engl J Med 359(13): 1367-80), demonstrating that early diagnosis of lung cancer is decisive to increase the probability of a successful therapy. Thus, a better understanding of the molecular mechanisms responsible for lung cancer initiation is extremely important.

[0782] It is proposed herein that many of the mechanisms involved in embryonic development are recapitulated in lung cancer initiation. Therefore, new experimental approaches based on studies of embryonic development are provided herein to elucidate the molecular mechanisms responsible for lung cancer initiation.

[0783] Consistently, two transcription factors that are key regulators of embryonic lung development, such as GATA6 (GATA Binding Factor 6) and NKX2-1 (NK2 homeobox 1, also known as Ttf-1, Thyroid transcription factor-1) (Keijzer R et al., (2001) Development 128(4): 503-11; Kolla V et al., (2007) Am J Respir Cell Mol Biol 36(2): 213-25; Zhang Y et al., (2007) Development 134(1): 189-98; Tian Y et al., (2011) Development 138(7): 1235-45), have been implicated in lung cancer formation and metastasis (Guo M et al., (2004) Clin Cancer Res 10(23): 7917-24; Gorshkova E V et al., (2005) Biochemistry (Mosc) 70(10): 1180-4; Lindholm P M et al., (2009) J Clin Pathol 62(4): 339-44; Winslow M M et al., (2011) Nature 473(7345): 101-4; Cheung W K et al., (2013) Cancer Cell 23(6): 725-38; Chen P M et al., (2013) Carcinogenesis 34(11): 2655-63).

[0784] Here it is shown that two different mRNAs are expressed from both GATA6 and NKX2-1. Furthermore the expression of both transcripts from the same gene is complementary and differentially regulated during embryonic lung development as well as in lung cancer. One transcript is expressed in early stages of embryonic lung development (embryonic isoform, Em-isoform), whereas the second transcript is expressed in late stages and in adult lung (adult isoform, Ad-isoform). Herein an enrichment of the Em-isoform in lung tumors is demonstrated, even at early stages of cancer, making the detection of these embryonic specific transcripts a powerful tool for early cancer diagnosis. Moreover, isoform specific expression analysis of GATA6 and NKX2-1 is demonstrated herein in exhaled breath condensates (EBCs). The Em- by Ad-expression ratio in each sample can be used as a non-invasive, specific and sensitive method for both early lung cancer diagnosis and identification of high risk patients.

Study Population.

[0785] 59 lung biopsies and 20 EBCs that were collected in three different cohorts located in different continents (America, Asia and Europe) were analyzed allowing us to investigate ethnic differences. The patients were studied according to a protocol approved by the institutional review board and ethical committee of the Hospital Regional de Alta Especialidad de Oaxaca (HRAEO), C.P. 71256, Oaxaca, Mexico; Union Hospital, Hong Kong; and Universitatsklinikum Gie en and Marburg, Germany. The cases were reviewed by our panel of expert lung pathologists in the different cohorts according to current criteria of the WHO.

[0786] To develop a diagnostic test based on the Em-Ad-expression ratio of GATA6 and NKX2-1, initially 39 cases were analysed that were originally diagnosed as NSCLC and confirmed as such by the pathological review. The qRT-PCR based expression analysis of the samples was in accord with the pathological diagnosis in all of the 39 cases.

Embryonic Isoforms of GATA6 and NKX2-1 are Highly Expressed in Human Lung Cancer Cell Lines and in a Mouse Model of Experimental Metastasis.

[0787] In silico analysis of GATA6 and NKX2-1 revealed a common gene structure (FIG. 12A, top). Two promoters were predicted in each of the genes, one 5' of the first exon and the other in the first intron. Further analysis showed that each of the predicted promoters was surrounded by CpG islands (greater than 200 bp, with more than 50% CG), suggesting that these might be epigenetically regulated functional promoters. Indeed, expression analysis showed that each gene gave rise to two distinct transcripts driven by different promoters (FIG. 12A, bottom). In silico analysis of the same genes in mice demonstrated a similar structure as in humans, which highlights that the identified gene structure was maintained during evolution and is conserved among species, reflecting its relevance.

[0788] Quantitative PCR after reverse transcription (qRT-PCR) based expression analysis during mouse lung development revealed that the expression of both isoforms of the same gene was complementary and differentially regulated, with the Em-isoform mainly expressed at early developmental stages while the Ad-isoform at later stages and in adult lung. Isoform specific expression analysis (FIG. 12B) in healthy human lung tissue (Ctrl), human lung adenocarcinoma (A549, A427) and human bronchoalveolar carcinoma (H322) cell lines showed that the expression of the Em-isoform of each one of the genes analyzed was higher than the expression of the Ad-isoform only in the lung cancer cell lines. In the healthy human lung tissue, we observed the opposite results, in which the Ad-isoforms expression was higher than the Em-isoforms expression. In addition, western blot (WB) analysis of protein extracts from A549 cells using NKX2-1- or GATA6-specific antibodies (FIG. 12C) confirmed that both transcripts of each one of the genes were translated into proteins of different molecular weight.

[0789] In a mouse model of experimental metastasis (FIG. 12D) (Elkin M and Vlodaysky I, (2001) Curr Protoc Cell Biol Chapter 19: Unit 19.2), in which lewis lung carcinoma (LLC1) cells were injected into the tail vein to induce 21 days later tumor formation in the mouse lung, elevated expression of the Em-isoforms of Gata6 and Nkx2-1 in the tumors was detected when compared to healthy lung tissue (Ctrl).

[0790] Summarizing, these results support the hypothesis that the Em-isoforms of GATA6 and NKX2-1 are relevant during lung cancer formation.

Em/Ad Expression Ratios of GATA6 and NKX2-1 as Marker for Lung Cancer Diagnosis.

[0791] To confirm that the Em-isoform of GATA6 and NKX2-1 are markers for detection of lung cancer, we turned to human lung biopsies from healthy donors and lung tumor patients (FIG. 13A). The pathological diagnosis of the 59 lung-biopsy specimens was considered the standard against which the molecular diagnosis based on the gene expression analysis was compared. Isoform specific expression analysis based on qRT-PCR showed that the Em-isoforms of GATA6 and NKX2-1 were enriched in the biopsies of lung tumor when compared to the healthy tissue, consistent with the expression analysis in cell culture and in the mouse model of experimental metastasis.

[0792] The Ad-isoform expression was used as internal control to minimize the effect of individual variations among the different lung-tumor-biopsy specimens by calculating the Em- by Ad-expression ratio (Em/Ad) of each sample. In healthy lung tissue biopsies, the Em/Ad was 0.642.+-.0.065 (n=20) for GATA6 and 0.475.+-.0.044 (n=20) for NKX2-1. The Em/Ad increased in the lung cancer biopsies to 2.63.+-.0.194 (n=39, P<0.001) for GATA6 and to 2.075.+-.0.22 (n=39; P=0.01) for NKX2-1, supporting that an increased Em/Ad of GATA6 and NKX2-1 can be used as marker for lung cancer diagnosis.

[0793] To estimate the sensitivity and specificity of the herein provided method for lung cancer diagnosis, a mathematical model was used to perform an unadjusted Receiver-Operating-Characteristics (ROC) curve analysis (FIG. 13B) [12878740] of the 59 biopsies that were analyzed in FIG. 13A. A ROC curve is a plot of the sensitivity versus 1 minus the specificity. Each point along the curve is specific for a particular Em/Ad value from the lung biopsies. The estimated ROC curves showed high sensitivity and high specificity predicting high accuracy for lung cancer diagnosis by using the Em/Ad values of GATA6 and NKX2-1. The elevated Em/Ad values of GATA6 and NKX2-1 in the lung tumor biopsies when compared to the healthy lung tissue were maintained after sample grouping by ethnicity (FIG. 13C) or by gender (FIG. 13D). Furthermore, sample grouping based on TNM classification recommended by the American Joint Committee on Cancer (FIG. 13D) revealed that the Em/Ad of GATA6 and NKX2-1 increased progressively with advancing stages of lung cancer from Grade I (2.395.+-.0.257; P<0.001 for GATA6 and 1.878.+-.0.129; P<0.001 for NKX2-1) through Grade II (3.436.+-.0.243; P<0.001 for GATA6 and 2.589.+-.0.257; P=0.002 for NKX2-1) till Grade III (2.838.+-.0.598; P=0.003 for GATA6 and 3.787.+-.0.392; P<0.001 for NKX2-1).

Detection of Em- and Ad-Isoforms of GATA6 and NKX2-1 in Exhaled Breath Condensate.

[0794] EBCs consist of three main components (FIG. 14A): distilled water condensed from the gas phase (>99%), droplets aerosolized from the airway lining fluid and water soluble respiratory gases (the last two make the remaining 1%) (Horvath I et al., (2005) Eur Respir J 26(3): 523-48; Montuschi P, (2007) Ther Adv Respir Dis 1(1): 5-23). EBC is a promising source of biomarkers for, but not only, lung diseases since the droplets contain nonvolatile biomarkers such as adenosine, prostaglandins, leukotriene, cytokines, etc. whereas the respiratory gases should be considered as water soluble volatile biomarkers such as nitrogen oxides that diffuse from both airspace and airway lining fluid (Ho L P et al., (1998) Thorax 53(8): 680-4; Shahid S K et al., (2002) Am J Respir Crit Care Med 165(9): 1290-3; Huszar E et al., (2002) Eur Respir J 20(6): 1393-8; Effros R M et al., (2002) Am Respir Crit Care Med 165(5): 663-9; Montuschi P et al., (2003) Thorax 58(7): 585-8; Kostikas K et al., (2003) Eur Respir J 22(5): 743-7; Effros R M et al., (2012) Am J Respir Crit Care Med 185(8): 803-4; Davis M D et al., (2012) Immunol Allergy Clin North Am 32(3): 363-75). EBCs are typically collected through cooling devices. Here, two of the most broadly used devices for EBC collection were tested for their suitability for subsequent RNA extraction (FIG. 14B).

[0795] Using the same conditions for EBC collection and RNA extraction, the RTube showed a yield of 573.+-.48 ng RNA per 500 .mu.l EBC (n=6) whereas the TurboDECCS showed a lower yield of 292.+-.42 ng RNA per 500 .mu.l EBC (n=6). Thus, we continued collecting the samples with the RTube and tested different EBC volumes to determine the best for RNA extraction (FIG. 14C). The RNA yield increased with the EBC volume following a sigmoid curve that reached a plateau at 573.+-.48 ng RNA using 500 .mu.l EBC. RNA extraction from more than 500 .mu.l EBC did not improve the RNA yield. In addition, conditions for cDNA synthesis by reverse transcription and qPCR amplification were optimized using 500 .mu.l EBC collected with the RTube (data not shown). Using the optimized conditions, we performed an isoform specific expression analysis of GATA6 and NKX2-1 in EBCs from healthy donors and lung cancer patients (FIG. 14D). In healthy donors EBCs, the Em/Ad was 0.475.+-.0.113 (n=20) for GATA6 and 0.456.+-.0.054 (n=20) for NKX2-1. Correlating with the expression analysis in the biopsies, the Em/Ad increased in the EBCs from lung cancer patients to 1.532.+-.0.274 (n=10, P<0.001) for GATA6 and to 2.778.+-.0.292 (n=10; P=0.01) for NKX2-1.

[0796] These results support that an increased Em/Ad of GATA6 and NKX2-1 in the EBCs can be used as marker for early lung cancer diagnosis. The specificity of the different qRT-PCR products detected in the EBCs was demonstrated by dissociation curve analysis, electrophoretic gel analysis and sequencing of the different qRT-PCR products (FIGS. 16A-D and 17A-D). Moreover, the estimated ROC curves of the 10 EBCs that were analyzed in FIG. 14D showed high sensitivity and high specificity predicting high accuracy for early lung cancer diagnosis by using the Em/Ad values of GATA6 and NKX2-1.

Correlation of EBC Based Lung Cancer Diagnosis with Classical Methods.

[0797] To confirm that an increased Em/Ad of GATA6 and/or NKX2-1 in the EBCs can be used as marker for early lung cancer diagnosis, the patients from which the EBC were obtained were diagnosed using classical methods. FIG. 15 shows representative results. Pulmonary nodules were clearly identified by chest X-ray radiography (CXR, FIG. 15A left) and low-dose helical computed tomography (CT, right) in the patients with elevated Em/Ad of GATA6 and NKX2-1. Furthermore, immunostaining on sections of biopsies from the same patients (FIG. 15B) using antibodies specific for the epithelial maker KRT (pan-cytokeratin) and NKX2-1 demonstrated that the nodules were primary adenocarcinomas of the lung.

[0798] To determine that markers that are used for the molecular diagnosis of cancer can be detected in EBC, we analyzed the expression of the oncogene MYC and the tumor suppressor genes CDKN2A (also known as P16 or INK4A) and TP53 in EBCs from healthy donors and tumor patients (FIG. 15C). In healthy donors, expression level of CDKNA2 was 0.6.+-.0.36 (n=5) and it decreased to 0.068.+-.0.09 (n=10; P=0.001). Similarly, for TP53 the expression level in healthy donors was 0.908.+-.0.52 (n=5) which decreased to 0.021.+-.0.03 (n=10; P<0.001) in tumor samples. Consistently, the expression of MYC increased in tumor patients to 0.046.+-.0.034 (n=10) from 0.004.+-.0.002 (n=5; P=0.01). The pathological and molecular diagnosis correlated with the increased Em/Ad of GATA6 and NKX2-1 in all of the 10 cases from which we obtained the EBCs.

[0799] EBC is a promising source of biomarkers for lung diseases. In chronic obstructive pulmonary diseases (COPD) and asthma, increase of several inflammatory mediators like adenosines, prostaglandins, leukotriene and cytokines has been determined in EBCs of patients (Huszar E et al., (2002) Eur Respir J 20(6): 1393-8; Shahid S K et al., (2002) Am J Respir Crit Care Med 165(9): 1290-3; Kostikas K et al., (2003) Eur Respir J 22(5): 743-7; Montuschi P et al., (2003) Thorax 58(7): 585-8). In lung cancer, it was shown that cytokines, survivin and cycloxygenase-2, the last two being associated with poor survival in NSCLC, were enriched in EBCs of patients (Kullmann T et al., (2008) Pathol Oncol Res 14(4): 481-3; Carpagnano G E et al., (2010) Lung Cancer 76(1): 108-13). In addition to small mediators, nucleic acid from pathogens has been isolated from EBCs with diagnostic purposes (Zakharkina T et al., (2011) Respirology 16(6): 932-8; Xu Z et al., (2012) Plos One 7(7): e41137). Furthermore, using genomic DNA isolated from EBCs from lung cancer patients, both promoter hypermethylation of the tumor suppressor gene CDKN2A and gene mutations in TP53 were detected (Gessner C et al., (2004) Lung Cancer 43(2): 215-22; Xiao P et al., (2014) Lung Cancer 83(1): 56-60).

[0800] Herein it is demonstrated that RNA isolated from EBC can be used for qRT-PCR based isoform specific expression analysis of GATA6 and NKX2-1 to determine the Em-by Ad-expression ratio as a non-invasive, specific and sensitive method for early lung cancer diagnosis. 59 lung biopsies and 20 EBCs from three cohorts located in different continents were analyzed and an increased Em/Ad of GATA6 and NKX2-1 was determined in NSCLC samples independent of the ethnic group, the gender and NSCLC subtype. Furthermore, a direct correlation between the Em/Ad value and the cancer stage was determined suggesting that the level of increase of Em/Ad may be an indicator for the stage of the disease.

[0801] Early lung cancer diagnosis is crucial to improve patient prognosis. The ROC curve analysis presented herein showed high sensitivity and high specificity predicting high accuracy for lung cancer diagnosis by using the Em/Ad values of GATA6 and NKX2-1. Thus, the method provided herein can be used in the screening of high risk groups, such as those that have a hereditary history and/or are exposed to tobacco smoke, environmental smoke, cooking fumes, indoor smoky coal emissions, asbestos, some metals (e.g. nickel, arsenic and cadmium), radon (particularly amongst miners) and ionizing radiation (IARC Monogr Eval Carcinog Risk Chem Hum (1986) 38:35-394; Xu Z Y et al., (1989) J Natl Cancer Inst 81(23): 1800-6; Zhong L et al., (1999) Cancer Causes Control 10(6): 607-16). Currently, CT and CXR are used to screen such high risk group individuals. CT imaging has been shown to be considerably superior to CXR in the identification of small pulmonary nodules (Henschke Cl et al., (1999) Lancet 354(9173): 99-105). However, despite the success of CT imaging for early lung cancer diagnosis, it suffers from serious limitations, including a high detection rate of benign non calcified nodules (>50% of participants) resulting in follow-up CT scans, biopsies and frequently unnecessary resection of the benign non calcified nodules (Jett J R, (2005) Clin Cancer Res 11 (13 Pt 2): 4988s-4992s). Implementation of the herein provided (EBC) based molecular diagnosis will improve and complement the success of CT and CXR for early lung cancer diagnosis.

[0802] Microarray based analysis of tumor samples not only led to identification of gene expression profiles that are associated with NSCLC subtypes (Bhattacharjee A et al., (2001) Proc Natl Acad Sci USA 98(24): 13790-5; Meyerson M and Carbone D, (2005) J Clin Oncol 23(14): 3219-26) but also predicted with relatively high accuracy the clinical outcome (Beer D G et al., (2002) Nat Med 8(8): 816-24; Chen H Y et al., (2007) N Engl J Med 356(1): 11-20). Although the method provided herein did not discriminate between different NSCLC subtypes, it will be superior to previous approaches of molecular and clinical lung cancer diagnosis due to its higher sensitivity and accuracy, straightforward and fast protocol, non-invasiveness and relative low price. A combination of the method provided herein with the existing clinical and molecular methods of lung cancer diagnosis can help to predict the response to specific therapies with the goal of tailoring personalized treatments. The diagnostic method may also be useful to monitor the effect of an anti-cancer therapy by detecting a reduction of the Em/Ad ratio of GATA6 and NKX2-1, thereby allowing to determine whether the therapy has a positive effect.

Example 10: Inhibitors of emGata6 in the Treatment of Cancer

[0803] In order to analyze the specificity and efficiency of siRNAs targeted to each isoform (FIG. 18A), mouse lung epithelial cell line (MLE-12) cells were transiently transfected with siRNAs directed to each isoform (siGata6 Em, siGata6 Ad) and a scrambled siRNA (siCtrl). Cells were harvested 48 hours after transfection and total RNA was isolated. Isoform specific gene expression analysis showed that the siRNA against each isoforms were highly specific and efficient, resulting in significant reduction of their respective target transcript with minimal off target effects to the other isoform. For instance, siGata6 Em induced 90% reduction of Gata6Em transcript while no significant reduction of the Gata6Ad transcript was observed (12%) when compared to the siCtrl transfected cells. Similarly, siGata6 Ad induced 50% reduction of its target transcript while no change for the Gata6 Em transcript was observed. To further analyse the functional role of the isoforms, MLE-12 were transfected with siCtrl, siGata6 Em or siGata6 Ad and allowed to grow to form a confluent monolayer (FIG. 12B). A scratch was made (0 hr) and cells were observed microscopically every 12 hours for closure of the scratch or "wound healing". It was observed that while the cells transfected with siCtrl and siGata6 Ad were comparable in their ability to close the scratch at 24 hr, cells transfected with siGata6 Em showed reduced ability to close the scratch suggesting reduced cell proliferation and/or reduced cell migration.

[0804] In a mouse model of experimental metastasis (FIG. 7A) (Elkin M and Vlodaysky I, (2001) Curr Protoc Cell Biol Chapter 19: Unit 19.2), in which lewis lung carcinoma (LLC1) cells were injected into the tail vein to induce 21 days later tumor formation in the mouse lung, elevated expression of the Em-isoform of Gata6 in the tumors was detected when compared to healthy lung tissue (Ctrl) (FIG. 12D). Thus, to analyze the therapeutic potential of isoform specific loss of function (LOF) of Gata6 Em, adult mice were injected with LLC1 cells in the tail vein. Three days after tail vein injection, mice were orotracheally administered siCtrl or siGata6 Em. At day 21, lungs were prepared from the mice and isoform specific gene expression analysis was performed using total lung RNA (FIG. 18C). Gata6 Em expression was reduced approximately 70% after orotracheal administration of siGata6 Em when compared to the mice that were treated with siCtrl. Expression of Gata6 Ad was not significantly affected by Gata6 Em LOF supporting the specificity of the herein provided system.

[0805] Further, macroscopic gross tumor formation (FIG. 7B, top, arrows) was significantly reduced in mice treated with siGata6 Em when compared to the mice treated with siCtrl. In addition, a more than 80% reduction in the number of surface tumors was observed (bottom left; P=0.002; n=5) in mice treated with siGata Em. Microscopic (bottom right) and histological analysis (Figure XF) revealed that in addition to the number of tumors, the size of tumors was also significantly reduced in mice treated with siGata6 Em. Summarizing, the data presented herein support that the inhibition of Gata6 Em is a good approach for targeted therapy against lung cancer.

Example 11: Integrin Beta 2 and 6 are Membrane Proteins of Alveolar Type II Cells

Material and Methods

Cell Culture

[0806] Primary alveolar type II cells (ATII cells) were isolated from C57BL/6 mice as previously described [PMID:22856132] with minor modifications. Crude cells suspensions from the lungs were prepared by intratracheal instillation of agarose containing Dispase (BD Heidelberg, cat. #354235) followed by mechanical disaggregation of the lungs. Crude cell suspensions were purified by negative selection using a system consisting of biotinylated antibodies (Biotin anti-mouse CD16/CD32, cat. #553143; Biotin anti-mouse CD45 (30-F11), cat. #553078, both from BD Biosciences), streptavidin coated magnetic beads (Promega, cat. #Z5481) and a magnetic separator stand (Promega, cat #Z5410). Purified ATII cells were seeded on fibronectin coated cell culture dishes and cultured up to 3 days in D-MEM/F-12 (1:1) (Life Technologies GmbH, cat. #31330038) supplemented with 10% FCS and 1% Penicillin/Streptomycin (Pen/Strep, Gibco, 15070) in an atmosphere of 5% CO2 at 37.degree. C.

[0807] Mouse epithelial lung cells (MLE-12, ATCC CRL-2110), mouse normal lung cells (MLg, ATCC CCL-206) and mouse fibroblast (NIH/3T3, ATCC CRL-1658) were obtained from the American Type Culture Collection. Mouse fetal lung mesenchyme cells (MFLM-4) were obtained from Seven Hills Bioreagents. All cell lines were cultured following the supplier instructions. MLE-12 cells were transiently transfected with Itgb2-YFP expression plasmid (Addgene, cat. #8638) using Lipofectamine 2000 transfection reagent (Invitrogen) at a ratio of 1:2 of DNA:Lipofectamine according to the manufacturer instructions. Cells were harvested 48 h after transfection for further analysis. Where indicated, MLE-12 cells were treated with Lithium Chloride (LiCl, 20 mM for 8 h) to activate the WNT signaling pathway.

Animal Experiments

[0808] C57BL/6 mice (stock #002644, Jackson Laboratories; (Xiang et al., 1990) were obtained from Charles River Laboratories at 5 to 6 week of age and Itgb2.sup.-/- (132 Integrin-deficient, B6.129S7-Itgb2.sup.tm2Bay/J, stock #003329, [8700894]) were obtained from Jackson Laboratory. Animals were housed and bred under controlled temperature and lighting [12/12-hour light/dark cycle], fed with commercial animal feed and water ad libitum. All experiments were performed with 6-8 week old mice according to the institutional guidelines that comply with national and international regulations. The lungs of wild type and Itgb2.sup.-/- mice were harvested and used for RNA isolation, protein isolation, flow cytometry analysis and/or immunohistochemistry.

[0809] Metabolic labeling of living C57BL/6 mice was achieved by a diet containing a nonradioactive-labeled isotopic form of the amino acid lysine ((13)C6-lysine, heavy). The administration of a heavy lysine containing diet for one mouse generation leads to a complete exchange of the natural isotope (12)C6-lysine (light) in the cellular proteins. The fully labeled SILAC (stable isotope labeling with amino acids in cell culture) mice were used as a heavy "spike-in" standard into nonlabeled ATII- or MLE-12 cells samples during global proteomic screening with high-performance mass spectrometers.

Membrane Protein Isolation

[0810] ATII cells or MLE-12 cells were mixed with lung tissue from SILAC-mice at a ratio of 1:1 (wet weight: wet weight). The membrane proteins of these mixtures were isolated as previously described [PMID:19848406 and 19153689]. After isolation, membrane protein fractions were solubilized in 0.1 M TRIS/HCl pH 7.6 containing 2% SDS and 50 mM DTT.

Mass Spectrometry: Sample Preparation, Methods and Data Analysis

[0811] Solubilized membrane protein fractions were prepared for proteome analysis by FASP (filter-aided sample preparation) as previously described [PMID:19377485].

[0812] Reverse phase nano-LC-MS/MS was performed by using an Agilent 1200 nanoflow LC system (Agilent Technologies, Santa Clara, Calif.) using a cooled thermostated 96-well autosampler. The LC system was coupled to LTQ-Orbitrap instrument (Thermo Fisher Scientific) equipped with a nano-electro-spray source (Proxeon, Denmark). Chromatographic separation of peptides was performed in a 10 cm long and 75 .mu.m C18 capillary needle. The column was custom-made with methanol slurry of reverse-phase ReproSil-Pur C18-AQ 3 .mu.m resin (Dr. Maisch GmbH). The tryptic peptide mixtures were auto-sampled at a flow rate of 0.5 .mu.l/min and then eluted with a linear gradient at a flow rate 0.25 .mu.l/min. The mass spectrometer was operated in the data-dependent mode to automatically measure MS and MS/MS spectra. LTQ-FT full scan MS spectra (from m/z 350 to 1750) were acquired with a resolution of r=60,000 at m/z=400. The five most intense ions were sequentially isolated and fragmented in the linear ion trap by using collision-induced dissociation with collision energy of 35%. Further mass spectrometric parameters: spray voltage of 2.4 kV, no sheath gas flow, and capillary temperature was 200.degree. C.

[0813] For data analysis we used the MaxQuant software tool (Version 1.2.0.8). The measured raw data were processed and quantitated as described [Cox et al. Nature Biotech 2009 & nature protocols 2009]. For Gene Ontology functional analysis of the data, the GORILLA online-tool was used in target and background mode for ATII enriched proteins (Eden, BMC Bioinformatics, 2009).

Semiquantitative and Quantitative RT-PCR.

[0814] Total RNA was isolated with RNeasy.RTM. plus mini kit (Qiagen). cDNA was synthesized from total RNA using the High Capacity cDNA Reverse Transcription kit (Applied Biosystem) according to manufacturer's instructions. The PCR results were normalized with respect to the housekeeping gene Gapdh. Quantitative real time PCR reactions were performed using SYBR.RTM. Green on the Step One plus Real-time PCR system (Applied Biosystem).

Western Blot

[0815] Protein concentrations were determined using BCA kit (Sigma). Western blot was performed using standard methods [22753500]. Immunodetection of blotted proteins was performed using ITGB2-, ITGB6-, CD14-, CD45-, AXIN2-, BMP4-, MYCN-, ABC- (all from Millipore) and LMNB1- (Santa Cruz) specific primary antibodies, the corresponding HRP-conjugated secondary antibodies, an enhanced chemiluminescent substrate (SuperSignal West Femto, Thermo Scientific) and a luminescent image analyzer (Las 4000, Fujifilm).

Flow Cytometry Analysis of Single Cell Suspension of the Lungs

[0816] Lung single cell suspensions were generated and analyzed by flow cytometry as previously described [21985786] with minor modifications. Primary antibodies used were Pro-SFTPC (Millipore), ITGB2-CD18/APC (BioLegend, 0.5 mg/mL), ITGB6/FITC (R&D). Secondary antibodies used were Alexa 488 (BIOTIUM) and Alexa 633 (BIOTIUM). After immunostaining, single cell suspensions were quantified using the 5.0 Zflow cytometer. Data were analyzed with the BD FACS DIVA.TM. Software Version 3.0. Cells were analysed using BD LSRII flow cytometry. Data were analysed with Weasel or FlowJo software (FlowJo version 7.6.5, USA).

Immunohistochemistry

[0817] For cryosections, mouse lungs were harvested and embedded in tissue freezing medium (Polyfreeze, Polysciences Inc.). Sections of 10 um were prepared on a cryostat (Leica Germany). and post-fixed in 4% PFA for 20 min. Antibody staining was performed following standard procedures. All incubations were performed with histobuffer containing 3% BSA and 0.2% Triton X-100 in 1.times.PBS, pH 7.4. Non-specific binding was blocked by incubating with 10% donkey serum and histobuffer (1:1 (v/v) ratio) for 45-60 minutes. The sections were then incubated with primary and secondary antibodies for 60 min followed by nuclear staining. The sections were examined with a Zeiss confocal microscope (Zeiss, Germany). Antibodies used were specific against Pro-SFTPC (Millipore), ITGB2/CD18 (R&D system), ITGB6 (R&D system). Secondary antibodies used were Alexa 488 and Alexa 594 (Invitrogen). Draq5 (Invitrogen) was used as nuclear dye.

[0818] For paraffin embedded mouse lung tissue, lungs were post-fixed overnight in 1% PFA at 4.degree. C., dehydrated over a graded series of alcohol, and paraffin embedded. Sections of 4 .mu.m were prepared on a microtome (Leica Germany). Antigen retrieval was performed by cooking using a rice-cooker for 20 min in citrate buffer containing 10 mM Sodium citrate, 0.05% Tween 20, pH 6.0. Antibody staining was performed following standard procedures. All incubations and washes were done with 1.times.PBS. Non-specific binding was blocked by incubating with 5% BSA in 1.times.PBS for 60 minutes at room temperature. The sections were then incubated with primary and secondary antibodies for 60 min each followed by nuclear staining. Primary antibody used was specific against activated .beta.-CATENIN (Millipore). The sections were examined with a Zeiss confocal microscope (Zeiss Germany).

Statistical Analysis

[0819] Statistical analyses were performed using Excel Solver. All data are represented as mean.+-.Standard Error (mean.+-.s.e.m). One-way analyses of variance (ANOVA) were used to determine the levels of difference between the groups and P values for significance. P values after one-way ANOVA, *P s 0.05; **P<0.01 and ***P<0.001

Results

Mass Spectrometry Analysis of Membrane Proteins of ATII and MLE-12 Cells.

[0820] FIG. 20A shows a schematic representation of the experimental procedure. Primary ATII cells from adult mouse lung were isolated and cultured as previously described [PMID:22856132]. ATII cells or MLE-12 cells were mixed with lung tissue from SILAC-mice at a ratio of 1:1 (wet weight:wet weight). Membrane proteins of these mixtures were isolated [PMID:19848406 and 19153689] and after adequate sample preparation [PMID:19377485] analyzed by high-resolution mass spectrometry based proteomic approach. Gene Ontology cellular component (GOCC) terms based analysis of identified proteins after mass spectrometric measurement (FIG. 20B) revealed that over 90% of the proteins are either membrane proteins or related to the Golgi apparatus, a cellular organelle with a high content of endomembrane that is particularly important in the processing of membrane proteins and proteins for secretion. These results support the high efficiency of our membrane protein fractionation; FIGS. 20C and 20D XYZ and FIG. 21 XYZ.

Identification of Potential ATII Cell Specific Membrane Proteins.

[0821] The transcriptomes of ATII and MLE-12 cells were determined by Affymetrix microarray based expression analysis. The transcriptome databases and the membrane proteome databases of both cells were cross analyzed (FIG. 22A) by calculating the ratios of expression of the genes in MLE-12 versus ATII cells and comparing them with the respective protein abundance ratio. This cross databases query led to the identification of 16 genes that are highly expressed in ATII cells whose gene products are enriched in the membrane of ATII cells (FIG. 22B). These 16 genes are ITGB2, PTGIS, BASP1, DES, ITGA2, CTSS, PTPRC, ANPEP, FILIP1L, MGLL, OSMR, ITGB6, AGPAT4, ASS1, CSPG4, and CDH11. The identified genes are potential ATII cell surface markers.

Integrin Beta 2 and 6 are Membrane Proteins of a Subpopulation of Alveolar Type II Cells.

[0822] We focused our attention on ITGB2 and ITGB6 for further analysis to confirm our results from the membrane proteome and transcriptome analysis. The expression of Itgb2 and Itgb6 was determined in MLg (mouse normal lung cells), MFLM-4 (mouse fetal lung mesenchyme cells), NIH/3T3 (mouse fibroblast), MLE-12 and ATII cells as well as in adult mouse lung by quantitative PCR after reverse transcription (qRT-PCR, FIG. 23A). Itgb2 and Itgb6 are highly expressed only in ATII cells when compared to the other cell lines tested. In contrast, Cox2 expression, another gene that was identified in the membrane proteome approach, was detected not only in ATII but also in MLg and MFLM-4 cells. Sftpc was expressed in ATII and MLE-12 cells, as expected. Consistently, western blot analysis of protein extracts (FIG. 23B) showed that the level of ITGB2 and ITGB6 is high in spleen, lung and ATII cells but not in any of the other cell lines tested. Our results support certain cellular specificity for the expression of Itgb2 and Itgb6. Since ITGB2 and ITGB6 are known to be present in blood cells, we decided to discard the possibility that our data are the result of contamination of the isolated ATII cells with remaining blood cells. Therefore, we tested the presence of two blood cell proteins, CD14 and CD45, in our protein extracts. CD14 and CD45 are present in the spleen protein extract, as expected, but absent in any of the other protein extracts analyzed, ruling out the possibility that our results are due to a contamination of the isolated ATII cells with remaining blood cells.

[0823] Flow cytometry analysis after single immunostaining in cell suspensions of adult lungs (FIG. 23C, top and middle) showed that 25% of the cells were ITGB2-positive, 7% were ITGB6-positive and 13% were SFTPC-positive (for each antibody P<0.01; n=4). Interestingly, similar analysis after double immunostaining (FIG. 23C, bottom) revealed that only 5% of the analyzed cells were SFTPC- and ITGB2-positive whereas 6% of the cells were SFTPC- and ITGB6-positive (for each antibody combination P<0.05; n=5), suggesting the existence of at least two different subpopulation of ATII cells in the adult lung. Our results were validated by double immunostaining in sections of adult lung (FIG. 23D) using SFTPC- and either ITGB2- (top) or ITGB6- (bottom) specific antibodies. SFTPC and ITGB2 co-localized in a subpopulation of SFTPC-positive cells of the adult lung. A similar result was obtained for ITGB6.

Integrin Beta 2 Antagonizes WNT Signaling Pathway.

[0824] Gene Ontology biological process (GOBP) terms based analysis of identified proteins after mass spectrometric measurement (FIG. 24A) revealed an enrichment of WNT signaling pathway proteins in the membrane of ATII cells. To identify a functional link between our results, we decided to monitor the WNT signaling pathway in the lung of Itgb2.sup.-/- mice. Activated beta catenin (ABC) is a mediator of and an indicator for active WNT signaling. Immunostaining for ABC in sections of adult lungs (FIG. 24B-C) demonstrated an enhancement of canonical WNT signaling after Itgb2 knockout (KO) that was further validated by enhanced expression (FIG. 24D) as well as increased protein levels (FIG. 24E) of canonical WNT targets in the adult lung of Itgb2.sup.-/- mice when compared to wild type mice (WT). Our results suggest a block release of WNT signaling after Itgb2-KO. To confirm an Itgb2 mediated negative regulation of WNT signaling, we transfected Itgb2 into MLE-12 cells that were either untreated or treated with LiCl to activate WNT signaling (FIG. 24F). Itgb2 reduced the basal level of expression of the WNT targets Axing, Bmp4 and Mycn. Moreover, Itgb2 antagonized the activation of the WNT signaling pathway induced by LiCl-treatment. Our results support the hypothesis of an Itgb2 mediated negative regulation of WNT signaling in the adult lung.

[0825] It is shown herein that Itgb2 is required for a negative regulation of WNT signaling in the lung. The previously reported integrin mediated activation of TGFB signaling [21900405, 23046811] suggest the possibility of an integrin mediated counteracting effect between these two signaling pathways that would be of interest for further investigation. A recent publication links a cross talk between WNT and TGFB signaling to pulmonary epithelial cell fate specification [23562608]. A potential integrin mediated cross talk between TGFB and WNT signaling becomes even more interesting within the context of an important biological paradigm, how is the balance between differentiation and self-renewal of progenitor cells. Moreover, given the ability of integrins to modulate both signaling pathways, it may be possible to use them as potential targets to activate these pathways to increase repair and regeneration after lung injury. However, due to the fact that integrins, TGFB and WNT have been involved in pulmonary fibrosis and lung cancer one has to be careful before modulating both signaling pathways for this purpose.

Example 12

[0826] In order to determine whether ATII cells were the cells of origin of the Gata6 Em induced hyperplasia observed we used inducible reporter lines for ATII cells. Sftpc-rtTA/TetOP-Cre//TK-LoxP-LacZ-LoxP-GFP, a triple transgenic mouse that specifically labels ATII cells with green fluorescent protein after induction with Doxycycline (FIG. 25). In these mice; expression of Tet-O transactivator (rtTA) gene is under the control of the surfactant protein C (sftpc) promoter. Sftpc is the most specific marker of lung epithelial Alveolar type II cells. In a Tet-On system, the rtTA protein is capable of binding the operator (TetOP) only if bound by a tetracycline or its derivative doxycycline. Thus the introduction of doxycycline to the system initiates the transcription of the CRE recombinase protein in the ATII cells triple transgenic mice lung and then CRE recombinase protein deletes LacZ flanked by LoxP sites which leads to expression of green fluorescent protein gene (GFP) under the control of thymidine kinase gene (TK) promoter specifically into Alveolar type II cells.

[0827] These mice were treated with with a Control (Ctrl) or Gata6 Em expression vector mixed with Polyethyleneimine (as in FIG. 4) and 3 days after the first treatment, doxyclycine was administered via water at a concentration of 4 mg/ml. After 7 weeks, we harvested and homogenized the lung from these mice and prepared single cell suspensions (FIG. 25). Lung epithelial cells were isolated following negative selection using antibodies against blood cells, CD16, CD45/32. The isolated cells were cultured in serum free medium supplemented with basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and heparin in low attachment dishes, allowing the growth of only those cells that have a stem cell like phenotype, or in this case, the highly tumorigenic cancer stem cells. As compared to the cells isolated from the control (Ctrl) treated lungs, Gata6 Em treated lung cells contained a subpopulation of cells that was able to stay in culture for several passages suggesting that these cells have undergone malignant transformation (FIG. 26). In addition, these cell clusters expressed EGFP supporting the hypothesis that these cells originated from ATII cells. To confirm the formation of cancer stem cells, we will investigate the two hallmarks of these cells, i.e. resistance to chemotherapeutic agents (in vitro) and subsequent tumor inducing potential after sub cutaneous injection in mice.

[0828] The present invention refers to the following nucleotide and amino acid sequences:

[0829] The sequences provided herein are available in the NCBI database and can be retrieved for example from world wide web at ncbi.nlm.nih.gov/sites/entrez?db=gene; Theses sequences also relate to annotated and modified sequences. The present invention also provides techniques and methods wherein homologous sequences, and variants of the concise sequences provided herein are used. Preferably, such "variants" are genetic variants.

SEQ ID No. 108:

[0830] Nucleotide sequence encoding Homo sapiens ITGB2 (integrin beta 2): Transcript var 1: NM_000211

SEQ ID No. 109:

[0831] Nucleotide sequence encoding Homo sapiens ITGB2 (integrin beta 2): Transcript var 2: NM_001127491.1

SEQ ID No. 110:

[0832] Amino acid sequence of Homo sapiens ITGB2 (integrin beta 2): Protein: NP_000202.2, NP_001120963.1

SEQ ID NO. 111:

[0833] Nucleotide sequence encoding Homo sapiens PTGIS (prostaglandin 12 (prostacyclin) synthase (PTGIS)): Transcript: NM_000961.3

SEQ ID NO. 112:

[0834] Amino acid sequence of Homo sapiens PTGIS (prostaglandin 12 (prostacyclin) synthase (PTGIS)): Protein: NP_000952.1

SEQ ID NO. 113:

[0835] Nucleic acid sequence encoding Homo sapiens BASP1 (brain abundant, membrane attached signal protein 1): Transcript Variant 1: NM_006317

SEQ ID NO. 114:

[0836] Nucleic acid sequence encoding Homo sapiens BASP1 (brain abundant, membrane attached signal protein 1): Transcript variant 2: NM_001271606

SEQ ID NO. 115:

[0837] Amino acid sequences of Homo sapiens BASP1 (brain abundant, membrane attached signal protein 1): Protein: NP_001258535, NP_006308

SEQ ID NO. 116:

[0838] Nucleic acid sequence encoding Homo sapiens DES (Desmin):Transcript: NM_001927

SEQ ID NO. 117:

[0839] Amino acid sequence of Homo sapiens DES (Desmin): Protein: NP_001918

SEQ ID NO. 118:

[0840] Nucleic acid sequence encoding Homo sapiens ITGA2 (integrin, alpha 2): Transcript: NM_002203

SEQ ID NO. 119:

[0841] Amino acid sequence of Homo sapiens ITGA2 (integrin, alpha 2): Protein: NP_002194

SEQ ID NO. 120:

[0842] Nucleic acid sequence encoding Homo sapiens CTSS (Cathepsin S): Transcript variant 1: NM_004079

SEQ ID NO. 121:

[0843] Nucleic acid sequence encoding Homo sapiens CTSS (Cathepsin S): Trascript variant 2: NM_001199739

SEQ ID NO. 122:

[0844] Amino acid sequence of Homo sapiens CTSS (Cathepsin S): Protein variant 1: NP_004070

SEQ ID NO. 123:

[0845] Amino acid sequence of Homo sapiens CTSS (Cathepsin S): Protein variant 2: NP_001186668

SEQ ID NO. 124:

[0846] Nucleic acid sequence encoding Homo sapiens PTPRC (protein tyrosine phosphatase, receptor type, C): Transcript variant 5: NM_001267798

SEQ ID NO. 125:

[0847] Nucleic acid sequence encoding Homo sapiens PTPRC (protein tyrosine phosphatase, receptor type, C): Transcript variant 1: NM_002838

SEQ ID NO. 126:

[0848] Nucleic acid sequence encoding Homo sapiens PTPRC (protein tyrosine phosphatase, receptor type, C): Transcript variant 2: NM_080921

SEQ ID NO. 127:

[0849] Nucleic acid sequence of Homo sapiens PTPRC (protein tyrosine phosphatase, receptor type, C): Transcript variant 4 (Non coding RNA): NR_052021

SEQ ID NO. 128:

[0850] Amino acid sequence of Homo sapiens PTPRC (protein tyrosine phosphatase, receptor type, C): Protein variant 5: NP_001254727

SEQ ID NO. 129:

[0851] Amino acid sequence of Homo sapiens PTPRC (protein tyrosine phosphatase, receptor type, C): Protein variant 1: NP_002829

SEQ ID NO. 130:

[0852] Amino acid sequence of Homo sapiens PTPRC (protein tyrosine phosphatase, receptor type, C): Protein variant 2: NP_563578

SEQ ID NO. 131:

[0853] Nucleic acid sequence encoding Homo sapiens ANPEP (alanyl (membrane) aminopeptidase): Transcript: NM_001150

SEQ ID NO. 132:

[0854] Amino acid sequence of Homo sapiens ANPEP (alanyl (membrane) aminopeptidase): Protein: NP_001141

SEQ ID NO. 133:

[0855] Nucleic acid sequence encoding Homo sapiens FILIP1L (filamin A interacting protein 1-like): Transcript variant 1: NM_182909

SEQ ID NO. 134:

[0856] Nucleic acid sequence encoding Homo sapiens FILIP1L (filamin A interacting protein 1-like): Transcript variant 2: NM_014890

SEQ ID NO. 135:

[0857] Nucleic acid sequence encoding Homo sapiens FILIP1L (filamin A interacting protein 1-like): Transcript variant 3: NM_001042459

SEQ ID NO. 136:

[0858] Amino acid sequence of Homo sapiens FILIP1L (filamin A interacting protein 1-like): Protein variant 1: NP_878913

SEQ ID NO. 137:

[0859] Amino acid sequence of Homo sapiens FILIP1L (filamin A interacting protein 1-like): Protein variant 2: NP_055705

SEQ ID NO. 138:

[0860] Amino acid sequence of Homo sapiens FILIP1L (filamin A interacting protein 1-like): Protein variant 3: NP_001035924

SEQ ID NO. 139:

[0861] Nucleic acid sequence encoding Homo sapiens MGLL (monoglyceride lipase): Transcript variant 1: NM_007283

SEQ ID NO. 140:

[0862] Nucleic acid sequence encoding Homo sapiens MGLL (monoglyceride lipase): Transcript variant 2: NM_001003794

SEQ ID NO. 141:

[0863] Nucleic acid sequence encoding Homo sapiens MGLL (monoglyceride lipase): Transcript variant 3: NM_001256585

SEQ ID NO. 142:

[0864] Amino acid sequence of Homo sapiens MGLL (monoglyceride lipase): Protein variant 1: NP_009214

SEQ ID NO. 143:

[0865] Amino acid sequence of Homo sapiens MGLL (monoglyceride lipase): Protein variant 2: NP_001003794

SEQ ID NO. 144:

[0866] Amino acid sequence of Homo sapiens MGLL (monoglyceride lipase): Protein variant 3: NP_001243514

SEQ ID NO. 145:

[0867] Nucleic acid sequence encoding Homo sapiens OSMR (oncostatin M receptor): Transcript variant 1: NM 003999

SEQ ID NO. 146:

[0868] Nucleic acid sequence encoding Homo sapiens OSMR (oncostatin M receptor): Transcript variant 2: NM_001168355

SEQ ID NO. 147:

[0869] Amino acid sequence of Homo sapiens OSMR (oncostatin M receptor): Protein Variant 1: NP_003990

SEQ ID NO. 148:

[0870] Amino acid sequence of Homo sapiens OSMR (oncostatin M receptor): Protein variant 2: NP_001161827

SEQ ID NO. 149:

[0871] Nucleic acid sequence encoding Homo sapiens ITGB6 (integrin, beta 6): Transcript: NM_000888

SEQ ID NO. 150:

[0872] Amino acid sequence of Homo sapiens ITGB6 (integrin, beta 6): Protein: NP_000879

SEQ ID NO. 151:

[0873] Nucleic acid sequence encoding Homo sapiens AGPAT4 (1-acylglycerol-3-phosphate O-acyltransferase 4): Transcript: NM_020133

SEQ ID NO. 152:

[0874] Amino acid sequence of Homo sapiens AGPAT4 (1-acylglycerol-3-phosphate O-acyltransferase 4): Protein: NP_064518

SEQ ID NO. 153:

[0875] Nucleic acid sequence encoding Homo sapiens ASS1 (argininosuccinate synthase 1): Transcript variant 1: NM_000050

SEQ ID NO. 154:

[0876] Nucleic acid sequence encoding Homo sapiens ASS1 (argininosuccinate synthase 1): Transcript variant 2: NM_054012

SEQ ID NO. 155:

[0877] Amino acid sequence of Homo sapiens ASS1 (argininosuccinate synthase 1): Protein: NP_000041, NP_446464

SEQ ID NO. 156:

[0878] Nucleic acid sequence encoding Homo sapiens CSPG4 (chondroitin sulfate proteoglycan 4): Transcript: NM_001897

SEQ ID NO. 157:

[0879] Amino acid sequence of Homo sapiens CSPG4 (chondroitin sulfate proteoglycan 4): Protein: NP 001888

SEQ ID NO. 158:

[0880] Nucleic acid sequence encoding Homo sapiens CDH11 (cadherin 11, type 2, OB-cadherin): Transcript: NM_001797

SEQ ID NO. 159:

[0881] Amino acid sequence of Homo sapiens CDH11 (cadherin 11, type 2, OB-cadherin): Protein: NP_001788

Sequence CWU 1

1

18713770RNAHomo sapiens 1gacccacagc cuggcacccu ucggcgagcg cuguuuguuu agggcucggu gaguccaauc 60aggagcccag gcugcaguuu uccggcagag caguaagagg cgccuccucu cuccuuuuua 120uucaccagca gcgcggcgca gaccccggac ucgcgcucgc ccgcuggcgc ccucggcuuc 180ucuccgcgcc ugggagcacc cuccgccgcg gccguucucc augcgcagcg cccgcccgag 240gagcuagacg ucagcuugga gcggcgccgg accguggaug gccuugacug acggcggcug 300gugcuugccg aagcgcuucg gggccgcggg ugcggacgcc agcgacucca gagccuuucc 360agcgcgggag cccuccacgc cgccuucccc caucucuucc ucguccuccu ccugcucccg 420gggcggagag cggggccccg gcggcgccag caacugcggg acgccucagc ucgacacgga 480ggcggcggcc ggacccccgg cccgcucgcu gcugcucagu uccuacgcuu cgcaucccuu 540cggggcuccc cacggaccuu cggcgccugg ggucgcgggc cccgggggca accugucgag 600cugggaggac uugcugcugu ucacugaccu cgaccaagcc gcgaccgcca gcaagcugcu 660gugguccagc cgcggcgcca agcugagccc cuucgcaccc gagcagccgg aggagaugua 720ccagacccuc gccgcucucu ccagccaggg uccggccgcc uacgacggcg cgcccggcgg 780cuucgugcac ucugcggccg cggcggcagc agccgcggcg gcggccagcu ccccggucua 840cgugcccacc acccgcgugg guuccaugcu gcccggccua ccguaccacc ugcagggguc 900gggcaguggg ccagccaacc acgcgggcgg cgcgggcgcg caccccggcu ggccucaggc 960cucggccgac agcccuccau acggcagcgg aggcggcgcg gcuggcggcg gggccgcggg 1020gccuggcggc gcuggcucag ccgcggcgca cgucucggcg cgcuuccccu acucucccag 1080cccgcccaug gccaacggcg ccgcgcggga gccgggaggc uacgcggcgg cgggcagugg 1140gggcgcggga ggcgugagcg gcggcggcag uagccuggcg gccaugggcg gccgcgagcc 1200ccaguacagc ucgcugucgg ccgcgcggcc gcugaacggg acguaccacc accaccacca 1260ccaccaccac caccauccga gccccuacuc gcccuacgug ggggcgccac ugacgccugc 1320cuggcccgcc ggacccuucg agaccccggu gcugcacagc cugcagagcc gcgccggagc 1380cccgcucccg gugccccggg gucccagugc agaccugcug gaggaccugu ccgagagccg 1440cgagugcgug aacugcggcu ccauccagac gccgcugugg cggcgggacg gcaccggcca 1500cuaccugugc aacgccugcg ggcucuacag caagaugaac ggccucagcc ggccccucau 1560caagccgcag aagcgcgugc cuucaucacg gcggcuugga uuguccugug ccaacuguca 1620caccacaacu accaccuuau ggcgcagaaa cgccgagggu gaacccgugu gcaaugcuug 1680uggacucuac augaaacucc auggggugcc cagaccacuu gcuaugaaaa aagagggaau 1740ucaaaccagg aaacgaaaac cuaagaacau aaauaaauca aagacuugcu cugguaauag 1800caauaauucc auucccauga cuccaacuuc caccucuucu aacucagaug auugcagcaa 1860aaauacuucc cccacaacac aaccuacagc cucaggggcg ggugccccgg ugaugacugg 1920ugcgggagag agcaccaauc ccgagaacag cgagcucaag uauucggguc aagaugggcu 1980cuacauaggc gucagucucg ccucgccggc cgaagucacg uccuccgugc gaccggauuc 2040cuggugcgcc cuggcccugg ccugagccca cgccgccagg aggcagggag ggcuccgccg 2100cgggccucac uccacucgug ucugcuuuug ugcagcgguc cagacagugg cgacugcgcu 2160gacagaacgu gauucucgug ccuuuauuuu gaaagagaug uuuuucccaa gaggcuugcu 2220gaaagaguga gagaagaugg aagggaaggg ccagugcaac ugggcgcuug ggccacucca 2280gccagcccgc cuccggggcg gacccugcuc cacuuccaga agccaggacu aggaccuggg 2340ccuugccugc uauggaauau ugagagagau uuuuuaaaaa agauuuugca uuuuguccaa 2400aaucaugugc uucuucugau caauuuuggu uguuccagaa uuucuucaua ccuuuuccac 2460auccagauuu caugugcguu cauggagaag aucacuugag gccauuuggu acacaucucu 2520ggaggcugag ucgguucaug aggucucuua ucaaaaauau uacucaguuu gcaagacugc 2580auuguaacuu uaacauacac ugugacugac guuucucaaa guucauauug uguggcugau 2640cugaagucag ucggaauuug uaaacagggu agcaaacaag auauuuuucu uccauguaua 2700caauaauuuu uuuaaaaagu gcaauuugcg uugcagcaau caguguuaaa ucauuugcau 2760aagauuuaac agcauuuuuu auaaugaaug uaaacauuuu aacuuaaugg uacuuaaaau 2820aauuuaaaag aaaaauguua acuuagacau ucuuaugcuu cuuuuacaac uacaucccau 2880uuuauauuuc caauuguuaa agaaaaauau uucaagaaca aaucuucucu caggaaaauu 2940gccuuucucu auuuguuaag aauuuuuaua caagaacacc aauauacccc cuuuauuuua 3000cuguggaaua ugugcuggaa aaauugcaac aacacuuuac uaccuaacgg auagcauuug 3060uaaauacucu agguaucugu aaacacucug augaagucug uauaguguga cuaacccaca 3120ggcagguugg uuuacauuaa uuuuuuuuuu ugaaugggau guccuaugga aaccuauuuc 3180accagaguuu uaaaaauaaa aaggguauug uuuugucuuc uguacaguga guuccuuccc 3240uuuucaaagc uuucuuuuua ugcuguaugu gacuauagau auucauauaa aacaagugca 3300cgugaaguuu gcaaaaugcu uuaaggccuu ccuuucaaag cauaguccuu uuggagccgu 3360uuuguaccuu uuauaccuug gcuuauuuga aguugacaca ugggguuagu uacuacucuc 3420caugugcauu ggggacaguu uuuauaagug ggaaggacuc aguauuauua uauuugagau 3480gauaagcauu uuguuuggga acaaugcuua aaaauauucc agaaaguuca gauuuuuuuu 3540cuuugugaau gaaauauauu cuggcccacg aacagggcga uuuccuuuca guuuuuuccu 3600uuugcaacgu gccuugaagu cucaaagcuc accugagguu gcagacguua cccccaacag 3660aagauaggua gaaaugauuc caguggccuc uuuguauuuu cuucauuguu gaguagauuu 3720caggaaauca ggagguguuu cacaauacag aaugauggcc uuuaacugug 377022352RNAHomo sapiens 2gaaacuuaaa gguguuuacc uugucaucag cauguaagcu aauuaucucg ggcaagaugu 60aggcuucuau ugucuuguug cuuuagcgcu uacgccccgc cucugguggc ugccuaaaac 120cuggcgccgg gcuaaaacaa acgcgaggca gcccccgagc cuccacucaa gccaauuaag 180gaggacucgg uccacuccgu uacguguaca uccaacaaga ucggcguuaa gguaacacca 240gaauauuugg caaagggaga aaaaaaaagc agcgaggcuu cgccuucccc cucucccuuu 300uuuuuccucc ucuuccuucc uccuccagcc gccgccgaau caugucgaug aguccaaagc 360acacgacucc guucucagug ucugacaucu ugaguccccu ggaggaaagc uacaagaaag 420ugggcaugga gggcggcggc cucggggcuc cgcuggcggc guacaggcag ggccaggcgg 480caccgccaac agcggccaug cagcagcacg ccguggggca ccacggcgcc gucaccgccg 540ccuaccacau gacggcggcg ggggugcccc agcucucgca cuccgccgug gggggcuacu 600gcaacggcaa ccugggcaac augagcgagc ugccgccgua ccaggacacc augaggaaca 660gcgccucugg ccccggaugg uacggcgcca acccagaccc gcgcuucccc gccaucuccc 720gcuucauggg cccggcgagc ggcaugaaca ugagcggcau gggcggccug ggcucgcugg 780gggacgugag caagaacaug gccccgcugc caagcgcgcc gcgcaggaag cgccgggugc 840ucuucucgca ggcgcaggug uacgagcugg agcgacgcuu caagcaacag aaguaccugu 900cggcgccgga gcgcgagcac cuggccagca ugauccaccu gacgcccacg caggucaaga 960ucugguucca gaaccaccgc uacaaaauga agcgccaggc caaggacaag gcggcgcagc 1020agcaacugca gcaggacagc ggcggcggcg ggggcggcgg gggcaccggg ugcccgcagc 1080agcaacaggc ucagcagcag ucgccgcgac gcguggcggu gccgguccug gugaaagacg 1140gcaaaccgug ccaggcgggu gcccccgcgc cgggcgccgc cagccuacaa ggccacgcgc 1200agcagcaggc gcagcaccag gcgcaggccg cgcaggcggc ggcagcggcc aucuccgugg 1260gcagcggugg cgccggccuu ggcgcacacc cgggccacca gccaggcagc gcaggccagu 1320cuccggaccu ggcgcaccac gccgccagcc ccgcggcgcu gcagggccag guauccagcc 1380ugucccaccu gaacuccucg ggcucggacu acggcaccau guccugcucc accuugcuau 1440acggucggac cuggugagag gacgccgggc cggcccuagc ccagcgcucu gccucaccgc 1500uucccuccug cccgccacac agaccaccau ccaccgcugc uccacgcgcu ucgacuuuuc 1560uuaacaaccu ggccgcguuu agaccaagga acaaaaaaac cacaaaggcc aaacugcugg 1620acgucuuucu uuuuuucccc cccuaaaauu uguggguuuu uuuuuuuaaa aaaagaaaau 1680gaaaaacaac caagcgcauc caaucucaag gaaucuuuaa gcagagaagg gcauaaaaca 1740gcuuuggggu gucuuuuuuu ggugauucaa auggguuuuc cacgcuaggg cggggcacag 1800auuggagagg gcucugugcu gacauggcuc uggacucuaa agaccaaacu ucacucuggg 1860cacacucugc cagcaaagag gacucgcuug uaaauaccag gauuuuuuuu uuuuuuugaa 1920gggaggacgg gagcugggga gaggaaagag ucuucaacau aacccacuug ucacugacac 1980aaaggaagug cccccucccc ggcacccucu ggccgccuag gcucagcggc gaccgcccuc 2040cgcgaaaaua guuuguuuaa ugugaacuug uagcuguaaa acgcugucaa aaguuggacu 2100aaaugccuag uuuuuaguaa ucuguacauu uuguuguaaa aagaaaaacc acucccaguc 2160cccagcccuu cacauuuuuu augggcauug acaaaucugu guauauuauu uggcaguuug 2220guauuugcgg cgucagucuu uuucuguugu aacuuaugua gauauuuggc uuaaauauag 2280uuccuaagaa gcuucuaaua aauuauacaa auuaaaaaga uucuuuuucu gauuaaaaaa 2340aaaaaaaaaa aa 235232428RNAHomo sapiens 3cccgcccacu uccaacuacc gccuccggcc ugcccaggga gagagaggga guggagccca 60gggagaggga gcgcgagaga gggagggagg aggggacggu gcuuuggcug acuuuuuuuu 120aaaagagggu gggggugggg ggugauugcu ggucguuugu uguggcuguu aaauuuuaaa 180cugccaugca cucggcuucc aguaugcugg gagcggugaa gauggaaggg cacgagccgu 240ccgacuggag cagcuacuau gcagagcccg agggcuacuc cuccgugagc aacaugaacg 300ccggccuggg gaugaacggc augaacacgu acaugagcau gucggcggcc gccaugggca 360gcggcucggg caacaugagc gcgggcucca ugaacauguc gucguacgug ggcgcuggca 420ugagcccguc ccuggcgggg augucccccg gcgcgggcgc cauggcgggc augggcggcu 480cggccggggc ggccggcgug gcgggcaugg ggccgcacuu gagucccagc cugagcccgc 540ucggggggca ggcggccggg gccaugggcg gccuggcccc cuacgccaac augaacucca 600ugagccccau guacgggcag gcgggccuga gccgcgcccg cgaccccaag accuacaggc 660gcagcuacac gcacgcaaag ccgcccuacu cguacaucuc gcucaucacc auggccaucc 720agcagagccc caacaagaug cugacgcuga gcgagaucua ccaguggauc auggaccucu 780uccccuucua ccggcagaac cagcagcgcu ggcagaacuc cauccgccac ucgcucuccu 840ucaacgacug uuuccugaag gugccccgcu cgcccgacaa gcccggcaag ggcuccuucu 900ggacccugca cccugacucg ggcaacaugu ucgagaacgg cugcuaccug cgccgccaga 960agcgcuucaa gugcgagaag cagcuggcgc ugaaggaggc cgcaggcgcc gccggcagcg 1020gcaagaaggc ggccgccgga gcccaggccu cacaggcuca acucggggag gccgccgggc 1080cggccuccga gacuccggcg ggcaccgagu cgccucacuc gagcgccucc ccgugccagg 1140agcacaagcg agggggccug ggagagcuga aggggacgcc ggcugcggcg cugagccccc 1200cagagccggc gcccucuccc gggcagcagc agcaggccgc ggcccaccug cugggcccgc 1260cccaccaccc gggccugccg ccugaggccc accugaagcc ggaacaccac uacgccuuca 1320accacccguu cuccaucaac aaccucaugu ccucggagca gcagcaccac cacagccacc 1380accaccacca accccacaaa auggaccuca aggccuacga acaggugaug cacuaccccg 1440gcuacgguuc ccccaugccu ggcagcuugg ccaugggccc ggucacgaac aaaacgggcc 1500uggacgccuc gccccuggcc gcagauaccu ccuacuacca ggggguguac ucccggccca 1560uuaugaacuc cucuuaagaa gacgacggcu ucaggcccgg cuaacucugg caccccggau 1620cgaggacaag ugagagagca aguggggguc gagacuuugg ggagacggug uugcagagac 1680gcaagggaga agaaauccau aacaccccca ccccaacacc cccaagacag cagucuucuu 1740cacccgcugc agccguuccg ucccaaacag agggccacac agauacccca cguucuauau 1800aaggaggaaa acgggaaaga auauaaaguu aaaaaaaagc cuccgguuuc cacuacugug 1860uagacuccug cuucuucaag caccugcaga uucugauuuu uuuguuguug uuguucuccu 1920ccauugcugu uguugcaggg aagucuuacu uaaaaaaaaa aaaaaauuuu gugagugacu 1980cgguguaaaa ccauguaguu uuaacagaac cagaggguug uacuauuguu uaaaaacagg 2040aaaaaaaaua auguaagggu cuguuguaaa ugaccaagaa aaagaaaaaa aaagcauucc 2100caaucuugac acggugaaau ccaggucucg gguccgauua auuuaugguu ucugcgugcu 2160uuauuuaugg cuuauaaaug uguauucugg cugcaagggc cagaguucca caaaucuaua 2220uuaaaguguu auacccgguu uuaucccuug aaucuuuucu uccagauuuu ucuuuucuuu 2280acuuggcuua caaaauauac aggcuuggaa auuauuucaa gaaggaggga gggauacccu 2340gucugguugc agguuguauu uuauuuuggc ccagggagug uugcuguuuu cccaacauuu 2400uauuaauaaa auuuucagac auaaaaaa 242841402RNAHomo sapiens 4ggggacgaag ggaagcucca gcguguggcc ccggcgagug cggauaaaag ccgccccgcc 60gggcucgggc uucauucuga gccgagcccg gugccaagcg cagcuagcuc agcaggcggc 120agcggcggcc ugagcuucag ggcagccagc ucccucccgg ucucgccuuc ccucgcgguc 180agcaugaaag ccuucagucc cgugaggucc guuaggaaaa acagccuguc ggaccacagc 240cugggcaucu cccggagcaa aaccccugug gacgacccga ugagccugcu auacaacaug 300aacgacugcu acuccaagcu caaggagcug gugcccagca ucccccagaa caagaaggug 360agcaagaugg aaauccugca gcacgucauc gacuacaucu uggaccugca gaucgcccug 420gacucgcauc ccacuauugu cagccugcau caccagagac ccgggcagaa ccaggcgucc 480aggacgccgc ugaccacccu caacacggau aucagcaucc uguccuugca ggcuucugaa 540uucccuucug aguuaauguc aaaugacagc aaagcacugu guggcugaau aagcgguguu 600caugauuucu uuuauucuuu gcacaacaac aacaacaaca aauucacgga aucuuuuaag 660ugcugaacuu auuuuucaac cauuucacaa ggaggacaag uugaauggac cuuuuuaaaa 720agaaaaaaaa aauggaagga aaacuaagaa ugaucaucuu cccagggugu ucucuuacuu 780ggacugugau auucguuauu uaugaaaaag acuuuuaaau gcccuuucug caguuggaag 840guuuucuuua uauacuauuc ccaccauggg gagcgaaaac guuaaaauca caaggaauug 900cccaaucuaa gcagacuuug ccuuuuuuca aagguggagc gugaauacca gaaggaucca 960guauucaguc acuuaaauga agucuuuugg ucagaaauua ccuuuuugac acaagccuac 1020ugaaugcugu guauauauuu auauauaaau auaucuauuu gagugaaacc uugugaacuc 1080uuuaauuaga guuuucuugu auaguggcag agaugucuau uucugcauuc aaaaguguaa 1140ugauguacuu auucaugcua aacuuuuuau aaaaguuuag uuguaaacuu aacccuuuua 1200uacaaaauaa aucaagugug uuuauugaau ggugauugcc ugcuuuauuu cagaggacca 1260gugcuuugau uuuuauuaug cuauguuaua acugaaccca aauaaauaca aguucaaauu 1320uauguagacu guauaagauu auaauaaaac augucugaag ucaaaaaaaa aaaaaaaaaa 1380aaaaaaaaaa aaaaaaaaaa aa 140253158RNAHomo sapiens 5auugaucucc acgcccgggg cagaaauagg aucuuugaga agucucaaau gggaucuuug 60agaagucaga ucccauuuga acuagaaaaa ggaguggagg cgagguagcg ugcagccuac 120gcucuuguua acccgucgau cuccuaccau acccgucucc cccaccccac cucaggagcu 180agacgucagc uuggagcggc gccggaccgu ggauggccuu gacugacggc ggcuggugcu 240ugccgaagcg cuucggggcc gcgggugcgg acgccagcga cuccagagcc uuuccagcgc 300gggagcccuc cacgccgccu ucccccaucu cuuccucguc cuccuccugc ucccggggcg 360gagagcgggg ccccggcggc gccagcaacu gcgggacgcc ucagcucgac acggaggcgg 420cggccggacc cccggcccgc ucgcugcugc ucaguuccua cgcuucgcau cccuucgggg 480cuccccacgg accuucggcg ccuggggucg cgggccccgg gggcaaccug ucgagcuggg 540aggacuugcu gcuguucacu gaccucgacc aagccgcgac cgccagcaag cugcuguggu 600ccagccgcgg cgccaagcug agccccuucg cacccgagca gccggaggag auguaccaga 660cccucgccgc ucucuccagc caggguccgg ccgccuacga cggcgcgccc ggcggcuucg 720ugcacucugc ggccgcggcg gcagcagccg cggcggcggc cagcuccccg gucuacgugc 780ccaccacccg cguggguucc augcugcccg gccuaccgua ccaccugcag gggucgggca 840gugggccagc caaccacgcg ggcggcgcgg gcgcgcaccc cggcuggccu caggccucgg 900ccgacagccc uccauacggc agcggaggcg gcgcggcugg cggcggggcc gcggggccug 960gcggcgcugg cucagccgcg gcgcacgucu cggcgcgcuu ccccuacucu cccagcccgc 1020ccauggccaa cggcgccgcg cgggagccgg gaggcuacgc ggcggcgggc agugggggcg 1080cgggaggcgu gagcggcggc ggcaguagcc uggcggccau gggcggccgc gagccccagu 1140acagcucgcu gucggccgcg cggccgcuga acgggacgua ccaccaccac caccaccacc 1200accaccacca uccgagcccc uacucgcccu acgugggggc gccacugacg ccugccuggc 1260ccgccggacc cuucgagacc ccggugcugc acagccugca gagccgcgcc ggagccccgc 1320ucccggugcc ccgggguccc agugcagacc ugcuggagga ccuguccgag agccgcgagu 1380gcgugaacug cggcuccauc cagacgccgc uguggcggcg ggacggcacc ggccacuacc 1440ugugcaacgc cugcgggcuc uacagcaaga ugaacggccu cagccggccc cucaucaagc 1500cgcagaagcg cgugccuuca ucacggcggc uuggauuguc cugugccaac ugucacacca 1560caacuaccac cuuauggcgc agaaacgccg agggugaacc cgugugcaau gcuuguggac 1620ucuacaugaa acuccauggg gugcccagac cacuugcuau gaaaaaagag ggaauucaaa 1680ccaggaaacg aaaaccuaag aacauaaaua aaucaaagac uugcucuggu aauagcaaua 1740auuccauucc caugacucca acuuccaccu cuucuaacuc agaugauugc agcaaaaaua 1800cuucccccac aacacaaccu acagccucag gggcgggugc cccggugaug acuggugcgg 1860gagagagcac caaucccgag aacagcgagc ucaaguauuc gggucaagau gggcucuaca 1920uaggcgucag ucucgccucg ccggccgaag ucacguccuc cgugcgaccg gauuccuggu 1980gcgcccuggc ccuggccuga gcccacgccg ccaggaggca gggagggcuc cgccgcgggc 2040cucacuccac ucgugucugc uuuugugcag cgguccagac aguggcgacu gcgcugacag 2100aacgugauuc ucgugccuuu auuuugaaag agauguuuuu cccaagaggc uugcugaaag 2160agugagagaa gauggaaggg aagggccagu gcaacugggc gcuugggcca cuccagccag 2220cccgccuccg gggcggaccc ugcuccacuu ccagaagcca ggacuaggac cugggccuug 2280ccugcuaugg aauauugaga gagauuuuuu aaaaaagauu uugcauuuug uccaaaauca 2340ugugcuucuu cugaucaauu uugguuguuc cagaauuucu ucauaccuuu uccacaucca 2400gauuucaugu gcguucaugg agaagaucac uugaggccau uugguacaca ucucuggagg 2460cugagucggu ucaugagguc ucuuaucaaa aauauuacuc aguuugcaag acugcauugu 2520aacuuuaaca uacacuguga cugacguuuc ucaaaguuca uauugugugg cugaucugaa 2580gucagucgga auuuguaaac aggguagcaa acaagauauu uuucuuccau guauacaaua 2640auuuuuuuaa aaagugcaau uugcguugca gcaaucagug uuaaaucauu ugcauaagau 2700uuaacagcau uuuuuauaau gaauguaaac auuuuaacuu aaugguacuu aaaauaauuu 2760aaaagaaaaa uguuaacuua gacauucuua ugcuucuuuu acaacuacau cccauuuuau 2820auuuccaauu guuaaagaaa aauauuucaa gaacaaaucu ucucucagga aaauugccuu 2880ucucuauuug uuaagaauuu uuauacaaga acaccaauau acccccuuua uuuuacugug 2940gaauaugugc uggaaaaauu gcaacaacac uuuacuaccu aacggauagc auuuguaaau 3000acucuaggua ucuguaaaca cucugaugaa gucuguauag ugugacuaac ccacaggcag 3060guugguuuac auuaauuuuu uuuuuugaau gggauguccu auggaaaccu auuucaccag 3120aguuuuaaaa auaaaaaggg uauuguuuug ucuucugu 315862197RNAHomo sapiens 6cugacagaca cguagaccaa cagugcggcc ccaggguucg uccccagacu cgcucgcuca 60uuuguuggcg acuggggcuc agcgcagcga agcccgaugu gguccggagg cagugggaag 120gcgcggggcu gggaggccgc ggcgggaggg aggagcagcc ccggcaggcu cagccgccgc 180cgaaucaugu cgaugagucc aaagcacacg acuccguucu cagugucuga caucuugagu 240ccccuggagg aaagcuacaa gaaagugggc auggagggcg gcggccucgg ggcuccgcug 300gcggcguaca ggcagggcca ggcggcaccg ccaacagcgg ccaugcagca gcacgccgug 360gggcaccacg gcgccgucac cgccgccuac cacaugacgg cggcgggggu gccccagcuc 420ucgcacuccg ccgugggggg cuacugcaac ggcaaccugg gcaacaugag cgagcugccg 480ccguaccagg acaccaugag gaacagcgcc ucuggccccg gaugguacgg cgccaaccca 540gacccgcgcu uccccgccau cucccgcuuc augggcccgg cgagcggcau gaacaugagc 600ggcaugggcg gccugggcuc gcugggggac gugagcaaga acauggcccc gcugccaagc 660gcgccgcgca ggaagcgccg ggugcucuuc ucgcaggcgc agguguacga gcuggagcga 720cgcuucaagc aacagaagua ccugucggcg ccggagcgcg agcaccuggc cagcaugauc 780caccugacgc ccacgcaggu caagaucugg uuccagaacc accgcuacaa aaugaagcgc 840caggccaagg acaaggcggc gcagcagcaa cugcagcagg acagcggcgg cggcgggggc 900ggcgggggca ccgggugccc gcagcagcaa caggcucagc agcagucgcc gcgacgcgug 960gcggugccgg uccuggugaa agacggcaaa ccgugccagg cgggugcccc cgcgccgggc 1020gccgccagcc uacaaggcca cgcgcagcag caggcgcagc accaggcgca ggccgcgcag 1080gcggcggcag cggccaucuc cgugggcagc gguggcgccg gccuuggcgc acacccgggc 1140caccagccag gcagcgcagg ccagucuccg gaccuggcgc accacgccgc cagccccgcg 1200gcgcugcagg gccagguauc cagccugucc caccugaacu ccucgggcuc ggacuacggc 1260accauguccu gcuccaccuu gcuauacggu cggaccuggu gagaggacgc cgggccggcc 1320cuagcccagc gcucugccuc accgcuuccc uccugcccgc cacacagacc accauccacc 1380gcugcuccac gcgcuucgac uuuucuuaac aaccuggccg cguuuagacc aaggaacaaa 1440aaaaccacaa aggccaaacu gcuggacguc uuucuuuuuu ucccccccua aaauuugugg 1500guuuuuuuuu uuaaaaaaag aaaaugaaaa acaaccaagc gcauccaauc ucaaggaauc 1560uuuaagcaga gaagggcaua aaacagcuuu ggggugucuu uuuuugguga uucaaauggg 1620uuuuccacgc uagggcgggg cacagauugg agagggcucu gugcugacau ggcucuggac

1680ucuaaagacc aaacuucacu cugggcacac ucugccagca aagaggacuc gcuuguaaau 1740accaggauuu uuuuuuuuuu uugaagggag gacgggagcu ggggagagga aagagucuuc 1800aacauaaccc acuugucacu gacacaaagg aagugccccc uccccggcac ccucuggccg 1860ccuaggcuca gcggcgaccg cccuccgcga aaauaguuug uuuaauguga acuuguagcu 1920guaaaacgcu gucaaaaguu ggacuaaaug ccuaguuuuu aguaaucugu acauuuuguu 1980guaaaaagaa aaaccacucc caguccccag cccuucacau uuuuuauggg cauugacaaa 2040ucuguguaua uuauuuggca guuugguauu ugcggcguca gucuuuuucu guuguaacuu 2100auguagauau uuggcuuaaa uauaguuccu aagaagcuuc uaauaaauua uacaaauuaa 2160aaagauucuu uuucugauua aaaaaaaaaa aaaaaaa 219772415RNAHomo sapiens 7cggccgcugc uagaggggcu gcuugcgcca ggcgccggcc gccccacugc gggucccugg 60cggccggugu cugaggaguc ggagagccga ggcggccaga ccgugcgccc cgcgcuucuc 120ccgaggccgu uccgggucug aacuguaaca gggaggggcc ucgcaggagc agcagcgggc 180gaguuaaagu augcugggag cggugaagau ggaagggcac gagccguccg acuggagcag 240cuacuaugca gagcccgagg gcuacuccuc cgugagcaac augaacgccg gccuggggau 300gaacggcaug aacacguaca ugagcauguc ggcggccgcc augggcagcg gcucgggcaa 360caugagcgcg ggcuccauga acaugucguc guacgugggc gcuggcauga gcccgucccu 420ggcggggaug ucccccggcg cgggcgccau ggcgggcaug ggcggcucgg ccggggcggc 480cggcguggcg ggcauggggc cgcacuugag ucccagccug agcccgcucg gggggcaggc 540ggccggggcc augggcggcc uggcccccua cgccaacaug aacuccauga gccccaugua 600cgggcaggcg ggccugagcc gcgcccgcga ccccaagacc uacaggcgca gcuacacgca 660cgcaaagccg cccuacucgu acaucucgcu caucaccaug gccauccagc agagccccaa 720caagaugcug acgcugagcg agaucuacca guggaucaug gaccucuucc ccuucuaccg 780gcagaaccag cagcgcuggc agaacuccau ccgccacucg cucuccuuca acgacuguuu 840ccugaaggug ccccgcucgc ccgacaagcc cggcaagggc uccuucugga cccugcaccc 900ugacucgggc aacauguucg agaacggcug cuaccugcgc cgccagaagc gcuucaagug 960cgagaagcag cuggcgcuga aggaggccgc aggcgccgcc ggcagcggca agaaggcggc 1020cgccggagcc caggccucac aggcucaacu cggggaggcc gccgggccgg ccuccgagac 1080uccggcgggc accgagucgc cucacucgag cgccuccccg ugccaggagc acaagcgagg 1140gggccuggga gagcugaagg ggacgccggc ugcggcgcug agccccccag agccggcgcc 1200cucucccggg cagcagcagc aggccgcggc ccaccugcug ggcccgcccc accacccggg 1260ccugccgccu gaggcccacc ugaagccgga acaccacuac gccuucaacc acccguucuc 1320caucaacaac cucauguccu cggagcagca gcaccaccac agccaccacc accaccaacc 1380ccacaaaaug gaccucaagg ccuacgaaca ggugaugcac uaccccggcu acgguucccc 1440caugccuggc agcuuggcca ugggcccggu cacgaacaaa acgggccugg acgccucgcc 1500ccuggccgca gauaccuccu acuaccaggg gguguacucc cggcccauua ugaacuccuc 1560uuaagaagac gacggcuuca ggcccggcua acucuggcac cccggaucga ggacaaguga 1620gagagcaagu gggggucgag acuuugggga gacgguguug cagagacgca agggagaaga 1680aauccauaac acccccaccc caacaccccc aagacagcag ucuucuucac ccgcugcagc 1740cguuccgucc caaacagagg gccacacaga uaccccacgu ucuauauaag gaggaaaacg 1800ggaaagaaua uaaaguuaaa aaaaagccuc cgguuuccac uacuguguag acuccugcuu 1860cuucaagcac cugcagauuc ugauuuuuuu guuguuguug uucuccucca uugcuguugu 1920ugcagggaag ucuuacuuaa aaaaaaaaaa aaauuuugug agugacucgg uguaaaacca 1980uguaguuuua acagaaccag aggguuguac uauuguuuaa aaacaggaaa aaaaauaaug 2040uaagggucug uuguaaauga ccaagaaaaa gaaaaaaaaa gcauucccaa ucuugacacg 2100gugaaaucca ggucucgggu ccgauuaauu uaugguuucu gcgugcuuua uuuauggcuu 2160auaaaugugu auucuggcug caagggccag aguuccacaa aucuauauua aaguguuaua 2220cccgguuuua ucccuugaau cuuuucuucc agauuuuucu uuucuuuacu uggcuuacaa 2280aauauacagg cuuggaaauu auuucaagaa ggagggaggg auacccuguc ugguugcagg 2340uuguauuuua uuuuggccca gggaguguug cuguuuuccc aacauuuuau uaauaaaauu 2400uucagacaua aaaaa 241581681RNAHomo sapiens 8caaaggcggc cuggccagcg cggagcuccc ggcccggagc ugcuucugau uaccgcgagg 60ggcccggacg cgagagccgc cgcggggccu gcccuagagg cggagugaug aacuguggcu 120uccccccugc ggugcugaac ucgcccgugu agcugugauu uuagagcugc cgacagcucu 180aagcugggcu cgcgccccgc ccaccccgcg gggauuggcu gcgaacgcgg aagaaccaag 240cccacgcccc gcgcccgcgc ccaccaaugg aagcgcccgc ucgucuugau agacgugcca 300ccuuccgcca auggggacga agggaagcuc cagcgugugg ccccggcgag ugcggauaaa 360agccgccccg ccgggcucgg gcuucauucu gagccgagcc cggugccaag cgcagcuagc 420ucagcaggcg gcagcggcgg ccugagcuuc agggcagcca gcucccuccc ggucucgccu 480ucccucgcgg ucagcaugaa agccuucagu cccgugaggu ccguuaggaa aaacagccug 540ucggaccaca gccugggcau cucccggagc aaaaccccug uggacgaccc gaugagccug 600cuauacaaca ugaacgacug cuacuccaag cucaaggagc uggugcccag caucccccag 660aacaagaagg ugagcaagau ggaaauccug cagcacguca ucgacuacau cuuggaccug 720cagaucgccc uggacucgca ucccacuauu gucagccugc aucaccagag acccgggcag 780aaccaggcgu ccaggacgcc gcugaccacc cucaacacgg auaucagcau ccuguccuug 840caggcuucug aauucccuuc ugaguuaaug ucaaaugaca gcaaagcacu guguggcuga 900auaagcggug uucaugauuu cuuuuauucu uugcacaaca acaacaacaa caaauucacg 960gaaucuuuua agugcugaac uuauuuuuca accauuucac aaggaggaca aguugaaugg 1020accuuuuuaa aaagaaaaaa aaaauggaag gaaaacuaag aaugaucauc uucccagggu 1080guucucuuac uuggacugug auauucguua uuuaugaaaa agacuuuuaa augcccuuuc 1140ugcaguugga agguuuucuu uauauacuau ucccaccaug gggagcgaaa acguuaaaau 1200cacaaggaau ugcccaaucu aagcagacuu ugccuuuuuu caaaggugga gcgugaauac 1260cagaaggauc caguauucag ucacuuaaau gaagucuuuu ggucagaaau uaccuuuuug 1320acacaagccu acugaaugcu guguauauau uuauauauaa auauaucuau uugagugaaa 1380ccuugugaac ucuuuaauua gaguuuucuu guauaguggc agagaugucu auuucugcau 1440ucaaaagugu aaugauguac uuauucaugc uaaacuuuuu auaaaaguuu aguuguaaac 1500uuaacccuuu uauacaaaau aaaucaagug uguuuauuga auggugauug ccugcuuuau 1560uucagaggac cagugcuuug auuuuuauua ugcuauguua uaacugaacc caaauaaaua 1620caaguucaaa uuuauguaga cuguauaaga uuauaauaaa acaugucuga agucaauacc 1680u 1681921DNAArtificial sequenceSynthetic nucleotide 9ctcggcttct ctccgcgcct g 211020DNAArtificial sequenceSynthetic nucleotide 10ttgactgacg gcggctggtg 201121DNAArtificial sequenceSynthetic nucleotide 11agctgaggcg tcccgcagtt g 211220DNAArtificial sequenceSynthetic nucleotide 12ctcccgcgct ggaaaggctc 201320DNAArtificial sequenceSynthetic nucleotide 13gcggtttcgt tttcggggac 201420DNAArtificial sequenceSynthetic nucleotide 14aggacccaga ctgctgcccc 201520DNAArtificial sequenceSynthetic nucleotide 15aagggatgcg aagcgtagga 201620DNAArtificial sequenceSynthetic nucleotide 16ctgaccagcc cgaacgcgag 201720DNAArtificial sequenceSynthetic nucleotide 17aaacctggcg ccgggctaaa 201820DNAArtificial sequenceSynthetic nucleotide 18cagcgaggct tcgccttccc 201921DNAArtificial sequenceSynthetic nucleotide 19ggagaggggg aaggcgaagc c 212020DNAArtificial sequenceSynthetic nucleotide 20tcgacatgat tcggcggcgg 202120DNAArtificial sequenceSynthetic nucleotide 21agcgaagccc gatgtggtcc 202220DNAArtificial sequenceSynthetic nucleotide 22tccggaggca gtgggaaggc 202321DNAArtificial sequenceSynthetic nucleotide 23ccgccctcca tgcccacttt c 212420DNAArtificial sequenceSynthetic nucleotide 24gacatgattc ggcggcggct 202521DNAArtificial sequenceSynthetic nucleotide 25tgccatgcac tcggcttcca g 212620DNAArtificial sequenceSynthetic nucleotide 26cagggagagg gagggcgaga 202720DNAArtificial sequenceSynthetic nucleotide 27tcatgttgcc cgagccgctg 202820DNAArtificial sequenceSynthetic nucleotide 28cccccacccc caccctcttt 202921DNAArtificial sequenceSynthetic nucleotide 29ctgctagagg ggctgcttgc g 213020DNAArtificial sequenceSynthetic nucleotide 30cgcttctccc gaggccgttc 203120DNAArtificial sequenceSynthetic nucleotide 31acggctcgtg cccttccatc 203220DNAArtificial sequenceSynthetic nucleotide 32taactcgccc gctgctgctc 203320DNAArtificial sequenceSynthetic nucleotide 33aacccctgtg gacgacccga 203420DNAArtificial sequenceSynthetic nucleotide 34tgcggataaa agccgccccg 203520DNAArtificial sequenceSynthetic nucleotide 35gcccgggtct ctggtgatgc 203620DNAArtificial sequenceSynthetic nucleotide 36agctagctgc gcttggcacc 203720DNAArtificial sequenceSynthetic nucleotide 37ctgcggtgct gaactcgccc 203820DNAArtificial sequenceSynthetic nucleotide 38ccccctgcgg tgctgaactc 203920DNAArtificial sequenceSynthetic nucleotide 39gacgagcggg cgcttccatt 204020DNAArtificial sequenceSynthetic nucleotide 40taactcgccc gctgctgctc 204121DNAArtificial sequenceSynthetic nucleotide 41ucaggagcgc aggcugcagt t 214221DNAArtificial sequenceSynthetic nucleotide 42gaggcgccuc cucucuccut t 214321DNAArtificial sequenceSynthetic nucleotide 43cugcagccug cgcuccugat t 214421DNAArtificial sequenceSynthetic nucleotide 44aggagagagg aggcgccuct t 214521DNAArtificial sequenceSynthetic nucleotide 45accgccaugc acucggcuut t 214621DNAArtificial sequenceSynthetic nucleotide 46aagccgagug cauggcggut t 214758DNAArtificial sequenceSynthetic nucleotide 47ccggcccatg aagaagaaag caattctcga gaattgcttt cttcttcatg ggtttttg 584862DNAArtificial sequenceSynthetic nucleotide 48gtaccggggg atcatccttg tagataaact cgagtttatc tacaaggatg atcccttttt 60tg 624958DNAArtificial sequenceSynthetic nucleotide 49ccggattcgg aatcagctag caattctcga gaattgctag ctgattccga attttttg 5850595PRTHomo sapiens 50Met Ala Leu Thr Asp Gly Gly Trp Cys Leu Pro Lys Arg Phe Gly Ala1 5 10 15Ala Gly Ala Asp Ala Ser Asp Ser Arg Ala Phe Pro Ala Arg Glu Pro 20 25 30Ser Thr Pro Pro Ser Pro Ile Ser Ser Ser Ser Ser Ser Cys Ser Arg 35 40 45Gly Gly Glu Arg Gly Pro Gly Gly Ala Ser Asn Cys Gly Thr Pro Gln 50 55 60Leu Asp Thr Glu Ala Ala Ala Gly Pro Pro Ala Arg Ser Leu Leu Leu65 70 75 80Ser Ser Tyr Ala Ser His Pro Phe Gly Ala Pro His Gly Pro Ser Ala 85 90 95Pro Gly Val Ala Gly Pro Gly Gly Asn Leu Ser Ser Trp Glu Asp Leu 100 105 110Leu Leu Phe Thr Asp Leu Asp Gln Ala Ala Thr Ala Ser Lys Leu Leu 115 120 125Trp Ser Ser Arg Gly Ala Lys Leu Ser Pro Phe Ala Pro Glu Gln Pro 130 135 140Glu Glu Met Tyr Gln Thr Leu Ala Ala Leu Ser Ser Gln Gly Pro Ala145 150 155 160Ala Tyr Asp Gly Ala Pro Gly Gly Phe Val His Ser Ala Ala Ala Ala 165 170 175Ala Ala Ala Ala Ala Ala Ala Ser Ser Pro Val Tyr Val Pro Thr Thr 180 185 190Arg Val Gly Ser Met Leu Pro Gly Leu Pro Tyr His Leu Gln Gly Ser 195 200 205Gly Ser Gly Pro Ala Asn His Ala Gly Gly Ala Gly Ala His Pro Gly 210 215 220Trp Pro Gln Ala Ser Ala Asp Ser Pro Pro Tyr Gly Ser Gly Gly Gly225 230 235 240Ala Ala Gly Gly Gly Ala Ala Gly Pro Gly Gly Ala Gly Ser Ala Ala 245 250 255Ala His Val Ser Ala Arg Phe Pro Tyr Ser Pro Ser Pro Pro Met Ala 260 265 270Asn Gly Ala Ala Arg Glu Pro Gly Gly Tyr Ala Ala Ala Gly Ser Gly 275 280 285Gly Ala Gly Gly Val Ser Gly Gly Gly Ser Ser Leu Ala Ala Met Gly 290 295 300Gly Arg Glu Pro Gln Tyr Ser Ser Leu Ser Ala Ala Arg Pro Leu Asn305 310 315 320Gly Thr Tyr His His His His His His His His His His Pro Ser Pro 325 330 335Tyr Ser Pro Tyr Val Gly Ala Pro Leu Thr Pro Ala Trp Pro Ala Gly 340 345 350Pro Phe Glu Thr Pro Val Leu His Ser Leu Gln Ser Arg Ala Gly Ala 355 360 365Pro Leu Pro Val Pro Arg Gly Pro Ser Ala Asp Leu Leu Glu Asp Leu 370 375 380Ser Glu Ser Arg Glu Cys Val Asn Cys Gly Ser Ile Gln Thr Pro Leu385 390 395 400Trp Arg Arg Asp Gly Thr Gly His Tyr Leu Cys Asn Ala Cys Gly Leu 405 410 415Tyr Ser Lys Met Asn Gly Leu Ser Arg Pro Leu Ile Lys Pro Gln Lys 420 425 430Arg Val Pro Ser Ser Arg Arg Leu Gly Leu Ser Cys Ala Asn Cys His 435 440 445Thr Thr Thr Thr Thr Leu Trp Arg Arg Asn Ala Glu Gly Glu Pro Val 450 455 460Cys Asn Ala Cys Gly Leu Tyr Met Lys Leu His Gly Val Pro Arg Pro465 470 475 480Leu Ala Met Lys Lys Glu Gly Ile Gln Thr Arg Lys Arg Lys Pro Lys 485 490 495Asn Ile Asn Lys Ser Lys Thr Cys Ser Gly Asn Ser Asn Asn Ser Ile 500 505 510Pro Met Thr Pro Thr Ser Thr Ser Ser Asn Ser Asp Asp Cys Ser Lys 515 520 525Asn Thr Ser Pro Thr Thr Gln Pro Thr Ala Ser Gly Ala Gly Ala Pro 530 535 540Val Met Thr Gly Ala Gly Glu Ser Thr Asn Pro Glu Asn Ser Glu Leu545 550 555 560Lys Tyr Ser Gly Gln Asp Gly Leu Tyr Ile Gly Val Ser Leu Ala Ser 565 570 575Pro Ala Glu Val Thr Ser Ser Val Arg Pro Asp Ser Trp Cys Ala Leu 580 585 590Ala Leu Ala 59551371PRTHomo sapiens 51Met Ser Met Ser Pro Lys His Thr Thr Pro Phe Ser Val Ser Asp Ile1 5 10 15Leu Ser Pro Leu Glu Glu Ser Tyr Lys Lys Val Gly Met Glu Gly Gly 20 25 30Gly Leu Gly Ala Pro Leu Ala Ala Tyr Arg Gln Gly Gln Ala Ala Pro 35 40 45Pro Thr Ala Ala Met Gln Gln His Ala Val Gly His His Gly Ala Val 50 55 60Thr Ala Ala Tyr His Met Thr Ala Ala Gly Val Pro Gln Leu Ser His65 70 75 80Ser Ala Val Gly Gly Tyr Cys Asn Gly Asn Leu Gly Asn Met Ser Glu 85 90 95Leu Pro Pro Tyr Gln Asp Thr Met Arg Asn Ser Ala Ser Gly Pro Gly 100 105 110Trp Tyr Gly Ala Asn Pro Asp Pro Arg Phe Pro Ala Ile Ser Arg Phe 115 120 125Met Gly Pro Ala Ser Gly Met Asn Met Ser Gly Met Gly Gly Leu Gly 130 135 140Ser Leu Gly Asp Val Ser Lys Asn Met Ala Pro Leu Pro Ser Ala Pro145 150 155 160Arg Arg Lys Arg Arg Val Leu Phe Ser Gln Ala Gln Val Tyr Glu Leu 165 170 175Glu Arg Arg Phe Lys Gln Gln Lys Tyr Leu Ser Ala Pro Glu Arg Glu 180 185 190His Leu Ala Ser Met Ile His Leu Thr Pro Thr Gln Val Lys Ile Trp 195 200 205Phe Gln Asn His Arg Tyr Lys Met Lys Arg Gln Ala Lys Asp Lys Ala 210 215 220Ala Gln Gln Gln Leu Gln Gln Asp Ser Gly Gly Gly Gly Gly Gly Gly225 230 235 240Gly Thr Gly Cys Pro Gln Gln Gln Gln Ala Gln Gln Gln Ser Pro Arg 245 250 255Arg Val Ala Val Pro Val Leu Val Lys Asp Gly Lys Pro Cys Gln Ala 260 265 270Gly Ala Pro Ala Pro Gly Ala Ala Ser Leu Gln Gly His Ala Gln Gln 275 280 285Gln Ala Gln His Gln Ala Gln Ala Ala Gln Ala Ala Ala Ala Ala Ile 290 295 300Ser Val Gly Ser Gly Gly Ala Gly Leu Gly Ala His Pro Gly His Gln305 310 315 320Pro Gly Ser Ala Gly Gln Ser Pro Asp Leu Ala His His Ala Ala Ser 325 330 335Pro Ala Ala Leu Gln Gly Gln Val Ser Ser Leu Ser His Leu Asn Ser 340 345 350Ser Gly Ser Asp Tyr Gly Thr Met Ser Cys Ser Thr Leu Leu Tyr Gly 355 360 365Arg Thr Trp

37052463PRTHomo sapiens 52Met His Ser Ala Ser Ser Met Leu Gly Ala Val Lys Met Glu Gly His1 5 10 15Glu Pro Ser Asp Trp Ser Ser Tyr Tyr Ala Glu Pro Glu Gly Tyr Ser 20 25 30Ser Val Ser Asn Met Asn Ala Gly Leu Gly Met Asn Gly Met Asn Thr 35 40 45Tyr Met Ser Met Ser Ala Ala Ala Met Gly Ser Gly Ser Gly Asn Met 50 55 60Ser Ala Gly Ser Met Asn Met Ser Ser Tyr Val Gly Ala Gly Met Ser65 70 75 80Pro Ser Leu Ala Gly Met Ser Pro Gly Ala Gly Ala Met Ala Gly Met 85 90 95Gly Gly Ser Ala Gly Ala Ala Gly Val Ala Gly Met Gly Pro His Leu 100 105 110Ser Pro Ser Leu Ser Pro Leu Gly Gly Gln Ala Ala Gly Ala Met Gly 115 120 125Gly Leu Ala Pro Tyr Ala Asn Met Asn Ser Met Ser Pro Met Tyr Gly 130 135 140Gln Ala Gly Leu Ser Arg Ala Arg Asp Pro Lys Thr Tyr Arg Arg Ser145 150 155 160Tyr Thr His Ala Lys Pro Pro Tyr Ser Tyr Ile Ser Leu Ile Thr Met 165 170 175Ala Ile Gln Gln Ser Pro Asn Lys Met Leu Thr Leu Ser Glu Ile Tyr 180 185 190Gln Trp Ile Met Asp Leu Phe Pro Phe Tyr Arg Gln Asn Gln Gln Arg 195 200 205Trp Gln Asn Ser Ile Arg His Ser Leu Ser Phe Asn Asp Cys Phe Leu 210 215 220Lys Val Pro Arg Ser Pro Asp Lys Pro Gly Lys Gly Ser Phe Trp Thr225 230 235 240Leu His Pro Asp Ser Gly Asn Met Phe Glu Asn Gly Cys Tyr Leu Arg 245 250 255Arg Gln Lys Arg Phe Lys Cys Glu Lys Gln Leu Ala Leu Lys Glu Ala 260 265 270Ala Gly Ala Ala Gly Ser Gly Lys Lys Ala Ala Ala Gly Ala Gln Ala 275 280 285Ser Gln Ala Gln Leu Gly Glu Ala Ala Gly Pro Ala Ser Glu Thr Pro 290 295 300Ala Gly Thr Glu Ser Pro His Ser Ser Ala Ser Pro Cys Gln Glu His305 310 315 320Lys Arg Gly Gly Leu Gly Glu Leu Lys Gly Thr Pro Ala Ala Ala Leu 325 330 335Ser Pro Pro Glu Pro Ala Pro Ser Pro Gly Gln Gln Gln Gln Ala Ala 340 345 350Ala His Leu Leu Gly Pro Pro His His Pro Gly Leu Pro Pro Glu Ala 355 360 365His Leu Lys Pro Glu His His Tyr Ala Phe Asn His Pro Phe Ser Ile 370 375 380Asn Asn Leu Met Ser Ser Glu Gln Gln His His His Ser His His His385 390 395 400His Gln Pro His Lys Met Asp Leu Lys Ala Tyr Glu Gln Val Met His 405 410 415Tyr Pro Gly Tyr Gly Ser Pro Met Pro Gly Ser Leu Ala Met Gly Pro 420 425 430Val Thr Asn Lys Thr Gly Leu Asp Ala Ser Pro Leu Ala Ala Asp Thr 435 440 445Ser Tyr Tyr Gln Gly Val Tyr Ser Arg Pro Ile Met Asn Ser Ser 450 455 46053134PRTHomo sapiens 53Met Lys Ala Phe Ser Pro Val Arg Ser Val Arg Lys Asn Ser Leu Ser1 5 10 15Asp His Ser Leu Gly Ile Ser Arg Ser Lys Thr Pro Val Asp Asp Pro 20 25 30Met Ser Leu Leu Tyr Asn Met Asn Asp Cys Tyr Ser Lys Leu Lys Glu 35 40 45Leu Val Pro Ser Ile Pro Gln Asn Lys Lys Val Ser Lys Met Glu Ile 50 55 60Leu Gln His Val Ile Asp Tyr Ile Leu Asp Leu Gln Ile Ala Leu Asp65 70 75 80Ser His Pro Thr Ile Val Ser Leu His His Gln Arg Pro Gly Gln Asn 85 90 95Gln Ala Ser Arg Thr Pro Leu Thr Thr Leu Asn Thr Asp Ile Ser Ile 100 105 110Leu Ser Leu Gln Ala Ser Glu Phe Pro Ser Glu Leu Met Ser Asn Asp 115 120 125Ser Lys Ala Leu Cys Gly 13054449PRTHomo sapiens 54Met Tyr Gln Thr Leu Ala Ala Leu Ser Ser Gln Gly Pro Ala Ala Tyr1 5 10 15Asp Gly Ala Pro Gly Gly Phe Val His Ser Ala Ala Ala Ala Ala Ala 20 25 30Ala Ala Ala Ala Ala Ser Ser Pro Val Tyr Val Pro Thr Thr Arg Val 35 40 45Gly Ser Met Leu Pro Gly Leu Pro Tyr His Leu Gln Gly Ser Gly Ser 50 55 60Gly Pro Ala Asn His Ala Gly Gly Ala Gly Ala His Pro Gly Trp Pro65 70 75 80Gln Ala Ser Ala Asp Ser Pro Pro Tyr Gly Ser Gly Gly Gly Ala Ala 85 90 95Gly Gly Gly Ala Ala Gly Pro Gly Gly Ala Gly Ser Ala Ala Ala His 100 105 110Val Ser Ala Arg Phe Pro Tyr Ser Pro Ser Pro Pro Met Ala Asn Gly 115 120 125Ala Ala Arg Glu Pro Gly Gly Tyr Ala Ala Ala Gly Ser Gly Gly Ala 130 135 140Gly Gly Val Ser Gly Gly Gly Ser Ser Leu Ala Ala Met Gly Gly Arg145 150 155 160Glu Pro Gln Tyr Ser Ser Leu Ser Ala Ala Arg Pro Leu Asn Gly Thr 165 170 175Tyr His His His His His His His His His His Pro Ser Pro Tyr Ser 180 185 190Pro Tyr Val Gly Ala Pro Leu Thr Pro Ala Trp Pro Ala Gly Pro Phe 195 200 205Glu Thr Pro Val Leu His Ser Leu Gln Ser Arg Ala Gly Ala Pro Leu 210 215 220Pro Val Pro Arg Gly Pro Ser Ala Asp Leu Leu Glu Asp Leu Ser Glu225 230 235 240Ser Arg Glu Cys Val Asn Cys Gly Ser Ile Gln Thr Pro Leu Trp Arg 245 250 255Arg Asp Gly Thr Gly His Tyr Leu Cys Asn Ala Cys Gly Leu Tyr Ser 260 265 270Lys Met Asn Gly Leu Ser Arg Pro Leu Ile Lys Pro Gln Lys Arg Val 275 280 285Pro Ser Ser Arg Arg Leu Gly Leu Ser Cys Ala Asn Cys His Thr Thr 290 295 300Thr Thr Thr Leu Trp Arg Arg Asn Ala Glu Gly Glu Pro Val Cys Asn305 310 315 320Ala Cys Gly Leu Tyr Met Lys Leu His Gly Val Pro Arg Pro Leu Ala 325 330 335Met Lys Lys Glu Gly Ile Gln Thr Arg Lys Arg Lys Pro Lys Asn Ile 340 345 350Asn Lys Ser Lys Thr Cys Ser Gly Asn Ser Asn Asn Ser Ile Pro Met 355 360 365Thr Pro Thr Ser Thr Ser Ser Asn Ser Asp Asp Cys Ser Lys Asn Thr 370 375 380Ser Pro Thr Thr Gln Pro Thr Ala Ser Gly Ala Gly Ala Pro Val Met385 390 395 400Thr Gly Ala Gly Glu Ser Thr Asn Pro Glu Asn Ser Glu Leu Lys Tyr 405 410 415Ser Gly Gln Asp Gly Leu Tyr Ile Gly Val Ser Leu Ala Ser Pro Ala 420 425 430Glu Val Thr Ser Ser Val Arg Pro Asp Ser Trp Cys Ala Leu Ala Leu 435 440 445Ala55401PRTHomo sapiens 55Met Trp Ser Gly Gly Ser Gly Lys Ala Arg Gly Trp Glu Ala Ala Ala1 5 10 15Gly Gly Arg Ser Ser Pro Gly Arg Leu Ser Arg Arg Arg Ile Met Ser 20 25 30Met Ser Pro Lys His Thr Thr Pro Phe Ser Val Ser Asp Ile Leu Ser 35 40 45Pro Leu Glu Glu Ser Tyr Lys Lys Val Gly Met Glu Gly Gly Gly Leu 50 55 60Gly Ala Pro Leu Ala Ala Tyr Arg Gln Gly Gln Ala Ala Pro Pro Thr65 70 75 80Ala Ala Met Gln Gln His Ala Val Gly His His Gly Ala Val Thr Ala 85 90 95Ala Tyr His Met Thr Ala Ala Gly Val Pro Gln Leu Ser His Ser Ala 100 105 110Val Gly Gly Tyr Cys Asn Gly Asn Leu Gly Asn Met Ser Glu Leu Pro 115 120 125Pro Tyr Gln Asp Thr Met Arg Asn Ser Ala Ser Gly Pro Gly Trp Tyr 130 135 140Gly Ala Asn Pro Asp Pro Arg Phe Pro Ala Ile Ser Arg Phe Met Gly145 150 155 160Pro Ala Ser Gly Met Asn Met Ser Gly Met Gly Gly Leu Gly Ser Leu 165 170 175Gly Asp Val Ser Lys Asn Met Ala Pro Leu Pro Ser Ala Pro Arg Arg 180 185 190Lys Arg Arg Val Leu Phe Ser Gln Ala Gln Val Tyr Glu Leu Glu Arg 195 200 205Arg Phe Lys Gln Gln Lys Tyr Leu Ser Ala Pro Glu Arg Glu His Leu 210 215 220Ala Ser Met Ile His Leu Thr Pro Thr Gln Val Lys Ile Trp Phe Gln225 230 235 240Asn His Arg Tyr Lys Met Lys Arg Gln Ala Lys Asp Lys Ala Ala Gln 245 250 255Gln Gln Leu Gln Gln Asp Ser Gly Gly Gly Gly Gly Gly Gly Gly Thr 260 265 270Gly Cys Pro Gln Gln Gln Gln Ala Gln Gln Gln Ser Pro Arg Arg Val 275 280 285Ala Val Pro Val Leu Val Lys Asp Gly Lys Pro Cys Gln Ala Gly Ala 290 295 300Pro Ala Pro Gly Ala Ala Ser Leu Gln Gly His Ala Gln Gln Gln Ala305 310 315 320Gln His Gln Ala Gln Ala Ala Gln Ala Ala Ala Ala Ala Ile Ser Val 325 330 335Gly Ser Gly Gly Ala Gly Leu Gly Ala His Pro Gly His Gln Pro Gly 340 345 350Ser Ala Gly Gln Ser Pro Asp Leu Ala His His Ala Ala Ser Pro Ala 355 360 365Ala Leu Gln Gly Gln Val Ser Ser Leu Ser His Leu Asn Ser Ser Gly 370 375 380Ser Asp Tyr Gly Thr Met Ser Cys Ser Thr Leu Leu Tyr Gly Arg Thr385 390 395 400Trp56457PRTHomo sapiens 56Met Leu Gly Ala Val Lys Met Glu Gly His Glu Pro Ser Asp Trp Ser1 5 10 15Ser Tyr Tyr Ala Glu Pro Glu Gly Tyr Ser Ser Val Ser Asn Met Asn 20 25 30Ala Gly Leu Gly Met Asn Gly Met Asn Thr Tyr Met Ser Met Ser Ala 35 40 45Ala Ala Met Gly Ser Gly Ser Gly Asn Met Ser Ala Gly Ser Met Asn 50 55 60Met Ser Ser Tyr Val Gly Ala Gly Met Ser Pro Ser Leu Ala Gly Met65 70 75 80Ser Pro Gly Ala Gly Ala Met Ala Gly Met Gly Gly Ser Ala Gly Ala 85 90 95Ala Gly Val Ala Gly Met Gly Pro His Leu Ser Pro Ser Leu Ser Pro 100 105 110Leu Gly Gly Gln Ala Ala Gly Ala Met Gly Gly Leu Ala Pro Tyr Ala 115 120 125Asn Met Asn Ser Met Ser Pro Met Tyr Gly Gln Ala Gly Leu Ser Arg 130 135 140Ala Arg Asp Pro Lys Thr Tyr Arg Arg Ser Tyr Thr His Ala Lys Pro145 150 155 160Pro Tyr Ser Tyr Ile Ser Leu Ile Thr Met Ala Ile Gln Gln Ser Pro 165 170 175Asn Lys Met Leu Thr Leu Ser Glu Ile Tyr Gln Trp Ile Met Asp Leu 180 185 190Phe Pro Phe Tyr Arg Gln Asn Gln Gln Arg Trp Gln Asn Ser Ile Arg 195 200 205His Ser Leu Ser Phe Asn Asp Cys Phe Leu Lys Val Pro Arg Ser Pro 210 215 220Asp Lys Pro Gly Lys Gly Ser Phe Trp Thr Leu His Pro Asp Ser Gly225 230 235 240Asn Met Phe Glu Asn Gly Cys Tyr Leu Arg Arg Gln Lys Arg Phe Lys 245 250 255Cys Glu Lys Gln Leu Ala Leu Lys Glu Ala Ala Gly Ala Ala Gly Ser 260 265 270Gly Lys Lys Ala Ala Ala Gly Ala Gln Ala Ser Gln Ala Gln Leu Gly 275 280 285Glu Ala Ala Gly Pro Ala Ser Glu Thr Pro Ala Gly Thr Glu Ser Pro 290 295 300His Ser Ser Ala Ser Pro Cys Gln Glu His Lys Arg Gly Gly Leu Gly305 310 315 320Glu Leu Lys Gly Thr Pro Ala Ala Ala Leu Ser Pro Pro Glu Pro Ala 325 330 335Pro Ser Pro Gly Gln Gln Gln Gln Ala Ala Ala His Leu Leu Gly Pro 340 345 350Pro His His Pro Gly Leu Pro Pro Glu Ala His Leu Lys Pro Glu His 355 360 365His Tyr Ala Phe Asn His Pro Phe Ser Ile Asn Asn Leu Met Ser Ser 370 375 380Glu Gln Gln His His His Ser His His His His Gln Pro His Lys Met385 390 395 400Asp Leu Lys Ala Tyr Glu Gln Val Met His Tyr Pro Gly Tyr Gly Ser 405 410 415Pro Met Pro Gly Ser Leu Ala Met Gly Pro Val Thr Asn Lys Thr Gly 420 425 430Leu Asp Ala Ser Pro Leu Ala Ala Asp Thr Ser Tyr Tyr Gln Gly Val 435 440 445Tyr Ser Arg Pro Ile Met Asn Ser Ser 450 45557141PRTHomo sapiens 57Met Lys Ala Phe Ser Pro Val Arg Ser Val Arg Lys Asn Ser Leu Ser1 5 10 15Asp His Ser Leu Gly Ile Ser Arg Ser Lys Thr Pro Val Asp Asp Pro 20 25 30Met Ser Leu Leu Tyr Asn Met Asn Asp Cys Tyr Ser Lys Leu Lys Glu 35 40 45Leu Val Pro Ser Ile Pro Gln Asn Lys Lys Val Ser Lys Met Glu Ile 50 55 60Leu Gln His Val Ile Asp Tyr Ile Leu Asp Leu Gln Ile Ala Leu Asp65 70 75 80Ser His Pro Thr Ile Val Ser Leu His His Gln Arg Pro Gly Gln Asn 85 90 95Gln Ala Ser Arg Thr Pro Leu Thr Thr Leu Asn Thr Asp Ile Ser Ile 100 105 110Leu Ser Leu Gln Val Arg Pro Ala Pro Gly Ser Pro Pro Arg Arg Arg 115 120 125Thr Leu Pro Arg Ser Ser Gly Leu Ser Leu Gly Asp Pro 130 135 1405821DNAArtificial sequenceSynthetic nucleotide 58aatcaggagc gcaggctgca g 215921DNAArtificial sequenceSynthetic nucleotide 59aagaggcgcc tcctctctcc t 216021DNAArtificial sequenceSynthetic nucleotide 60aaaccgccat gcactcggct t 216124DNAArtificial sequenceSynthetic nucleotide 61tgaccttgat ttattttgca tacc 246223DNAArtificial sequenceSynthetic nucleotide 62tttgctttcc ttggtcaggc agt 236320DNAArtificial sequenceSynthetic nucleotide 63cgagcaagac gttcagtcct 206422DNAArtificial sequenceSynthetic nucleotide 64cgtggggtcc ttttcaccag ca 226521DNAArtificial sequenceSynthetic nucleotide 65tgagtatgtc gtggagtcta c 216619DNAArtificial sequenceSynthetic nucleotide 66gcaaattcca tggcaccgt 196721DNAArtificial sequenceSynthetic nucleotide 67ggcccgattt ctcctccggg t 216819DNAArtificial sequenceSynthetic nucleotide 68tggactgtgg tcatgagcc 196919DNAArtificial sequenceSynthetic nucleotide 69tcgccccact tgattttgg 197021DNAArtificial sequenceSynthetic nucleotide 70ggtgaccagg cgcccaatac g 217125DNAArtificial sequenceSynthetic nucleotide 71gctagcgctg tttgtttagg gctcg 257220DNAArtificial sequenceSynthetic nucleotide 72gccccgaaac gcttcggcag 207320DNAArtificial sequenceSynthetic nucleotide 73tttggggtgg cctcggctct 207420DNAArtificial sequenceSynthetic nucleotide 74ccaggccaac cgcacacctt 207518DNAArtificial sequenceSynthetic nucleotide 75gcggccatgc agcagcac 187620DNAArtificial sequenceSynthetic nucleotide 76ccatgttctt gctcacgtcc 207721DNAArtificial sequenceSynthetic nucleotide 77actcttttgg tggtgactgg g 217820DNAArtificial sequenceSynthetic nucleotide 78ctcatgttgc ccaggttgcc 207920DNAArtificial sequenceSynthetic nucleotide 79accgccatgc actcggcttc 208020DNAArtificial sequenceSynthetic nucleotide 80ggctcattcc agcgcccaca 208120DNAArtificial sequenceSynthetic nucleotide 81ggcactgcgc ttcactcccc

208220DNAArtificial sequenceSynthetic nucleotide 82ggctcattcc agcgcccaca 208320DNAArtificial sequenceSynthetic nucleotide 83ctgaaccgag cctggtgccg 208420DNAArtificial sequenceSynthetic nucleotide 84gctccgggag atgcccaagc 208525DNAArtificial sequenceSynthetic nucleotide 85gggtgctgaa agattccaaa cctcg 258623DNAArtificial sequenceSynthetic nucleotide 86tgtgcccttc agtgtaggtg gca 238720DNAArtificial sequenceSynthetic nucleotide 87ccgaagccac acgctgcctt 208820DNAArtificial sequenceSynthetic nucleotide 88agcacggttg cagtgggagc 208919DNAArtificial sequenceSynthetic nucleotide 89gctggtgatg atgctccca 199021DNAArtificial sequenceSynthetic nucleotide 90gcccattcca accattactc c 219120DNAArtificial sequenceSynthetic nucleotide 91tgtggacctc aggttggact 209221DNAArtificial sequenceSynthetic nucleotide 92cttctgcagg gctttcatgt c 21933270DNAMus musculus 93ttcacctccg cacccagcag cttgtagaga gcagttccga cccacagcct ggcacccttc 60ggctagcgct gtttgtttag ggctcggtga gtccaatcag gagcgcaggc tgcagttttc 120cggcagagca gtaagaggcg cctcctctct cctttttatt caccagcagc gactagcaga 180ccccggactc tcgctctccc gccggcgccc tccgcctctc tccgcgcccc ggagcaccct 240cggtcgcggc cgttcttctc gcacatcgct cgaggaatca aaagtcaggt tggagtagcg 300ccggacagtg gatggccttg actgacggcg gctggtgcct gccaaagcgt ttcggggctg 360ctgctgcgga cgccggcgac tccgggccct ttccagcgcg ggagccctcc tcgccgcttt 420cccccatctc gtcttcgtcc tcctcctgct cccggggcgg ggatcgcggt ccctgcggcg 480ccagcaactg caggacgccg cagctcgacg ccgaggcggt ggcgggacct ccgggccgct 540cgctcttgct cagcccctac gcctcgcatc ccttcgccgc tgcccacgga gccgcggcgc 600ccggggtcgc aggccccggg agcgccctgt cgacttggga ggacctgttg ctcttcactg 660acctcgatca ggccgcgacc gccagcaagc tgttgtggtc cagccggggc gccaaactga 720gccccttcgc ggccgagcag ccggaggaaa tgtaccagac cctcgccgcc ctgtccagcc 780aggggcccgc cgcttacgac ggcgcgcccg gcggcttcgt gcactccgca gcggcggcgg 840ccgctgccgc cgcggcagcc agctccccgg tctacgtgcc caccacgcgc gtgggctcca 900tgctgtccgg cctgccctac cttcaagggg cgggcagcgg gcccagcaat cacgcgggcg 960gagcgggtgc ccacccaggc tggtcccagg cctccgccga cagccccccg tatggcgggg 1020gtggcgcagc cggcggcggc gcggccggac ctggaggtgc gggatcggct acggcccacg 1080cctctgcacg ctttccctac tcgcccagcc cgcccatggc caacggcgcc gcgcgagacc 1140ccgggggcta cgtggctgcg ggcggcacgg gcgcaggcag tgtgagtgga ggtggcggca 1200gcctggcggc catgggtggc cgggagcacc agtacagctc gctgtccgca gctcggccgc 1260tgaacggaac gtaccaccac caccatcacc atcacccgac ctactcgccc tacatggccg 1320caccgctgac tcctgcctgg ccagcaggac ccttcgaaac gccggtgctc cacagcttac 1380agggccgcgc gggagctcca ctcccggtgc cacggggccc cagcacagac ctgttggagg 1440acctgtcgga gagccgcgag tgcgtgaact gcggctccat ccagacgcca ctgtggagac 1500gagacggcac cggtcattac ctgtgcaatg catgcggtct ctacagcaag atgaatggcc 1560tcagcaggcc cctcatcaag ccacagaagc gcgtgccttc atcacggcgg cttggactgt 1620cctgtgccaa ctgtcacacc acaaccacta ccttatggcg tagaaatgct gagggtgagc 1680ctgtgtgcaa tgcttgcggg ctctatatga aactccatgg ggtgcctcga ccacttgcta 1740tgaaaaaaga aggaattcaa accaggaaac gaaaacctaa aaatataaat aagtcaaaag 1800cttgctccgg taacagcagt ggctctgtcc ctatgactcc tacttcctct tcttctaatt 1860cagatgactg caccaaaaat acttctcctt ctacacaagc gaccacctca ggggtagggg 1920catcagtgat gtctgcagtg ggagaaaacg ccaaccccga gaacagtgac ctcaagtatt 1980caggtcaaga cggcctctac ataggtgtca gtctgtcctc ccctgccgaa gtcacatcct 2040ccgtgcgaca ggattcttgg tgtgctctgg ccctggcctg agctggtgct accaagaggc 2100aaggagggct ctgaaggcct cataccactt gtgtctgata ttgtccagca gtccagatgg 2160cagcaaaaat gcagacataa cattccttcg atgcgtgatt tctgtgcctt tgttttgaaa 2220gagatatatt tctcaagaag cttactgaag taagaagaga tgggcttttg caggaagggc 2280cagcaccgtg ggcatgtggc ctgctcctgc cagcctgggc tgcttcctgc ctctgactct 2340gccccatacc agtgggagaa actgtgacaa tgaccggggc cttgtctgct aaggaagatt 2400gagagattta agagaaaatg tttgtgtatt gctccaaatc atgtgcttct tgtgatcaac 2460ctcggttatc ccagaaccca ttcatccccg accaccgtgc acatttcaca agcgttcgtg 2520gagaggagca ctgggagcca tttggtctat cctggaggcg gagtgcattc ctggggtctc 2580aacaagaata ttaatttgca agattgcatc atgacagaca ctgactgact tatctcaacg 2640ttcatcgtaa cgtggctgat ctgaggtcac ttggaatttg taaacagggt agcaaacaag 2700atatttttct tccatgtaca caataatttt tttaagtgca atttgcgttg cagcaatcag 2760tgttaaatca tttgcataag atttaacagc atttttataa tgaatgtaaa cattttaact 2820taatggtact taaaataatt taaaaaaaag ttaactttag acatatgctt cttacactca 2880cagcccactt ctgtgttccc aattgtttaa aagaaaaaaa aaaagatttc aagaacaaat 2940cttctctcag gaaattgcct tttctccatt tatgaatttt tatacaagaa caccaacaca 3000gtccccgttc ttttactgag gaaaaagtgc tggaaattgc aacaaacctt tactacctag 3060agaatagcat ttgtaaatat tctaagtatc tgtaacactc ttgacgcctg taccacgtga 3120ccaacccaca ggttggttta cattattatt ttttttaatg ggatatcata tggaaaccta 3180tttcaccaga gttttaaaaa ataaaaaggg tattgttttg tgttctgtac agtgagatcc 3240ttccttttca tcttatttca atgctgtgtg 3270942097DNAMus musculus 94tgggcattaa ttttagtgtg gttatctccg atgagcctaa gcgatttgga aaagcagccc 60ggtggaggcc tgcctggttc cccaccccct ccaagtctcc ctgtcattct tcctgctctc 120ccctttgggg tggcctcggc tctggggcgg tctcaccccc ctcccctcct gcgttttccc 180ctccttttct ctgcgctctg ctccacccta ctatgaccaa ttccagaacg atctggcctt 240tcccctgctg gggttgacca tggggtgggc caggggtggc ccggcccgcc tgagtacgca 300cgctggtggt tgtaaggcgg tttgtgttta aggaatcaaa agtcaggttg gagtagcgcc 360ggacagtgga tggccttgac tgacggcggc tggtgcctgc caaagcgttt cggggctgct 420gctgcggacg ccggcgactc cgggcccttt ccagcgcggg agccctcctc gccgctttcc 480cccatctcgt cttcgtcctc ctcctgctcc cggggcgggg atcgcggtcc ctgcggcgcc 540agcaactgca ggacgccgca gctcgacgcc gaggcggtgg cgggacctcc gggccgctcg 600ctcttgctca gcccctacgc ctcgcatccc ttcgccgctg cccacggagc cgcggcgccc 660ggggtcgcag gccccgggag cgccctgtcg acttgggagg acctgttgct cttcactgac 720ctcgatcagg ccgcgaccgc cagcaagctg ttgtggtcca gccggggcgc caaactgagc 780cccttcgcgg ccgagcagcc ggaggaaatg taccagaccc tcgccgccct gtccagccag 840gggcccgccg cttacgacgg cgcgcccggc ggcttcgtgc actccgcagc ggcggcggcc 900gctgccgccg cggcagccag ctccccggtc tacgtgccca ccacgcgcgt gggctccatg 960ctgtccggcc tgccctacct tcaaggggcg ggcagcgggc ccagcaatca cgcgggcgga 1020gcgggtgccc acccaggctg gtcccaggcc tccgccgaca gccccccgta tggcgggggt 1080ggcgcagccg gcggcggcgc ggccggacct ggaggtgcgg gatcggctac ggcccacgcc 1140tctgcacgct ttccctactc gcccagcccg cccatggcca acggcgccgc gcgagacccc 1200gggggctacg tggctgcggg cggcacgggc gcaggcagtg tgagtggagg tggcggcagc 1260ctggcggcca tgggtggccg ggagcaccag tacagctcgc tgtccgcagc tcggccgctg 1320aacggaacgt accaccacca ccatcaccat cacccgacct actcgcccta catggccgca 1380ccgctgactc ctgcctggcc agcaggaccc ttcgaaacgc cggtgctcca cagcttacag 1440ggccgcgcgg gagctccact cccggtgcca cggggcccca gcacagacct gttggaggac 1500ctgtcggaga gccgcgagtg cgtgaactgc ggctccatcc agacgccact gtggagacga 1560gacggcaccg gtcattacct gtgcaatgca tgcggtctct acagcaagat gaatggcctc 1620agcaggcccc tcatcaagcc acagaagcgc gtgccttcat cacggcggct tggactgtcc 1680tgtgccaact gtcacaccac aaccactacc ttatggcgta gaaatgctga gggtgagcct 1740gtgtgcaatg cttgcgggct ctatatgaaa ctccatgggg tatgttgctc ctgtttatcc 1800atacatacaa ctagcacctg aattgtaaat ttttagttat aagacagaat cagcaaatga 1860aaaaaggtgt aaaagtgtgt acatatgcct tgtagcgaat tcaagctgct cttaattgta 1920atgtgaccag tcagttcagc cactaaggag ccaggagata aaacccacta ccaaccaatc 1980cggcactaac attctctgtg aaacatctct acattttaga aatgtgaaaa tgagccaagt 2040gtaactgtga atgcctttaa tccaagatag ccagggctac acggagaaac ctgtagc 2097952265DNAMus musculus 95tttttttttt cctcctcttc cttcctcctc cagccgacgc cgaatcatgt cgatgagtcc 60aaagcacacg actccgttct cagtgtctga catcttgagt cccctggagg aaagctacaa 120gaaagtgggc atggagggcg gcggcctcgg ggctccgctc gcagcgtaca gacagggcca 180ggcggcccca ccggccgcgg ccatgcagca gcacgccgtg gggcaccacg gcgccgtcac 240cgccgcctac cacatgacgg cggcgggggt gccccagctc tcgcactccg ccgtgggggg 300ctactgcaac ggcaacctgg gcaacatgag cgagctgccg ccttaccagg acaccatgcg 360gaacagcgct tcgggccccg gatggtacgg cgccaaccca gacccgcgct tccccgccat 420ctcccgcttc atgggcccgg cgagcggcat gaatatgagt ggcatgggcg gcctgggctc 480gctgggggac gtgagcaaga acatggcccc gctgcccagt gcgccccgcc ggaagcgccg 540ggtgctcttc tcccaggcgc aggtgtacga gctcgagcga cgtttcaagc aacagaagta 600cctgtcggcg ccggagcgcg agcatctggc cagcatgatt cacctgacac ccacgcaggt 660caagatctgg ttccagaacc accgctacaa gatgaagcgc caggctaagg acaaggcggc 720gcagcaacaa ctgcagcagg acagcggcgg cggcggaggc ggcggtggcg gtgcgggatg 780cccgcagcag cagcaagctc agcagcagtc gccgcgccgg gtggccgtgc cggtcctagt 840caaagacggc aaaccctgcc aggcgggcgc ccctgccccg ggagccgcaa gcctgcaaag 900ccacgcgcag caacaagctc agcagcaggc gcaggcggcg caagcggctg ccgcggccat 960ctcagtgggc agcggtggcg cgggtctagg agcacaccca ggccaccagc cgggcagcgc 1020agggcagtcc ccggacctgg cgcaccacgc agccagcccc gcggggctgc agggccaggt 1080ctccagccta tcccatctga actcctcggg ctcggactat ggcgccatgt cttgttctac 1140cttgctttat ggtcggacct ggtgagacgt gagatgcgct tgagccccgc gcgacctcaa 1200cgcttcccct ctgccttccg caaagaccac cattcgcccg ctgctccacg cgcttctact 1260ttttttaaga atctgtttat gtttagacca aggaaaagta cacaaagacc aaactgctgg 1320acgacttctt cttcttcttc ttcttcttct tcttcttctt cttcttcttc ttcttcttct 1380tcttcttctt cttcttcttc ttcttcttct tctcctcctc ctcctcctcc tcctcctcct 1440cctcctcttc ctccttcttg tccccgctcg ttcttttctt tctccccctc ctcttctgtt 1500tccttcttcc ttcatctttc cccccttcct ttctctttac tatctaaaac ttgcagactt 1560tttgtttttt aacataaaaa gaaaatagaa acagccaagc aaattcaacc ctttacggat 1620tctttaaaca gagaaggaca gagaacaaat ttggggtgtc tttctggtag ttcaaatggg 1680ttcccaagct taggcatggc acagttttgg agcctgttct atgcttccat ggccctgaac 1740tctaaagacg gaaaactttt ctgtggatgc accctgccag caaagtgagc ttgcttgtaa 1800ataccaggat ttttcgtttg tttgtatgtt tcagaaggga ggacagacgc tggagatagg 1860aaagtcttca gcataaccca tttgtacctg acacaaagga agtgtcccct cccaggcgcc 1920ctctggccct acaggttcag tccaggctgg cctttcagaa aattgtttta ggtttgatgt 1980gaacttgtag ctgtaaaatg ctgttaaaag ttggactaaa tgcctagttt ttagtaacct 2040gtacattatg ttgtaaaaag aaccccagtc ccagtcccta gtccctcact ttttcaaggg 2100gcattgacaa acctgtgtat attatttggc agtttggtat ttgcagcacc aatccttttt 2160ttttttctgt tgtaacttat gtagatattt ggcttaaata tagttcctaa gaagcttcta 2220ataaattata cgaattaaaa aagatggttt ttttcctgat taaaa 2265962832DNAMus musculus 96ctggtaacag caatgaggct gacgcccccg ggcccgctag ggagcacagc ccacagctcc 60cccttgccag gcgcccaagg accctcaagg cgcggggctc acacttgaag cctgggaacg 120ctcagacagg aaacccactt cctcctaagc agtttcttcc tagccggatg agaggcgccc 180aattgaagca gaatgatcct catctactaa tatccagcgt ggccacaaag cgaccggcca 240tttacgccgc cactttagac aaagatattt ggttattccc ggggaagcaa gtgcactttt 300gcatggctga gctccgggag gaggcgagcc tcagcccagc ctcccgcccg ctgggctgcg 360ggcgtcgaga tattcgcctc ctcccggaca acgagttcca cccgggttca gactcagttc 420cactctgcaa cggatctgcg ggcgctcacg cggctccccg cccgggcttt cactgaagca 480tcggaaggga aaactgcggg gatctgagct ggggtgctgg gactgggatg tcctcggaaa 540gacagcatca gcttctgaag ccgaagtatc caggccatgg gcaagggtca ggggcaccag 600ccgacgccga atcatgtcga tgagtccaaa gcacacgact ccgttctcag tgtctgacat 660cttgagtccc ctggaggaaa gctacaagaa agtgggcatg gagggcggcg gcctcggggc 720tccgctcgca gcgtacagac agggccaggc ggccccaccg gccgcggcca tgcagcagca 780cgccgtgggg caccacggcg ccgtcaccgc cgcctaccac atgacggcgg cgggggtgcc 840ccagctctcg cactccgccg tggggggcta ctgcaacggc aacctgggca acatgagcga 900gctgccgcct taccaggaca ccatgcggaa cagcgcttcg ggccccggat ggtacggcgc 960caacccagac ccgcgcttcc ccgccatctc ccgcttcatg ggcccggcga gcggcatgaa 1020tatgagtggc atgggcggcc tgggctcgct gggggacgtg agcaagaaca tggccccgct 1080gcccagtgcg ccccgccgga agcgccgggt gctcttctcc caggcgcagg tgtacgagct 1140cgagcgacgt ttcaagcaac agaagtacct gtcggcgccg gagcgcgagc atctggccag 1200catgattcac ctgacaccca cgcaggtcaa gatctggttc cagaaccacc gctacaagat 1260gaagcgccag gctaaggaca aggcggcgca gcaacaactg cagcaggaca gcggcggcgg 1320cggaggcggc ggtggcggtg cgggatgccc gcagcagcag caagctcagc agcagtcgcc 1380gcgccgggtg gccgtgccgg tcctagtcaa agacggcaaa ccctgccagg cgggcgcccc 1440tgccccggga gccgcaagcc tgcaaagcca cgcgcagcaa caagctcagc agcaggcgca 1500ggcggcgcaa gcggctgccg cggccatctc agtgggcagc ggtggcgcgg gtctaggagc 1560acacccaggc caccagccgg gcagcgcagg gcagtccccg gacctggcgc accacgcagc 1620cagccccgcg gggctgcagg gccaggtctc cagcctatcc catctgaact cctcgggctc 1680ggactatggc gccatgtctt gttctacctt gctttatggt cggacctggt gagacgtgag 1740atgcgcttga gccccgcgcg acctcaacgc ttcccctctg ccttccgcaa agaccaccat 1800tcgcccgctg ctccacgcgc ttctactttt tttaagaatc tgtttatgtt tagaccaagg 1860aaaagtacac aaagaccaaa ctgctggacg acttcttctt cttcttcttc ttcttcttct 1920tcttcttctt cttcttcttc ttcttcttct tcttcttctt cttcttcttc ttcttcttct 1980cctcctcctc ctcctcctcc tcctcctcct cctcttcctc cttcttgtcc ccgctcgttc 2040ttttctttct ccccctcctc ttctgtttcc ttcttccttc atctttcccc ccttcctttc 2100tctttactat ctaaaacttg cagacttttt gttttttaac ataaaaagaa aatagaaaca 2160gccaagcaaa ttcaaccctt tacggattct ttaaacagag aaggacagag aacaaatttg 2220gggtgtcttt ctggtagttc aaatgggttc ccaagcttag gcatggcaca gttttggagc 2280ctgttctatg cttccatggc cctgaactct aaagacggaa aacttttctg tggatgcacc 2340ctgccagcaa agtgagcttg cttgtaaata ccaggatttt tcgtttgttt gtatgtttca 2400gaagggagga cagacgctgg agataggaaa gtcttcagca taacccattt gtacctgaca 2460caaaggaagt gtcccctccc aggcgccctc tggccctaca ggttcagtcc aggctggcct 2520ttcagaaaat tgttttaggt ttgatgtgaa cttgtagctg taaaatgctg ttaaaagttg 2580gactaaatgc ctagttttta gtaacctgta cattatgttg taaaaagaac cccagtccca 2640gtccctagtc cctcactttt tcaaggggca ttgacaaacc tgtgtatatt atttggcagt 2700ttggtatttg cagcaccaat cctttttttt tttctgttgt aacttatgta gatatttggc 2760ttaaatatag ttcctaagaa gcttctaata aattatacga attaaaaaag atggtttttt 2820tcctgattaa aa 2832972070DNAMus musculus 97ggtcgtttgt tgtggctgtt aaattttaaa ccgccatgca ctcggcttcc agtatgctgg 60gagccgtgaa gatggaaggg cacgagccat ccgactggag cagctactac gcggagcccg 120agggctactc ttccgtgagc aacatgaacg ccggcctggg gatgaatggc atgaacacat 180acatgagcat gtccgcggct gccatgggcg gcggttccgg caacatgagc gcgggctcca 240tgaacatgtc atcctatgtg ggcgctggaa tgagcccgtc gctagctggc atgtccccgg 300gcgccggcgc catggcgggc atgagcggct cagccggggc ggccggcgtg gcgggcatgg 360gacctcacct gagtccgagt ctgagcccgc tcgggggaca ggcggccggg gccatgggtg 420gccttgcccc ctacgccaac atgaactcga tgagccccat gtacgggcag gccggcctga 480gccgcgctcg ggaccccaag acataccgac gcagctacac acacgccaaa cctccctact 540cgtacatctc gctcatcacc atggccatcc agcagagccc caacaagatg ctgacgctga 600gcgagatcta tcagtggatc atggacctct tccctttcta ccggcagaac cagcagcgct 660ggcagaactc catccgccac tctctctcct tcaacgactg ctttctcaag gtgccccgct 720cgccagacaa gcctggcaag ggctccttct ggaccctgca cccagactcg ggcaacatgt 780tcgagaacgg ctgctacctg cgccgccaga agcgcttcaa gtgtgagaag caactggcac 840tgaaggaagc cgcgggtgcg gccagtagcg gaggcaagaa gaccgctcct gggtcccagg 900cctctcaggc tcagctcggg gaggccgcgg gctcggcctc cgagactccg gcgggcaccg 960agtcccccca ttccagcgct tctccgtgtc aggagcacaa gcgaggtggc ctaagcgagc 1020taaagggagc acctgcctct gcgctgagtc ctcccgagcc ggcgccctcg cctgggcagc 1080agcagcaggc tgcagcccac ctgctgggcc cacctcacca cccaggcctg ccaccagagg 1140cccacctgaa gcccgagcac cattacgcct tcaaccaccc cttctctatc aacaacctca 1200tgtcgtccga gcagcaacat caccacagcc accaccacca tcagccccac aaaatggacc 1260tcaaggccta cgaacaggtc atgcactacc cagggggcta tggttccccc atgccaggca 1320gcttggccat gggcccagtc acgaacaaag cgggcctgga tgcctcgccc ctggctgcag 1380acacttccta ctaccaagga gtgtactcca ggcctattat gaactcatcc taagaagatg 1440gctttcaggc cctgctagct ctggtcactg gggacaaggg aaatgagagg ctgagtggag 1500actttgggag agctttgagg aaaagtagcc accacacttc aggcctcaag ggagcagtct 1560cacctgtctg tgtccctaaa tagatgggcc acagtgatct gtcattctaa atagggaagg 1620gaatggaaat atatatgtat acatataaac ttgttttaaa ggagcctttg gtctcctcta 1680tgtagactac tgcttctcaa gacatctgca gagtttgatt tttgttgttg ttctctattg 1740ctgttgttgc agaaaagtct gactttaaaa acaaacaaac aaacaaaaaa cttttgtgag 1800tgacttggtg taaaaccatg tagttttaac agaaaaccag agggttgtac tgatgttgaa 1860aagaggaaag aaaaataatg taagagtctg gtgtaccgga ccaggagaaa ggagaaaaac 1920acatcccatt ctggacatgg tgaaatccag gtctcgggtc tgatttaatt tatggtttct 1980gcgtgcttta tttatggctt ataaatgtgt gttctggcta gaatggccag aattccacaa 2040atctatatta aagtgttatt gccgatttta 2070982127DNAMus musculus 98ctgacgacca gggcggccag accacgcgag tcctacgcgc ctcctgaggc cgccccggga 60cttaactgta acggggaggg gcctccggag cagcggccag cgagttaaag tatgctggga 120gccgtgaaga tggaagggca cgagccatcc gactggagca gctactacgc ggagcccgag 180ggctactctt ccgtgagcaa catgaacgcc ggcctgggga tgaatggcat gaacacatac 240atgagcatgt ccgcggctgc catgggcggc ggttccggca acatgagcgc gggctccatg 300aacatgtcat cctatgtggg cgctggaatg agcccgtcgc tagctggcat gtccccgggc 360gccggcgcca tggcgggcat gagcggctca gccggggcgg ccggcgtggc gggcatggga 420cctcacctga gtccgagtct gagcccgctc gggggacagg cggccggggc catgggtggc 480cttgccccct acgccaacat gaactcgatg agccccatgt acgggcaggc cggcctgagc 540cgcgctcggg accccaagac ataccgacgc agctacacac acgccaaacc tccctactcg 600tacatctcgc tcatcaccat ggccatccag cagagcccca acaagatgct gacgctgagc 660gagatctatc agtggatcat ggacctcttc cctttctacc ggcagaacca gcagcgctgg 720cagaactcca tccgccactc tctctccttc aacgactgct ttctcaaggt gccccgctcg 780ccagacaagc ctggcaaggg ctccttctgg accctgcacc cagactcggg caacatgttc 840gagaacggct gctacctgcg ccgccagaag cgcttcaagt gtgagaagca actggcactg 900aaggaagccg cgggtgcggc cagtagcgga ggcaagaaga ccgctcctgg gtcccaggcc 960tctcaggctc agctcgggga ggccgcgggc tcggcctccg agactccggc gggcaccgag 1020tccccccatt ccagcgcttc tccgtgtcag gagcacaagc gaggtggcct aagcgagcta 1080aagggagcac ctgcctctgc gctgagtcct cccgagccgg cgccctcgcc

tgggcagcag 1140cagcaggctg cagcccacct gctgggccca cctcaccacc caggcctgcc accagaggcc 1200cacctgaagc ccgagcacca ttacgccttc aaccacccct tctctatcaa caacctcatg 1260tcgtccgagc agcaacatca ccacagccac caccaccatc agccccacaa aatggacctc 1320aaggcctacg aacaggtcat gcactaccca gggggctatg gttcccccat gccaggcagc 1380ttggccatgg gcccagtcac gaacaaagcg ggcctggatg cctcgcccct ggctgcagac 1440acttcctact accaaggagt gtactccagg cctattatga actcatccta agaagatggc 1500tttcaggccc tgctagctct ggtcactggg gacaagggaa atgagaggct gagtggagac 1560tttgggagag ctttgaggaa aagtagccac cacacttcag gcctcaaggg agcagtctca 1620cctgtctgtg tccctaaata gatgggccac agtgatctgt cattctaaat agggaaggga 1680atggaaatat atatgtatac atataaactt gttttaaagg agcctttggt ctcctctatg 1740tagactactg cttctcaaga catctgcaga gtttgatttt tgttgttgtt ctctattgct 1800gttgttgcag aaaagtctga ctttaaaaac aaacaaacaa acaaaaaact tttgtgagtg 1860acttggtgta aaaccatgta gttttaacag aaaaccagag ggttgtactg atgttgaaaa 1920gaggaaagaa aaataatgta agagtctggt gtaccggacc aggagaaagg agaaaaacac 1980atcccattct ggacatggtg aaatccaggt ctcgggtctg atttaattta tggtttctgc 2040gtgctttatt tatggcttat aaatgtgtgt tctggctaga atggccagaa ttccacaaat 2100ctatattaaa gtgttattgc cgatttt 2127991285DNAMus musculus 99gcttcattct gaaccgagcc tggtgccgcg cagtcagctc agccccctgt ggcggctccc 60tcccggtctt cctcctacga gcagcatgaa agccttcagt ccggtgaggt ccgttaggaa 120aaacagcctg tcggaccaca gcttgggcat ctcccggagc aaaaccccgg tggacgaccc 180gatgagtctg ctctacaaca tgaacgactg ctactccaag ctcaaggaac tggtgcccag 240catcccccag aacaagaagg tgaccaagat ggaaatcctg cagcacgtca tcgattacat 300cttggacctg cagatcgccc tggactcgca tcccactatc gtcagcctgc atcaccagag 360acctggacag aaccaggcgt ccaggacgcc gctgaccacc ctgaacacgg acatcagcat 420cctgtccttg caggcatctg aattcccttc tgagcttatg tcgaatgata gcaaagtact 480ctgtggctaa ataaatggca tttggggact tttttttttc tttttacttt ctctttttct 540tttgcacaag aagaagtcta caagatcttt taagactttt gttatcagcc atttcaccag 600gagaacacgt tgaatggacc tttttaaaaa gaaagcggaa ggaaaactaa ggatgatcgt 660cttgcccagg tgtcgttctc cggcctggac tgtgataccg ttatttatga gagactttca 720gtgccctttc tacagttgga aggttttctt tatatactat tcccaccatg gggagcgaaa 780acgttaaaaa aaaaagaaaa aaatcacaag gaattgccca atgtaagcag actttgcctt 840ttcacaaagg tggagcgtga ataccagaag gacccagtat tcggttactt aaatgaagtc 900ttcggtcaga aatggccttt ttgacacgag cctactgaat gctgtgtata tatttatata 960taaatatata tatattgagt gaaccttgtg gactctttaa ttagagtttt cttgtatagt 1020ggcagaaata acctatttct gcattaaaat gtaatgacgt acttatgcta aactttttat 1080aaaagtttag ttgtaaactt aaccctttta tacaaaataa atcaagtgtg tttattgaat 1140gttgattgct tgctttattt cagacaacca gtgctttgat tttttttatg ctatgttata 1200actgaaccca aataaatacc agttcaaatt tatgtagact gtattaagat tataataaaa 1260tgtgtctgac atcaatgccg ggatt 12851001839DNAMus musculus 100agcaaaacaa gaattcagaa ttaaagcatt ggagtcaaga gctctaaact ttttcaaaat 60gtggctgcat ctaggaaggg tgctgaaaga ttccaaacct cgtacgtaac agaattttct 120tttaaaaaca gcgataagct gtcagtcaat agctaggacc acctacctga caaagagctt 180cccaagagct ctaagtgttg gaatgtgaca ccagaaatca cgatttgtgc ataattaatc 240gcatcacttt gccacctaca ctgaagggca cagaccaagg gcagtgtatg taaatgtagt 300tccagtgtgc aaaccccact aatgaccttc gattaatgga gtcattatag taaccctgcc 360tcattcttgg gggtgggggg agttccgaat gcaccgggtc cctcggggct cctctgcggt 420ctgagggaga ccgcacagtg ttcctacaat tcgtgtcact gagtttccga gaaggcctcc 480cgcgttgctc caagttgcaa agcttcacgc taaacctgtc gtggacgtgt atgtgggcat 540tggctgcgaa cgcggaagaa ccgagagctc atactcacca atgggagaat tcgcctggta 600tgatggacgg gagcccttcc accaatggca attcagggat gcccgattga gcggccaggg 660cgagtgcaca taaaagacgc cccgcccggc tcgcgcttca ttctgaaccg agcctggtgc 720cgcgcagtca gctcagcccc ctgtggcggc tccctcccgg tcttcctcct acgagcagca 780tgaaagcctt cagtccggtg aggtccgtta ggaaaaacag cctgtcggac cacagcttgg 840gcatctcccg gagcaaaacc ccggtggacg acccgatgag tctgctctac aacatgaacg 900actgctactc caagctcaag gaactggtgc ccagcatccc ccagaacaag aaggtgacca 960agatggaaat cctgcagcac gtcatcgatt acatcttgga cctgcagatc gccctggact 1020cgcatcccac tatcgtcagc ctgcatcacc agagacctgg acagaaccag gcgtccagga 1080cgccgctgac caccctgaac acggacatca gcatcctgtc cttgcaggtg agactagctt 1140gcaagtacgc cactgcccag acgctccggg tctcccgagc tgtcactctt aaagcccatc 1200gtagagacag gttcattaac tttatttttg aggaaactgt atattgagcg tcatgtgaaa 1260tcgctactta taagttctgt gtgggttgca tctggatctg cgctgtagca tgatcctgtt 1320tcatgggact tgttggcact tttgtgaaag gaggaggggg gctaccttcc tttaagatta 1380cctaatatcc tgccttttat cctctttctc cccaggcatc tgaattccct tctgagctta 1440tgtcgaatga tagcaaagta ctctgtggct aaataaatgg tgagtgttgc gggtgcctcc 1500tgtgtgcgcg tttcggtaat gtgcttgtgt gtctgttaaa tgtttggttt ggtaaatgca 1560tgcttacttc actgtgttac gggtgccgct tgacttacca cataggcatg aaggggcttg 1620tagctgtggt tgctcaggac tacagaacag ttgcctttac aaaaacagaa aagaaagaaa 1680aaaaagaaag aaaagaaatg ccagtaactt actatgaagg tgtcaggacc aagtgtggct 1740gacttttatg agcccagtgg cggtacactg aggtggtaac ctcagctgta attaatctta 1800tcgccacaaa ttccatagtg attctctttt cccaaaact 1839101589PRTMus musculus 101Met Ala Leu Thr Asp Gly Gly Trp Cys Leu Pro Lys Arg Phe Gly Ala1 5 10 15Ala Ala Ala Asp Ala Gly Asp Ser Gly Pro Phe Pro Ala Arg Glu Pro 20 25 30Ser Ser Pro Leu Ser Pro Ile Ser Ser Ser Ser Ser Ser Cys Ser Arg 35 40 45Gly Gly Asp Arg Gly Pro Cys Gly Ala Ser Asn Cys Arg Thr Pro Gln 50 55 60Leu Asp Ala Glu Ala Val Ala Gly Pro Pro Gly Arg Ser Leu Leu Leu65 70 75 80Ser Pro Tyr Ala Ser His Pro Phe Ala Ala Ala His Gly Ala Ala Ala 85 90 95Pro Gly Val Ala Gly Pro Gly Ser Ala Leu Ser Thr Trp Glu Asp Leu 100 105 110Leu Leu Phe Thr Asp Leu Asp Gln Ala Ala Thr Ala Ser Lys Leu Leu 115 120 125Trp Ser Ser Arg Gly Ala Lys Leu Ser Pro Phe Ala Ala Glu Gln Pro 130 135 140Glu Glu Met Tyr Gln Thr Leu Ala Ala Leu Ser Ser Gln Gly Pro Ala145 150 155 160Ala Tyr Asp Gly Ala Pro Gly Gly Phe Val His Ser Ala Ala Ala Ala 165 170 175Ala Ala Ala Ala Ala Ala Ala Ser Ser Pro Val Tyr Val Pro Thr Thr 180 185 190Arg Val Gly Ser Met Leu Ser Gly Leu Pro Tyr Leu Gln Gly Ala Gly 195 200 205Ser Gly Pro Ser Asn His Ala Gly Gly Ala Gly Ala His Pro Gly Trp 210 215 220Ser Gln Ala Ser Ala Asp Ser Pro Pro Tyr Gly Gly Gly Gly Ala Ala225 230 235 240Gly Gly Gly Ala Ala Gly Pro Gly Gly Ala Gly Ser Ala Thr Ala His 245 250 255Ala Ser Ala Arg Phe Pro Tyr Ser Pro Ser Pro Pro Met Ala Asn Gly 260 265 270Ala Ala Arg Asp Pro Gly Gly Tyr Val Ala Ala Gly Gly Thr Gly Ala 275 280 285Gly Ser Val Ser Gly Gly Gly Gly Ser Leu Ala Ala Met Gly Gly Arg 290 295 300Glu His Gln Tyr Ser Ser Leu Ser Ala Ala Arg Pro Leu Asn Gly Thr305 310 315 320Tyr His His His His His His His Pro Thr Tyr Ser Pro Tyr Met Ala 325 330 335Ala Pro Leu Thr Pro Ala Trp Pro Ala Gly Pro Phe Glu Thr Pro Val 340 345 350Leu His Ser Leu Gln Gly Arg Ala Gly Ala Pro Leu Pro Val Pro Arg 355 360 365Gly Pro Ser Thr Asp Leu Leu Glu Asp Leu Ser Glu Ser Arg Glu Cys 370 375 380Val Asn Cys Gly Ser Ile Gln Thr Pro Leu Trp Arg Arg Asp Gly Thr385 390 395 400Gly His Tyr Leu Cys Asn Ala Cys Gly Leu Tyr Ser Lys Met Asn Gly 405 410 415Leu Ser Arg Pro Leu Ile Lys Pro Gln Lys Arg Val Pro Ser Ser Arg 420 425 430Arg Leu Gly Leu Ser Cys Ala Asn Cys His Thr Thr Thr Thr Thr Leu 435 440 445Trp Arg Arg Asn Ala Glu Gly Glu Pro Val Cys Asn Ala Cys Gly Leu 450 455 460Tyr Met Lys Leu His Gly Val Pro Arg Pro Leu Ala Met Lys Lys Glu465 470 475 480Gly Ile Gln Thr Arg Lys Arg Lys Pro Lys Asn Ile Asn Lys Ser Lys 485 490 495Ala Cys Ser Gly Asn Ser Ser Gly Ser Val Pro Met Thr Pro Thr Ser 500 505 510Ser Ser Ser Asn Ser Asp Asp Cys Thr Lys Asn Thr Ser Pro Ser Thr 515 520 525Gln Ala Thr Thr Ser Gly Val Gly Ala Ser Val Met Ser Ala Val Gly 530 535 540Glu Asn Ala Asn Pro Glu Asn Ser Asp Leu Lys Tyr Ser Gly Gln Asp545 550 555 560Gly Leu Tyr Ile Gly Val Ser Leu Ser Ser Pro Ala Glu Val Thr Ser 565 570 575Ser Val Arg Gln Asp Ser Trp Cys Ala Leu Ala Leu Ala 580 585102443PRTMus musculus 102Met Tyr Gln Thr Leu Ala Ala Leu Ser Ser Gln Gly Pro Ala Ala Tyr1 5 10 15Asp Gly Ala Pro Gly Gly Phe Val His Ser Ala Ala Ala Ala Ala Ala 20 25 30Ala Ala Ala Ala Ala Ser Ser Pro Val Tyr Val Pro Thr Thr Arg Val 35 40 45Gly Ser Met Leu Ser Gly Leu Pro Tyr Leu Gln Gly Ala Gly Ser Gly 50 55 60Pro Ser Asn His Ala Gly Gly Ala Gly Ala His Pro Gly Trp Ser Gln65 70 75 80Ala Ser Ala Asp Ser Pro Pro Tyr Gly Gly Gly Gly Ala Ala Gly Gly 85 90 95Gly Ala Ala Gly Pro Gly Gly Ala Gly Ser Ala Thr Ala His Ala Ser 100 105 110Ala Arg Phe Pro Tyr Ser Pro Ser Pro Pro Met Ala Asn Gly Ala Ala 115 120 125Arg Asp Pro Gly Gly Tyr Val Ala Ala Gly Gly Thr Gly Ala Gly Ser 130 135 140Val Ser Gly Gly Gly Gly Ser Leu Ala Ala Met Gly Gly Arg Glu His145 150 155 160Gln Tyr Ser Ser Leu Ser Ala Ala Arg Pro Leu Asn Gly Thr Tyr His 165 170 175His His His His His His Pro Thr Tyr Ser Pro Tyr Met Ala Ala Pro 180 185 190Leu Thr Pro Ala Trp Pro Ala Gly Pro Phe Glu Thr Pro Val Leu His 195 200 205Ser Leu Gln Gly Arg Ala Gly Ala Pro Leu Pro Val Pro Arg Gly Pro 210 215 220Ser Thr Asp Leu Leu Glu Asp Leu Ser Glu Ser Arg Glu Cys Val Asn225 230 235 240Cys Gly Ser Ile Gln Thr Pro Leu Trp Arg Arg Asp Gly Thr Gly His 245 250 255Tyr Leu Cys Asn Ala Cys Gly Leu Tyr Ser Lys Met Asn Gly Leu Ser 260 265 270Arg Pro Leu Ile Lys Pro Gln Lys Arg Val Pro Ser Ser Arg Arg Leu 275 280 285Gly Leu Ser Cys Ala Asn Cys His Thr Thr Thr Thr Thr Leu Trp Arg 290 295 300Arg Asn Ala Glu Gly Glu Pro Val Cys Asn Ala Cys Gly Leu Tyr Met305 310 315 320Lys Leu His Gly Val Pro Arg Pro Leu Ala Met Lys Lys Glu Gly Ile 325 330 335Gln Thr Arg Lys Arg Lys Pro Lys Asn Ile Asn Lys Ser Lys Ala Cys 340 345 350Ser Gly Asn Ser Ser Gly Ser Val Pro Met Thr Pro Thr Ser Ser Ser 355 360 365Ser Asn Ser Asp Asp Cys Thr Lys Asn Thr Ser Pro Ser Thr Gln Ala 370 375 380Thr Thr Ser Gly Val Gly Ala Ser Val Met Ser Ala Val Gly Glu Asn385 390 395 400Ala Asn Pro Glu Asn Ser Asp Leu Lys Tyr Ser Gly Gln Asp Gly Leu 405 410 415Tyr Ile Gly Val Ser Leu Ser Ser Pro Ala Glu Val Thr Ser Ser Val 420 425 430Arg Gln Asp Ser Trp Cys Ala Leu Ala Leu Ala 435 440103372PRTMus musculus 103Met Ser Met Ser Pro Lys His Thr Thr Pro Phe Ser Val Ser Asp Ile1 5 10 15Leu Ser Pro Leu Glu Glu Ser Tyr Lys Lys Val Gly Met Glu Gly Gly 20 25 30Gly Leu Gly Ala Pro Leu Ala Ala Tyr Arg Gln Gly Gln Ala Ala Pro 35 40 45Pro Ala Ala Ala Met Gln Gln His Ala Val Gly His His Gly Ala Val 50 55 60Thr Ala Ala Tyr His Met Thr Ala Ala Gly Val Pro Gln Leu Ser His65 70 75 80Ser Ala Val Gly Gly Tyr Cys Asn Gly Asn Leu Gly Asn Met Ser Glu 85 90 95Leu Pro Pro Tyr Gln Asp Thr Met Arg Asn Ser Ala Ser Gly Pro Gly 100 105 110Trp Tyr Gly Ala Asn Pro Asp Pro Arg Phe Pro Ala Ile Ser Arg Phe 115 120 125Met Gly Pro Ala Ser Gly Met Asn Met Ser Gly Met Gly Gly Leu Gly 130 135 140Ser Leu Gly Asp Val Ser Lys Asn Met Ala Pro Leu Pro Ser Ala Pro145 150 155 160Arg Arg Lys Arg Arg Val Leu Phe Ser Gln Ala Gln Val Tyr Glu Leu 165 170 175Glu Arg Arg Phe Lys Gln Gln Lys Tyr Leu Ser Ala Pro Glu Arg Glu 180 185 190His Leu Ala Ser Met Ile His Leu Thr Pro Thr Gln Val Lys Ile Trp 195 200 205Phe Gln Asn His Arg Tyr Lys Met Lys Arg Gln Ala Lys Asp Lys Ala 210 215 220Ala Gln Gln Gln Leu Gln Gln Asp Ser Gly Gly Gly Gly Gly Gly Gly225 230 235 240Gly Gly Ala Gly Cys Pro Gln Gln Gln Gln Ala Gln Gln Gln Ser Pro 245 250 255Arg Arg Val Ala Val Pro Val Leu Val Lys Asp Gly Lys Pro Cys Gln 260 265 270Ala Gly Ala Pro Ala Pro Gly Ala Ala Ser Leu Gln Ser His Ala Gln 275 280 285Gln Gln Ala Gln Gln Gln Ala Gln Ala Ala Gln Ala Ala Ala Ala Ala 290 295 300Ile Ser Val Gly Ser Gly Gly Ala Gly Leu Gly Ala His Pro Gly His305 310 315 320Gln Pro Gly Ser Ala Gly Gln Ser Pro Asp Leu Ala His His Ala Ala 325 330 335Ser Pro Ala Gly Leu Gln Gly Gln Val Ser Ser Leu Ser His Leu Asn 340 345 350Ser Ser Gly Ser Asp Tyr Gly Ala Met Ser Cys Ser Thr Leu Leu Tyr 355 360 365Gly Arg Thr Trp 370104465PRTMus musculus 104Met His Ser Ala Ser Ser Met Leu Gly Ala Val Lys Met Glu Gly His1 5 10 15Glu Pro Ser Asp Trp Ser Ser Tyr Tyr Ala Glu Pro Glu Gly Tyr Ser 20 25 30Ser Val Ser Asn Met Asn Ala Gly Leu Gly Met Asn Gly Met Asn Thr 35 40 45Tyr Met Ser Met Ser Ala Ala Ala Met Gly Gly Gly Ser Gly Asn Met 50 55 60Ser Ala Gly Ser Met Asn Met Ser Ser Tyr Val Gly Ala Gly Met Ser65 70 75 80Pro Ser Leu Ala Gly Met Ser Pro Gly Ala Gly Ala Met Ala Gly Met 85 90 95Ser Gly Ser Ala Gly Ala Ala Gly Val Ala Gly Met Gly Pro His Leu 100 105 110Ser Pro Ser Leu Ser Pro Leu Gly Gly Gln Ala Ala Gly Ala Met Gly 115 120 125Gly Leu Ala Pro Tyr Ala Asn Met Asn Ser Met Ser Pro Met Tyr Gly 130 135 140Gln Ala Gly Leu Ser Arg Ala Arg Asp Pro Lys Thr Tyr Arg Arg Ser145 150 155 160Tyr Thr His Ala Lys Pro Pro Tyr Ser Tyr Ile Ser Leu Ile Thr Met 165 170 175Ala Ile Gln Gln Ser Pro Asn Lys Met Leu Thr Leu Ser Glu Ile Tyr 180 185 190Gln Trp Ile Met Asp Leu Phe Pro Phe Tyr Arg Gln Asn Gln Gln Arg 195 200 205Trp Gln Asn Ser Ile Arg His Ser Leu Ser Phe Asn Asp Cys Phe Leu 210 215 220Lys Val Pro Arg Ser Pro Asp Lys Pro Gly Lys Gly Ser Phe Trp Thr225 230 235 240Leu His Pro Asp Ser Gly Asn Met Phe Glu Asn Gly Cys Tyr Leu Arg 245 250 255Arg Gln Lys Arg Phe Lys Cys Glu Lys Gln Leu Ala Leu Lys Glu Ala 260 265 270Ala Gly Ala Ala Ser Ser Gly Gly Lys Lys Thr Ala Pro Gly Ser Gln 275 280 285Ala Ser Gln Ala Gln Leu Gly Glu Ala Ala Gly Ser Ala Ser Glu Thr 290 295 300Pro Ala Gly Thr Glu Ser Pro His Ser Ser Ala Ser Pro Cys Gln Glu305 310 315 320His Lys Arg Gly Gly Leu Ser Glu Leu Lys Gly Ala Pro Ala Ser Ala 325 330 335Leu Ser Pro Pro Glu Pro Ala Pro Ser Pro Gly Gln Gln Gln Gln Ala 340 345 350Ala Ala His Leu Leu Gly Pro Pro His His Pro Gly Leu Pro

Pro Glu 355 360 365Ala His Leu Lys Pro Glu His His Tyr Ala Phe Asn His Pro Phe Ser 370 375 380Ile Asn Asn Leu Met Ser Ser Glu Gln Gln His His His Ser His His385 390 395 400His His Gln Pro His Lys Met Asp Leu Lys Ala Tyr Glu Gln Val Met 405 410 415His Tyr Pro Gly Gly Tyr Gly Ser Pro Met Pro Gly Ser Leu Ala Met 420 425 430Gly Pro Val Thr Asn Lys Ala Gly Leu Asp Ala Ser Pro Leu Ala Ala 435 440 445Asp Thr Ser Tyr Tyr Gln Gly Val Tyr Ser Arg Pro Ile Met Asn Ser 450 455 460Ser465105459PRTMus musculus 105Met Leu Gly Ala Val Lys Met Glu Gly His Glu Pro Ser Asp Trp Ser1 5 10 15Ser Tyr Tyr Ala Glu Pro Glu Gly Tyr Ser Ser Val Ser Asn Met Asn 20 25 30Ala Gly Leu Gly Met Asn Gly Met Asn Thr Tyr Met Ser Met Ser Ala 35 40 45Ala Ala Met Gly Gly Gly Ser Gly Asn Met Ser Ala Gly Ser Met Asn 50 55 60Met Ser Ser Tyr Val Gly Ala Gly Met Ser Pro Ser Leu Ala Gly Met65 70 75 80Ser Pro Gly Ala Gly Ala Met Ala Gly Met Ser Gly Ser Ala Gly Ala 85 90 95Ala Gly Val Ala Gly Met Gly Pro His Leu Ser Pro Ser Leu Ser Pro 100 105 110Leu Gly Gly Gln Ala Ala Gly Ala Met Gly Gly Leu Ala Pro Tyr Ala 115 120 125Asn Met Asn Ser Met Ser Pro Met Tyr Gly Gln Ala Gly Leu Ser Arg 130 135 140Ala Arg Asp Pro Lys Thr Tyr Arg Arg Ser Tyr Thr His Ala Lys Pro145 150 155 160Pro Tyr Ser Tyr Ile Ser Leu Ile Thr Met Ala Ile Gln Gln Ser Pro 165 170 175Asn Lys Met Leu Thr Leu Ser Glu Ile Tyr Gln Trp Ile Met Asp Leu 180 185 190Phe Pro Phe Tyr Arg Gln Asn Gln Gln Arg Trp Gln Asn Ser Ile Arg 195 200 205His Ser Leu Ser Phe Asn Asp Cys Phe Leu Lys Val Pro Arg Ser Pro 210 215 220Asp Lys Pro Gly Lys Gly Ser Phe Trp Thr Leu His Pro Asp Ser Gly225 230 235 240Asn Met Phe Glu Asn Gly Cys Tyr Leu Arg Arg Gln Lys Arg Phe Lys 245 250 255Cys Glu Lys Gln Leu Ala Leu Lys Glu Ala Ala Gly Ala Ala Ser Ser 260 265 270Gly Gly Lys Lys Thr Ala Pro Gly Ser Gln Ala Ser Gln Ala Gln Leu 275 280 285Gly Glu Ala Ala Gly Ser Ala Ser Glu Thr Pro Ala Gly Thr Glu Ser 290 295 300Pro His Ser Ser Ala Ser Pro Cys Gln Glu His Lys Arg Gly Gly Leu305 310 315 320Ser Glu Leu Lys Gly Ala Pro Ala Ser Ala Leu Ser Pro Pro Glu Pro 325 330 335Ala Pro Ser Pro Gly Gln Gln Gln Gln Ala Ala Ala His Leu Leu Gly 340 345 350Pro Pro His His Pro Gly Leu Pro Pro Glu Ala His Leu Lys Pro Glu 355 360 365His His Tyr Ala Phe Asn His Pro Phe Ser Ile Asn Asn Leu Met Ser 370 375 380Ser Glu Gln Gln His His His Ser His His His His Gln Pro His Lys385 390 395 400Met Asp Leu Lys Ala Tyr Glu Gln Val Met His Tyr Pro Gly Gly Tyr 405 410 415Gly Ser Pro Met Pro Gly Ser Leu Ala Met Gly Pro Val Thr Asn Lys 420 425 430Ala Gly Leu Asp Ala Ser Pro Leu Ala Ala Asp Thr Ser Tyr Tyr Gln 435 440 445Gly Val Tyr Ser Arg Pro Ile Met Asn Ser Ser 450 455106134PRTMus musculus 106Met Lys Ala Phe Ser Pro Val Arg Ser Val Arg Lys Asn Ser Leu Ser1 5 10 15Asp His Ser Leu Gly Ile Ser Arg Ser Lys Thr Pro Val Asp Asp Pro 20 25 30Met Ser Leu Leu Tyr Asn Met Asn Asp Cys Tyr Ser Lys Leu Lys Glu 35 40 45Leu Val Pro Ser Ile Pro Gln Asn Lys Lys Val Thr Lys Met Glu Ile 50 55 60Leu Gln His Val Ile Asp Tyr Ile Leu Asp Leu Gln Ile Ala Leu Asp65 70 75 80Ser His Pro Thr Ile Val Ser Leu His His Gln Arg Pro Gly Gln Asn 85 90 95Gln Ala Ser Arg Thr Pro Leu Thr Thr Leu Asn Thr Asp Ile Ser Ile 100 105 110Leu Ser Leu Gln Ala Ser Glu Phe Pro Ser Glu Leu Met Ser Asn Asp 115 120 125Ser Lys Val Leu Cys Gly 130107155PRTMus musculus 107Met Lys Ala Phe Ser Pro Val Arg Ser Val Arg Lys Asn Ser Leu Ser1 5 10 15Asp His Ser Leu Gly Ile Ser Arg Ser Lys Thr Pro Val Asp Asp Pro 20 25 30Met Ser Leu Leu Tyr Asn Met Asn Asp Cys Tyr Ser Lys Leu Lys Glu 35 40 45Leu Val Pro Ser Ile Pro Gln Asn Lys Lys Val Thr Lys Met Glu Ile 50 55 60Leu Gln His Val Ile Asp Tyr Ile Leu Asp Leu Gln Ile Ala Leu Asp65 70 75 80Ser His Pro Thr Ile Val Ser Leu His His Gln Arg Pro Gly Gln Asn 85 90 95Gln Ala Ser Arg Thr Pro Leu Thr Thr Leu Asn Thr Asp Ile Ser Ile 100 105 110Leu Ser Leu Gln Val Arg Leu Ala Cys Lys Tyr Ala Thr Ala Gln Thr 115 120 125Leu Arg Val Ser Arg Ala Val Thr Leu Lys Ala His Arg Arg Asp Arg 130 135 140Phe Ile Asn Phe Ile Phe Glu Glu Thr Val Tyr145 150 1551082977DNAHomo sapiens 108gggccgctct ctgacatcag agctgctgta gagcggagag gggcaggggt gaagggccac 60ggtggtgcaa cccaccactt cctccaagga ggagctgaga ggaacaggaa gtgtcaggac 120tttacgaccc gcgcctccag ctgaggtttc tagacgtgac ccagggcaga ctggtagcaa 180agcccccacg cccagccagg agcaccgccg aggactccag cacaccgagg gacatgctgg 240gcctgcgccc cccactgctc gccctggtgg ggctgctctc cctcgggtgc gtcctctctc 300aggagtgcac gaagttcaag gtcagcagct gccgggaatg catcgagtcg gggcccggct 360gcacctggtg ccagaagctg aacttcacag ggccggggga tcctgactcc attcgctgcg 420acacccggcc acagctgctc atgaggggct gtgcggctga cgacatcatg gaccccacaa 480gcctcgctga aacccaggaa gaccacaatg ggggccagaa gcagctgtcc ccacaaaaag 540tgacgcttta cctgcgacca ggccaggcag cagcgttcaa cgtgaccttc cggcgggcca 600agggctaccc catcgacctg tactatctga tggacctctc ctactccatg cttgatgacc 660tcaggaatgt caagaagcta ggtggcgacc tgctccgggc cctcaacgag atcaccgagt 720ccggccgcat tggcttcggg tccttcgtgg acaagaccgt gctgccgttc gtgaacacgc 780accctgataa gctgcgaaac ccatgcccca acaaggagaa agagtgccag cccccgtttg 840ccttcaggca cgtgctgaag ctgaccaaca actccaacca gtttcagacc gaggtcggga 900agcagctgat ttccggaaac ctggatgcac ccgagggtgg gctggacgcc atgatgcagg 960tcgccgcctg cccggaggaa atcggctggc gcaacgtcac gcggctgctg gtgtttgcca 1020ctgatgacgg cttccatttc gcgggcgacg ggaagctggg cgccatcctg acccccaacg 1080acggccgctg tcacctggag gacaacttgt acaagaggag caacgaattc gactacccat 1140cggtgggcca gctggcgcac aagctggctg aaaacaacat ccagcccatc ttcgcggtga 1200ccagtaggat ggtgaagacc tacgagaaac tcaccgagat catccccaag tcagccgtgg 1260gggagctgtc tgaggactcc agcaatgtgg tccaactcat taagaatgct tacaataaac 1320tctcctccag ggtcttcctg gatcacaacg ccctccccga caccctgaaa gtcacctacg 1380actccttctg cagcaatgga gtgacgcaca ggaaccagcc cagaggtgac tgtgatggcg 1440tgcagatcaa tgtcccgatc accttccagg tgaaggtcac ggccacagag tgcatccagg 1500agcagtcgtt tgtcatccgg gcgctgggct tcacggacat agtgaccgtg caggttcttc 1560cccagtgtga gtgccggtgc cgggaccaga gcagagaccg cagcctctgc catggcaagg 1620gcttcttgga gtgcggcatc tgcaggtgtg acactggcta cattgggaaa aactgtgagt 1680gccagacaca gggccggagc agccaggagc tggaaggaag ctgccggaag gacaacaact 1740ccatcatctg ctcagggctg ggggactgtg tctgcgggca gtgcctgtgc cacaccagcg 1800acgtccccgg caagctgata tacgggcagt actgcgagtg tgacaccatc aactgtgagc 1860gctacaacgg ccaggtctgc ggcggcccgg ggagggggct ctgcttctgc gggaagtgcc 1920gctgccaccc gggctttgag ggctcagcgt gccagtgcga gaggaccact gagggctgcc 1980tgaacccgcg gcgtgttgag tgtagtggtc gtggccggtg ccgctgcaac gtatgcgagt 2040gccattcagg ctaccagctg cctctgtgcc aggagtgccc cggctgcccc tcaccctgtg 2100gcaagtacat ctcctgcgcc gagtgcctga agttcgaaaa gggccccttt gggaagaact 2160gcagcgcggc gtgtccgggc ctgcagctgt cgaacaaccc cgtgaagggc aggacctgca 2220aggagaggga ctcagagggc tgctgggtgg cctacacgct ggagcagcag gacgggatgg 2280accgctacct catctatgtg gatgagagcc gagagtgtgt ggcaggcccc aacatcgccg 2340ccatcgtcgg gggcaccgtg gcaggcatcg tgctgatcgg cattctcctg ctggtcatct 2400ggaaggctct gatccacctg agcgacctcc gggagtacag gcgctttgag aaggagaagc 2460tcaagtccca gtggaacaat gataatcccc ttttcaagag cgccaccacg acggtcatga 2520accccaagtt tgctgagagt taggagcact tggtgaagac aaggccgtca ggacccacca 2580tgtctgcccc atcacgcggc cgagacatgg cttgccacag ctcttgagga tgtcaccaat 2640taaccagaaa tccagttatt ttccgccctc aaaatgacag ccatggccgg ccgggtgctt 2700ctgggggctc gtcgggggga cagctccact ctgactggca cagtctttgc atggagactt 2760gaggagggag ggcttgaggt tggtgaggtt aggtgcgtgt ttcctgtgca agtcaggaca 2820tcagtctgat taaaggtggt gccaatttat ttacatttaa acttgtcagg gtataaaatg 2880acatcccatt aattatattg ttaatcaatc acgtgtatag aaaaaaaata aaacttcaat 2940acaggctgtc catggaaaaa aaaaaaaaaa aaaaaaa 29771092932DNAHomo sapiens 109atccagggtg aggaaggcag cccacacttt tcttggagac acatccccaa agaagtcctc 60acgtggctcc gtttgggcag aaaccatgaa ttgaacggga aaagaaatat gtcaagtatc 120agaaagaaga gtggcatgct ttgacagcaa gtggactccg agtccagggc agagcctcag 180ttagggacat gctgggcctg cgccccccac tgctcgccct ggtggggctg ctctccctcg 240ggtgcgtcct ctctcaggag tgcacgaagt tcaaggtcag cagctgccgg gaatgcatcg 300agtcggggcc cggctgcacc tggtgccaga agctgaactt cacagggccg ggggatcctg 360actccattcg ctgcgacacc cggccacagc tgctcatgag gggctgtgcg gctgacgaca 420tcatggaccc cacaagcctc gctgaaaccc aggaagacca caatgggggc cagaagcagc 480tgtccccaca aaaagtgacg ctttacctgc gaccaggcca ggcagcagcg ttcaacgtga 540ccttccggcg ggccaagggc taccccatcg acctgtacta tctgatggac ctctcctact 600ccatgcttga tgacctcagg aatgtcaaga agctaggtgg cgacctgctc cgggccctca 660acgagatcac cgagtccggc cgcattggct tcgggtcctt cgtggacaag accgtgctgc 720cgttcgtgaa cacgcaccct gataagctgc gaaacccatg ccccaacaag gagaaagagt 780gccagccccc gtttgccttc aggcacgtgc tgaagctgac caacaactcc aaccagtttc 840agaccgaggt cgggaagcag ctgatttccg gaaacctgga tgcacccgag ggtgggctgg 900acgccatgat gcaggtcgcc gcctgcccgg aggaaatcgg ctggcgcaac gtcacgcggc 960tgctggtgtt tgccactgat gacggcttcc atttcgcggg cgacgggaag ctgggcgcca 1020tcctgacccc caacgacggc cgctgtcacc tggaggacaa cttgtacaag aggagcaacg 1080aattcgacta cccatcggtg ggccagctgg cgcacaagct ggctgaaaac aacatccagc 1140ccatcttcgc ggtgaccagt aggatggtga agacctacga gaaactcacc gagatcatcc 1200ccaagtcagc cgtgggggag ctgtctgagg actccagcaa tgtggtccaa ctcattaaga 1260atgcttacaa taaactctcc tccagggtct tcctggatca caacgccctc cccgacaccc 1320tgaaagtcac ctacgactcc ttctgcagca atggagtgac gcacaggaac cagcccagag 1380gtgactgtga tggcgtgcag atcaatgtcc cgatcacctt ccaggtgaag gtcacggcca 1440cagagtgcat ccaggagcag tcgtttgtca tccgggcgct gggcttcacg gacatagtga 1500ccgtgcaggt tcttccccag tgtgagtgcc ggtgccggga ccagagcaga gaccgcagcc 1560tctgccatgg caagggcttc ttggagtgcg gcatctgcag gtgtgacact ggctacattg 1620ggaaaaactg tgagtgccag acacagggcc ggagcagcca ggagctggaa ggaagctgcc 1680ggaaggacaa caactccatc atctgctcag ggctggggga ctgtgtctgc gggcagtgcc 1740tgtgccacac cagcgacgtc cccggcaagc tgatatacgg gcagtactgc gagtgtgaca 1800ccatcaactg tgagcgctac aacggccagg tctgcggcgg cccggggagg gggctctgct 1860tctgcgggaa gtgccgctgc cacccgggct ttgagggctc agcgtgccag tgcgagagga 1920ccactgaggg ctgcctgaac ccgcggcgtg ttgagtgtag tggtcgtggc cggtgccgct 1980gcaacgtatg cgagtgccat tcaggctacc agctgcctct gtgccaggag tgccccggct 2040gcccctcacc ctgtggcaag tacatctcct gcgccgagtg cctgaagttc gaaaagggcc 2100cctttgggaa gaactgcagc gcggcgtgtc cgggcctgca gctgtcgaac aaccccgtga 2160agggcaggac ctgcaaggag agggactcag agggctgctg ggtggcctac acgctggagc 2220agcaggacgg gatggaccgc tacctcatct atgtggatga gagccgagag tgtgtggcag 2280gccccaacat cgccgccatc gtcgggggca ccgtggcagg catcgtgctg atcggcattc 2340tcctgctggt catctggaag gctctgatcc acctgagcga cctccgggag tacaggcgct 2400ttgagaagga gaagctcaag tcccagtgga acaatgataa tccccttttc aagagcgcca 2460ccacgacggt catgaacccc aagtttgctg agagttagga gcacttggtg aagacaaggc 2520cgtcaggacc caccatgtct gccccatcac gcggccgaga catggcttgc cacagctctt 2580gaggatgtca ccaattaacc agaaatccag ttattttccg ccctcaaaat gacagccatg 2640gccggccggg tgcttctggg ggctcgtcgg ggggacagct ccactctgac tggcacagtc 2700tttgcatgga gacttgagga gggagggctt gaggttggtg aggttaggtg cgtgtttcct 2760gtgcaagtca ggacatcagt ctgattaaag gtggtgccaa tttatttaca tttaaacttg 2820tcagggtata aaatgacatc ccattaatta tattgttaat caatcacgtg tatagaaaaa 2880aaataaaact tcaatacagg ctgtccatgg aaaaaaaaaa aaaaaaaaaa aa 2932110769PRTHomo sapiens 110Met Leu Gly Leu Arg Pro Pro Leu Leu Ala Leu Val Gly Leu Leu Ser1 5 10 15Leu Gly Cys Val Leu Ser Gln Glu Cys Thr Lys Phe Lys Val Ser Ser 20 25 30Cys Arg Glu Cys Ile Glu Ser Gly Pro Gly Cys Thr Trp Cys Gln Lys 35 40 45Leu Asn Phe Thr Gly Pro Gly Asp Pro Asp Ser Ile Arg Cys Asp Thr 50 55 60Arg Pro Gln Leu Leu Met Arg Gly Cys Ala Ala Asp Asp Ile Met Asp65 70 75 80Pro Thr Ser Leu Ala Glu Thr Gln Glu Asp His Asn Gly Gly Gln Lys 85 90 95Gln Leu Ser Pro Gln Lys Val Thr Leu Tyr Leu Arg Pro Gly Gln Ala 100 105 110Ala Ala Phe Asn Val Thr Phe Arg Arg Ala Lys Gly Tyr Pro Ile Asp 115 120 125Leu Tyr Tyr Leu Met Asp Leu Ser Tyr Ser Met Leu Asp Asp Leu Arg 130 135 140Asn Val Lys Lys Leu Gly Gly Asp Leu Leu Arg Ala Leu Asn Glu Ile145 150 155 160Thr Glu Ser Gly Arg Ile Gly Phe Gly Ser Phe Val Asp Lys Thr Val 165 170 175Leu Pro Phe Val Asn Thr His Pro Asp Lys Leu Arg Asn Pro Cys Pro 180 185 190Asn Lys Glu Lys Glu Cys Gln Pro Pro Phe Ala Phe Arg His Val Leu 195 200 205Lys Leu Thr Asn Asn Ser Asn Gln Phe Gln Thr Glu Val Gly Lys Gln 210 215 220Leu Ile Ser Gly Asn Leu Asp Ala Pro Glu Gly Gly Leu Asp Ala Met225 230 235 240Met Gln Val Ala Ala Cys Pro Glu Glu Ile Gly Trp Arg Asn Val Thr 245 250 255Arg Leu Leu Val Phe Ala Thr Asp Asp Gly Phe His Phe Ala Gly Asp 260 265 270Gly Lys Leu Gly Ala Ile Leu Thr Pro Asn Asp Gly Arg Cys His Leu 275 280 285Glu Asp Asn Leu Tyr Lys Arg Ser Asn Glu Phe Asp Tyr Pro Ser Val 290 295 300Gly Gln Leu Ala His Lys Leu Ala Glu Asn Asn Ile Gln Pro Ile Phe305 310 315 320Ala Val Thr Ser Arg Met Val Lys Thr Tyr Glu Lys Leu Thr Glu Ile 325 330 335Ile Pro Lys Ser Ala Val Gly Glu Leu Ser Glu Asp Ser Ser Asn Val 340 345 350Val Gln Leu Ile Lys Asn Ala Tyr Asn Lys Leu Ser Ser Arg Val Phe 355 360 365Leu Asp His Asn Ala Leu Pro Asp Thr Leu Lys Val Thr Tyr Asp Ser 370 375 380Phe Cys Ser Asn Gly Val Thr His Arg Asn Gln Pro Arg Gly Asp Cys385 390 395 400Asp Gly Val Gln Ile Asn Val Pro Ile Thr Phe Gln Val Lys Val Thr 405 410 415Ala Thr Glu Cys Ile Gln Glu Gln Ser Phe Val Ile Arg Ala Leu Gly 420 425 430Phe Thr Asp Ile Val Thr Val Gln Val Leu Pro Gln Cys Glu Cys Arg 435 440 445Cys Arg Asp Gln Ser Arg Asp Arg Ser Leu Cys His Gly Lys Gly Phe 450 455 460Leu Glu Cys Gly Ile Cys Arg Cys Asp Thr Gly Tyr Ile Gly Lys Asn465 470 475 480Cys Glu Cys Gln Thr Gln Gly Arg Ser Ser Gln Glu Leu Glu Gly Ser 485 490 495Cys Arg Lys Asp Asn Asn Ser Ile Ile Cys Ser Gly Leu Gly Asp Cys 500 505 510Val Cys Gly Gln Cys Leu Cys His Thr Ser Asp Val Pro Gly Lys Leu 515 520 525Ile Tyr Gly Gln Tyr Cys Glu Cys Asp Thr Ile Asn Cys Glu Arg Tyr 530 535 540Asn Gly Gln Val Cys Gly Gly Pro Gly Arg Gly Leu Cys Phe Cys Gly545 550 555 560Lys Cys Arg Cys His Pro Gly Phe Glu Gly Ser Ala Cys Gln Cys Glu 565 570 575Arg Thr Thr Glu Gly Cys Leu Asn Pro Arg Arg Val Glu Cys Ser Gly 580 585 590Arg Gly Arg Cys Arg Cys Asn Val Cys Glu Cys His Ser Gly Tyr Gln 595 600 605Leu Pro Leu Cys Gln Glu Cys Pro Gly Cys Pro Ser Pro Cys Gly Lys 610 615 620Tyr Ile Ser Cys Ala Glu Cys Leu Lys Phe Glu Lys Gly Pro Phe Gly625

630 635 640Lys Asn Cys Ser Ala Ala Cys Pro Gly Leu Gln Leu Ser Asn Asn Pro 645 650 655Val Lys Gly Arg Thr Cys Lys Glu Arg Asp Ser Glu Gly Cys Trp Val 660 665 670Ala Tyr Thr Leu Glu Gln Gln Asp Gly Met Asp Arg Tyr Leu Ile Tyr 675 680 685Val Asp Glu Ser Arg Glu Cys Val Ala Gly Pro Asn Ile Ala Ala Ile 690 695 700Val Gly Gly Thr Val Ala Gly Ile Val Leu Ile Gly Ile Leu Leu Leu705 710 715 720Val Ile Trp Lys Ala Leu Ile His Leu Ser Asp Leu Arg Glu Tyr Arg 725 730 735Arg Phe Glu Lys Glu Lys Leu Lys Ser Gln Trp Asn Asn Asp Asn Pro 740 745 750Leu Phe Lys Ser Ala Thr Thr Thr Val Met Asn Pro Lys Phe Ala Glu 755 760 765Ser1115603DNAHomo sapiens 111ggagtgggcc aggccgccag ccccgccagc cccgccagcc ccgccagccc cgcgatggct 60tgggccgcgc tcctcggcct cctggccgca ctgttgctgc tgctgctact gagccgccgc 120cgcacgcggc gacctggtga gcctcccctg gacctgggca gcatcccctg gttggggtat 180gccttggact ttggaaaaga tgctgccagc ttcctcacga ggatgaagga gaagcacggt 240gacatcttta ctatactggt tgggggcagg tatgtcaccg ttctcctgga cccacactcc 300tacgacgcgg tggtgtggga gcctcgcacc aggctcgact tccatgccta tgccatcttc 360ctcatggaga ggatttttga tgtgcagctt ccacattaca gccccagtga tgaaaaggcc 420aggatgaaac tgactcttct ccacagagag ctccaggcac tcacagaagc catgtatacc 480aacctccatg cagtgctgtt gggcgatgct acagaagcag gcagtggctg gcacgagatg 540ggtctcctcg acttctccta cagcttcctg ctcagagccg gctacctgac tctttacgga 600attgaggcgc tgccacgcac ccatgaaagc caggcccagg accgcgtcca ctcagctgat 660gtcttccaca cctttcgcca gctcgaccgg ctgctcccca aactggcccg tggctccctg 720tcagtggggg acaaggacca catgtgcagt gtcaaaagtc gcctgtggaa gctgctatcc 780ccagccaggc tggccaggcg ggcccaccgg agcaaatggc tggagagtta cctgctgcac 840ctggaggaga tgggtgtgtc agaggagatg caggcacggg ccctggtgct gcagctgtgg 900gccacacagg ggaatatggg tcccgctgcc ttctggctcc tgctcttcct tctcaagaat 960cctgaagccc tggctgctgt ccgcggagag ctcgagagta tcctttggca agcggagcag 1020cctgtctcgc agacgaccac tctcccacag aaggttctag acagcacacc tgtgcttgat 1080agcgtgctga gtgagagcct caggcttaca gctgccccct tcatcacccg cgaggttgtg 1140gtggacctgg ccatgcccat ggcagacggg cgagaattca acctgcgacg tggtgaccgc 1200ctcctcctct tccccttcct gagcccccag agagacccag aaatctacac agacccagag 1260gtatttaaat acaaccgatt cctgaaccct gacggatcag agaagaaaga cttttacaag 1320gatgggaaac ggctgaagaa ttacaacatg ccctgggggg cggggcacaa tcactgcctg 1380gggaggagtt atgcggtcaa cagcatcaaa caatttgtgt tccttgtgct ggtgcacttg 1440gacttggagc tgatcaacgc agatgtggag atccctgagt ttgacctcag caggtacggc 1500ttcggtctga tgcagccgga acacgacgtg cccgtccgct accgcatccg cccatgacac 1560agggagcaga tggatccacg tgctcgcctc tgcccagcct gccccagcct gccccagcct 1620cccagctttc tgtgtgcaca gttggcccgg gtgcaggtgc tagcattacc acttccctgc 1680ttttctccca gaaggctggg tccaggggag ggaaaagcta agagggtgaa caaagaaaag 1740acattgaaag ctctatggat tatccactgc aaagttttct ttccaaaatc aggctttgtc 1800tgctcccaat tcacctcgtt actctcacct cgtgatatcc acaaatgcta ttcagataag 1860gcagaactag gagtcttcac tgctctgccc ccaactcccg gaggtgtcac cttcctagtt 1920cttatgagct agcatggccc gggccttatc cagtcaaagc ggatgctggc cacagaaagg 1980ccactcagga tgtcctttgt gtccattgat gtcattcagc agtcagtccc ccaataatcc 2040ttaaactagc taaaaccaaa ggagtccctt agaagatctg cttccctggg gccccatttg 2100ccagattgcc ccattgctca cactacttga gaaaatgcag gagagcttcc cccaaggctg 2160atgcattccc ggtgcagaac aggggcaccc tccaaacact gggctctgag gagtggagtt 2220ctctgttcta gagtgacagg caccagatgg gatgggcttt ctcagtgtca gcactcaggt 2280agggagctaa ggaagacaca gcccagacaa gatggctgga aggagccagc caggactcct 2340tagactgatc aagccaaaaa agaaggtgcc gatttcatgc attctagtgc agaagcccca 2400actgtgatca cgatccagtc tgcagacgtg ttttgtttgg acttcactta aaaaaatgcc 2460ttagttgtta tcatctttgg gagagttcat tcaaaatgtc cagcttctct tgaaaacttg 2520gtatatctgg ccacactggg ctcacattcc caagggtaac tcttggccag agctgagtgg 2580cagccgcctc ccttatgcag gacatgtgct ctcggcttca ccagggttct gaccgggtct 2640gcttctgcat tcacagcgcc tcctggacct gaaggcatct gagtgtgaga ccctgttcta 2700actcttagaa gtgacattgt aagaggtggt ggggaccagc taattggtcc aacccagcct 2760gagtgcacca ccctttgaac aaatgtatca gtgatgaaaa tttgcctttg ccccggcttg 2820cctgtaatcc cagcactttg ggaggccgag gtgggcggat cacttgaggt cgggagttca 2880agaccagcct ggccaacatg gcgaaacccc gtctctacta aacataaaaa aattagtcag 2940gtgtggcggt gcgtgcctgt aatcccagct attcaggagg ctgaggcacc agaattgctt 3000gaacccagga ggtggaggtt gcagtgaact gagactgcgc cacggcactc cagcctgggc 3060gacagagcaa gactctgtct caataaataa ataattaatt aaaataaaaa acagcttaaa 3120gagaaaaatg gcctgcaaac cttttttatg atgctatttt tattaatata aagtcctgtt 3180tattgagacc ctttaaatgc ctgcgagaga ccctacagac agtatgtcta ctcctcacag 3240catctctatg aagagaagga gggttgtgcc cacttcatag atgagaaaac tgagaggtga 3300ggtgacttgc ctggggccac atagctcata agctgtagaa ctctgcaggc agatttactg 3360tcccaggagc aaatgctgga tgagcaactc ctgttctttg ggctcaaggg gactggtgat 3420gggacaattc ttctcgactt caggagctga cagagccaga ggcacctaaa cttgggtaca 3480tcttgtaaga cacataatga ggtccctcta gctttagctg gagggagata aaagaacccc 3540agacctctga atgtcccaga ggctagtctc ttctcagagc agcactgggg tttgggggct 3600tccctgggcc tcagcctcca ggcaccccca ggattcccag agagacgctg tgattggcag 3660gaggcaggat atccccaggg aaacccatct tcacgcctgg gtgaccccca ctgccgcctc 3720cttcttaact ctgcaggaaa tcagagctgg cagcctccag tgggaggaca gagccggttt 3780ccgtggcaac cctcagctgc ctcatcgtgg ctgggaaggg aaggaagcaa gccggcagaa 3840atagctatgg aaggtcttgc gcaggctgca accctggtgt gctgggcgaa aacccttatg 3900actcccccct tccaaatcag gctgggttgt cactgagact agattctcac ctgccttcaa 3960agaagggcca attcccttta aaggtcgcac ctccttggaa ccacagtcat tagtgaatta 4020cactcaagga aaagatgtgc tcccaccagg cagctccagc tgttacctga gatactgaag 4080tgcagctcag gagacgatta tttaaacctg cccttgtttt aatcgttatt tttctcttta 4140aaaaaaatag aagctataaa gaaaagaggg agagatgagt gggttagcta cctgctatgc 4200gctagttagg aagttacctg gatgccattg tatttcttca tcccttgctt aagaatcaaa 4260attactggac atatgttagg aatactcttt ctttctttct ttctttttaa gctcagtggc 4320aagaatgaaa tactcttttt tttttttttt ttttgagatg gagtctcgct ctgctgccca 4380ggctagagtg cagtggcgtg atctcggctc actgcaagct ctgcctcccg tgttcacacc 4440attctcctgc ctcagcctcc tgagtagctg ggactacagg cacccgccac cacacccggc 4500taatttttgg atttttagta gagatgggat ttcaccgtat tagccaggat ggtcttgatc 4560tcctgagctc gtgatctgcc cgcctcggcc tcccaaagtg ctgggattac aggtgtgagc 4620caccgcgccc agccaagaat aaaatactct taagttgatc taatgaagtg tttccttacc 4680attgtgatta ttgttactat tatttgctat attttaatat tgttgtttac caaatattct 4740cctttaaaca gactcgcttt ttaaactttt tttttttttt ttgagacgga gtttcacgct 4800tattgcccag gctggagtgc aatggcacga tctcagctca ccacaacctc cacctcctgg 4860gtttaagcaa tgcttctgcc tcagcttccc aagtagctga gattacaggc gcacaccacc 4920acgcccaact gatttttgta tttttagtag agacggggtt tccccatgtt ggtcaggctg 4980gtctcgaact cctgacctcg tgatttgcct gcctgggcct cccaaagtgc taggattaca 5040ggcatgagcc accatgcccg gcctaaactt tgtttttaaa atgaactttt tttcccccca 5100attgctgcca atagtggata acatgtatca ctcactgcca aaaatagaaa gtgaccatga 5160aaaataaatt cgctggggaa gggggctcca tgctggtgtg gccaaggctg agagctctct 5220cttctctgtt acaaaacgag ataagcaagt gttagaattg ccttaaggcc acactggcat 5280ctccctgacc ttctccaggg acagaagcag gagtaagttt ctcatcccat gggcgaccag 5340ggccatctcc tcccaccagt ggcccccact cacagggagc tggcaatgcc ctacctgcct 5400gttctccaga tggagaaaca ggctctgaga tttcacaggt cttgcccaaa gtcattgatt 5460ttgatgatta aaaagaataa acacagtgtt tcctgagtag cagtgattgt tatgccttgc 5520tattttaata aagattctat tttcgtataa cattgtcaag tggaaacatg ctgaaatcta 5580ttaaaccatc tttgtttgtg gaa 5603112500PRTHomo sapiens 112Met Ala Trp Ala Ala Leu Leu Gly Leu Leu Ala Ala Leu Leu Leu Leu1 5 10 15Leu Leu Leu Ser Arg Arg Arg Thr Arg Arg Pro Gly Glu Pro Pro Leu 20 25 30Asp Leu Gly Ser Ile Pro Trp Leu Gly Tyr Ala Leu Asp Phe Gly Lys 35 40 45Asp Ala Ala Ser Phe Leu Thr Arg Met Lys Glu Lys His Gly Asp Ile 50 55 60Phe Thr Ile Leu Val Gly Gly Arg Tyr Val Thr Val Leu Leu Asp Pro65 70 75 80His Ser Tyr Asp Ala Val Val Trp Glu Pro Arg Thr Arg Leu Asp Phe 85 90 95His Ala Tyr Ala Ile Phe Leu Met Glu Arg Ile Phe Asp Val Gln Leu 100 105 110Pro His Tyr Ser Pro Ser Asp Glu Lys Ala Arg Met Lys Leu Thr Leu 115 120 125Leu His Arg Glu Leu Gln Ala Leu Thr Glu Ala Met Tyr Thr Asn Leu 130 135 140His Ala Val Leu Leu Gly Asp Ala Thr Glu Ala Gly Ser Gly Trp His145 150 155 160Glu Met Gly Leu Leu Asp Phe Ser Tyr Ser Phe Leu Leu Arg Ala Gly 165 170 175Tyr Leu Thr Leu Tyr Gly Ile Glu Ala Leu Pro Arg Thr His Glu Ser 180 185 190Gln Ala Gln Asp Arg Val His Ser Ala Asp Val Phe His Thr Phe Arg 195 200 205Gln Leu Asp Arg Leu Leu Pro Lys Leu Ala Arg Gly Ser Leu Ser Val 210 215 220Gly Asp Lys Asp His Met Cys Ser Val Lys Ser Arg Leu Trp Lys Leu225 230 235 240Leu Ser Pro Ala Arg Leu Ala Arg Arg Ala His Arg Ser Lys Trp Leu 245 250 255Glu Ser Tyr Leu Leu His Leu Glu Glu Met Gly Val Ser Glu Glu Met 260 265 270Gln Ala Arg Ala Leu Val Leu Gln Leu Trp Ala Thr Gln Gly Asn Met 275 280 285Gly Pro Ala Ala Phe Trp Leu Leu Leu Phe Leu Leu Lys Asn Pro Glu 290 295 300Ala Leu Ala Ala Val Arg Gly Glu Leu Glu Ser Ile Leu Trp Gln Ala305 310 315 320Glu Gln Pro Val Ser Gln Thr Thr Thr Leu Pro Gln Lys Val Leu Asp 325 330 335Ser Thr Pro Val Leu Asp Ser Val Leu Ser Glu Ser Leu Arg Leu Thr 340 345 350Ala Ala Pro Phe Ile Thr Arg Glu Val Val Val Asp Leu Ala Met Pro 355 360 365Met Ala Asp Gly Arg Glu Phe Asn Leu Arg Arg Gly Asp Arg Leu Leu 370 375 380Leu Phe Pro Phe Leu Ser Pro Gln Arg Asp Pro Glu Ile Tyr Thr Asp385 390 395 400Pro Glu Val Phe Lys Tyr Asn Arg Phe Leu Asn Pro Asp Gly Ser Glu 405 410 415Lys Lys Asp Phe Tyr Lys Asp Gly Lys Arg Leu Lys Asn Tyr Asn Met 420 425 430Pro Trp Gly Ala Gly His Asn His Cys Leu Gly Arg Ser Tyr Ala Val 435 440 445Asn Ser Ile Lys Gln Phe Val Phe Leu Val Leu Val His Leu Asp Leu 450 455 460Glu Leu Ile Asn Ala Asp Val Glu Ile Pro Glu Phe Asp Leu Ser Arg465 470 475 480Tyr Gly Phe Gly Leu Met Gln Pro Glu His Asp Val Pro Val Arg Tyr 485 490 495Arg Ile Arg Pro 5001131902DNAHomo sapiens 113ggcactgggc aggaagggga gggggagcga gcgcgagaaa tgcagaggct gcagcggcgg 60cggcggcggc agtagcggca gcggcgacga cggcggcggc agcgctccaa ctggctcctc 120gctccgggct ccgccgtcga gccgggagag agcctccgcc agcggccagg caccagccag 180acgacgccag cgaccccggc ctctcggcgg caccgcgcta actcaggggc tgcataggca 240cccagagccg aactccaaga tgggaggcaa gctcagcaag aagaagaagg gctacaatgt 300gaacgacgag aaagccaagg agaaagacaa gaaggccgag ggcgcggcga cggaagagga 360ggggaccccg aaggagagtg agccccaggc ggccgcagag cccgccgagg ccaaggaggg 420caaggagaag cccgaccagg acgccgaggg caaggccgag gagaaggagg gcgagaagga 480cgcggcggct gccaaggagg aggccccgaa ggcggagccc gagaagacgg agggcgcggc 540agaggccaag gctgagcccc cgaaggcgcc cgagcaggag caggcggccc ccggccccgc 600tgcgggcggc gaggccccca aagctgctga ggccgccgcg gccccggccg agagcgcggc 660ccctgccgcc ggggaggagc ccagcaagga ggaaggggaa cccaaaaaga ctgaggcgcc 720cgcagctcct gccgcccagg agaccaaaag tgacggggcc ccagcttcag actcaaaacc 780cggcagctcg gaggctgccc cctcttccaa ggagaccccc gcagccacgg aagcgcctag 840ttccacaccc aaggcccagg gccccgcagc ctctgcagaa gagcccaagc cggtggaggc 900cccggcagct aattccgacc aaaccgtaac cgtgaaagag tgacaaggac agcctatagg 960aaaaacaata ccacttaaaa caatctcctc tctctctctc tctctctctc tctatctctc 1020tctctatctc ctctctctct ctcctctcct atctctcctc tctctctctc ctatactaac 1080ttgtttcaaa ttggaagtaa tgatatgtat tgcccaagga aaaatacagg atgttgtccc 1140atcaagggag ggagggggtg ggagaatcca aatagtattt ttgtggggaa atatctaata 1200taccttcagt caactttacc aagaagtcct ggatttccaa gatccgcgtc tgaaagtgca 1260gtacatcgtt tgtacctgaa actgccgcca catgcactcc tccaccgctg agagttgaat 1320agcttttctt ctgcaatggg agttgggagt gatgcgtttg attctgccca cagggcctgt 1380gccaaggcaa tcagatcttt atgagagcag tattttctgt gttttctttt taatttacag 1440cctttcttat tttgatattt ttttaatgtt gtggatgaat gccagctttc agacagagcc 1500cacttagctt gtccacatgg atctcaatgc caatcctcca ttcttcctct ccagatattt 1560ttgggagtga caaacattct ctcatcctac ttagcctacc tagatttctc atgacgagtt 1620aatgcatgtc cgtggttggg tgcacctgta gttctgttta ttggtcagtg gaaatgaaaa 1680aaaaaaaaaa aaaaagtctg cgttcattgc agttccagtt tctcttccat tctgtgtcac 1740agacaccaac acaccactca ttggaaaatg gaaaaaaaaa acaaaaaaaa aacaaaaaaa 1800tgtacaatgg atgcattgaa attatatgta attgtataaa tggtgcaaca gtaataaagt 1860taaacaatta aaaagaagta ataaagacaa aaaaaaaaaa aa 19021141727DNAHomo sapiens 114gcgcaactcg tttgcagcgg cgcagcccag acgcgcctgc agctggggct caccccaacc 60tcgctgccag ccgagaactc caagatggga ggcaagctca gcaagaagaa gaagggctac 120aatgtgaacg acgagaaagc caaggagaaa gacaagaagg ccgagggcgc ggcgacggaa 180gaggagggga ccccgaagga gagtgagccc caggcggccg cagagcccgc cgaggccaag 240gagggcaagg agaagcccga ccaggacgcc gagggcaagg ccgaggagaa ggagggcgag 300aaggacgcgg cggctgccaa ggaggaggcc ccgaaggcgg agcccgagaa gacggagggc 360gcggcagagg ccaaggctga gcccccgaag gcgcccgagc aggagcaggc ggcccccggc 420cccgctgcgg gcggcgaggc ccccaaagct gctgaggccg ccgcggcccc ggccgagagc 480gcggcccctg ccgccgggga ggagcccagc aaggaggaag gggaacccaa aaagactgag 540gcgcccgcag ctcctgccgc ccaggagacc aaaagtgacg gggccccagc ttcagactca 600aaacccggca gctcggaggc tgccccctct tccaaggaga cccccgcagc cacggaagcg 660cctagttcca cacccaaggc ccagggcccc gcagcctctg cagaagagcc caagccggtg 720gaggccccgg cagctaattc cgaccaaacc gtaaccgtga aagagtgaca aggacagcct 780ataggaaaaa caataccact taaaacaatc tcctctctct ctctctctct ctctctctat 840ctctctctct atctcctctc tctctctcct ctcctatctc tcctctctct ctctcctata 900ctaacttgtt tcaaattgga agtaatgata tgtattgccc aaggaaaaat acaggatgtt 960gtcccatcaa gggagggagg gggtgggaga atccaaatag tatttttgtg gggaaatatc 1020taatatacct tcagtcaact ttaccaagaa gtcctggatt tccaagatcc gcgtctgaaa 1080gtgcagtaca tcgtttgtac ctgaaactgc cgccacatgc actcctccac cgctgagagt 1140tgaatagctt ttcttctgca atgggagttg ggagtgatgc gtttgattct gcccacaggg 1200cctgtgccaa ggcaatcaga tctttatgag agcagtattt tctgtgtttt ctttttaatt 1260tacagccttt cttattttga tattttttta atgttgtgga tgaatgccag ctttcagaca 1320gagcccactt agcttgtcca catggatctc aatgccaatc ctccattctt cctctccaga 1380tatttttggg agtgacaaac attctctcat cctacttagc ctacctagat ttctcatgac 1440gagttaatgc atgtccgtgg ttgggtgcac ctgtagttct gtttattggt cagtggaaat 1500gaaaaaaaaa aaaaaaaaaa gtctgcgttc attgcagttc cagtttctct tccattctgt 1560gtcacagaca ccaacacacc actcattgga aaatggaaaa aaaaaacaaa aaaaaaacaa 1620aaaaatgtac aatggatgca ttgaaattat atgtaattgt ataaatggtg caacagtaat 1680aaagttaaac aattaaaaag aagtaataaa gacaaaaaaa aaaaaaa 1727115227PRTHomo sapiens 115Met Gly Gly Lys Leu Ser Lys Lys Lys Lys Gly Tyr Asn Val Asn Asp1 5 10 15Glu Lys Ala Lys Glu Lys Asp Lys Lys Ala Glu Gly Ala Ala Thr Glu 20 25 30Glu Glu Gly Thr Pro Lys Glu Ser Glu Pro Gln Ala Ala Ala Glu Pro 35 40 45Ala Glu Ala Lys Glu Gly Lys Glu Lys Pro Asp Gln Asp Ala Glu Gly 50 55 60Lys Ala Glu Glu Lys Glu Gly Glu Lys Asp Ala Ala Ala Ala Lys Glu65 70 75 80Glu Ala Pro Lys Ala Glu Pro Glu Lys Thr Glu Gly Ala Ala Glu Ala 85 90 95Lys Ala Glu Pro Pro Lys Ala Pro Glu Gln Glu Gln Ala Ala Pro Gly 100 105 110Pro Ala Ala Gly Gly Glu Ala Pro Lys Ala Ala Glu Ala Ala Ala Ala 115 120 125Pro Ala Glu Ser Ala Ala Pro Ala Ala Gly Glu Glu Pro Ser Lys Glu 130 135 140Glu Gly Glu Pro Lys Lys Thr Glu Ala Pro Ala Ala Pro Ala Ala Gln145 150 155 160Glu Thr Lys Ser Asp Gly Ala Pro Ala Ser Asp Ser Lys Pro Gly Ser 165 170 175Ser Glu Ala Ala Pro Ser Ser Lys Glu Thr Pro Ala Ala Thr Glu Ala 180 185 190Pro Ser Ser Thr Pro Lys Ala Gln Gly Pro Ala Ala Ser Ala Glu Glu 195 200 205Pro Lys Pro Val Glu Ala Pro Ala Ala Asn Ser Asp Gln Thr Val Thr 210 215 220Val Lys Glu2251162268DNAHomo sapiens 116gtctcccctc gccgcatcca ctctccggcc ggccgcctgc ccgccgcctc ctccgtgcgc 60ccgccagcct cgcccgcgcc gtcaccatga gccaggccta ctcgtccagc cagcgcgtgt 120cctcctaccg ccgcaccttc ggcggggccc cgggcttccc actcggctcc ccgctgagtt 180cgcccgtgtt cccgcgggcg ggtttcggct ctaagggctc ctccagctcg gtgacgtccc 240gcgtgtacca ggtgtcgcgc acgtcgggcg gggccggggg cctggggtcg ctgcgggcca 300gccggctggg gaccacccgc acgccctcct cctacggcgc aggcgagctg ctggacttct 360cactggccga cgcggtgaac caggagtttc

tgaccacgcg caccaacgag aaggtggagc 420tgcaggagct caatgaccgc ttcgccaact acatcgagaa ggtgcgcttc ctggagcagc 480agaacgcggc gctcgccgcc gaagtgaacc ggctcaaggg ccgcgagccg acgcgagtgg 540ccgagctcta cgaggaggag ctgcgggagc tgcggcgcca ggtggaggtg ctcactaacc 600agcgcgcgcg cgtcgacgtc gagcgcgaca acctgctcga cgacctgcag cggctcaagg 660ccaagctgca ggaggagatt cagttgaagg aagaagcaga gaacaatttg gctgccttcc 720gagcggacgt ggatgcagct actctagctc gcattgacct ggagcgcaga attgaatctc 780tcaacgagga gatcgcgttc cttaagaaag tgcatgaaga ggagatccgt gagttgcagg 840ctcagcttca ggaacagcag gtccaggtgg agatggacat gtctaagcca gacctcactg 900ccgccctcag ggacatccgg gctcagtatg agaccatcgc ggctaagaac atttctgaag 960ctgaggagtg gtacaagtcg aaggtgtcag acctgaccca ggcagccaac aagaacaacg 1020acgccctgcg ccaggccaag caggagatga tggaataccg acaccagatc cagtcctaca 1080cctgcgagat tgacgccctg aagggcacta acgattccct gatgaggcag atgcgggaat 1140tggaggaccg atttgccagt gaggccagtg gctaccagga caacattgcg cgcctggagg 1200aggaaatccg gcacctcaag gatgagatgg cccgccatct gcgcgagtac caggacctgc 1260tcaacgtgaa gatggccctg gatgtggaga ttgccaccta ccggaagctg ctggagggag 1320aggagagccg gatcaatctc cccatccaga cctactctgc cctcaacttc cgagaaacca 1380gccctgagca aaggggttct gaggtccata ccaagaagac ggtgatgatc aagaccatcg 1440agacacggga tggggaggtc gtcagtgagg ccacacagca gcagcatgaa gtgctctaaa 1500gacagagacc ctctgccacc agagaccgtc ctcacccctg tcctcactgc tccctgaagc 1560cagccttctt ccatcccagg acaccacacc cagcctcagt cctcccctca cagcctctga 1620cccctcctca ctggccatcc ctcgtggtcc ccaacagcga catagcccat ccctgcctgg 1680tcacagggca tgccccggcc acctctgcgg accccagctg tgagccttgg ctgttggcag 1740tgagtgagcc tggctcttgt gctggatgga gcccaggcgg gagcggtggc cctgtccctc 1800ccacctctgt gacctcaggc actagccttt ggctctggag acagccccag agcagggtgt 1860tgggatactg cagggccagg actgagcccc gcagacctcc ccagccccta gcccaggaga 1920gagaaagcca ggcaggtagc cagggggact agcccctgtg gagactgggg ggcttgaaat 1980tgtccccgtg gtctcttact ttcctttccc cagcccaggg tggacttaga aagcaggggc 2040tacaagaggg aatccccgaa ggtgctggag gtgggagcag gagattgaga aggagagaaa 2100gtgggtgaga tgctggagaa gagaggagag gagagaggca gagagcggtc tcaggctggt 2160gggaggggcg cccacctccc cacgccctcc cctcccctgc tgcaggggct ctggagagaa 2220acaataaaga gattcacaca caagccaaaa aaaaaaaaaa aaaaaaaa 2268117470PRTHomo sapiens 117Met Ser Gln Ala Tyr Ser Ser Ser Gln Arg Val Ser Ser Tyr Arg Arg1 5 10 15Thr Phe Gly Gly Ala Pro Gly Phe Pro Leu Gly Ser Pro Leu Ser Ser 20 25 30Pro Val Phe Pro Arg Ala Gly Phe Gly Ser Lys Gly Ser Ser Ser Ser 35 40 45Val Thr Ser Arg Val Tyr Gln Val Ser Arg Thr Ser Gly Gly Ala Gly 50 55 60Gly Leu Gly Ser Leu Arg Ala Ser Arg Leu Gly Thr Thr Arg Thr Pro65 70 75 80Ser Ser Tyr Gly Ala Gly Glu Leu Leu Asp Phe Ser Leu Ala Asp Ala 85 90 95Val Asn Gln Glu Phe Leu Thr Thr Arg Thr Asn Glu Lys Val Glu Leu 100 105 110Gln Glu Leu Asn Asp Arg Phe Ala Asn Tyr Ile Glu Lys Val Arg Phe 115 120 125Leu Glu Gln Gln Asn Ala Ala Leu Ala Ala Glu Val Asn Arg Leu Lys 130 135 140Gly Arg Glu Pro Thr Arg Val Ala Glu Leu Tyr Glu Glu Glu Leu Arg145 150 155 160Glu Leu Arg Arg Gln Val Glu Val Leu Thr Asn Gln Arg Ala Arg Val 165 170 175Asp Val Glu Arg Asp Asn Leu Leu Asp Asp Leu Gln Arg Leu Lys Ala 180 185 190Lys Leu Gln Glu Glu Ile Gln Leu Lys Glu Glu Ala Glu Asn Asn Leu 195 200 205Ala Ala Phe Arg Ala Asp Val Asp Ala Ala Thr Leu Ala Arg Ile Asp 210 215 220Leu Glu Arg Arg Ile Glu Ser Leu Asn Glu Glu Ile Ala Phe Leu Lys225 230 235 240Lys Val His Glu Glu Glu Ile Arg Glu Leu Gln Ala Gln Leu Gln Glu 245 250 255Gln Gln Val Gln Val Glu Met Asp Met Ser Lys Pro Asp Leu Thr Ala 260 265 270Ala Leu Arg Asp Ile Arg Ala Gln Tyr Glu Thr Ile Ala Ala Lys Asn 275 280 285Ile Ser Glu Ala Glu Glu Trp Tyr Lys Ser Lys Val Ser Asp Leu Thr 290 295 300Gln Ala Ala Asn Lys Asn Asn Asp Ala Leu Arg Gln Ala Lys Gln Glu305 310 315 320Met Met Glu Tyr Arg His Gln Ile Gln Ser Tyr Thr Cys Glu Ile Asp 325 330 335Ala Leu Lys Gly Thr Asn Asp Ser Leu Met Arg Gln Met Arg Glu Leu 340 345 350Glu Asp Arg Phe Ala Ser Glu Ala Ser Gly Tyr Gln Asp Asn Ile Ala 355 360 365Arg Leu Glu Glu Glu Ile Arg His Leu Lys Asp Glu Met Ala Arg His 370 375 380Leu Arg Glu Tyr Gln Asp Leu Leu Asn Val Lys Met Ala Leu Asp Val385 390 395 400Glu Ile Ala Thr Tyr Arg Lys Leu Leu Glu Gly Glu Glu Ser Arg Ile 405 410 415Asn Leu Pro Ile Gln Thr Tyr Ser Ala Leu Asn Phe Arg Glu Thr Ser 420 425 430Pro Glu Gln Arg Gly Ser Glu Val His Thr Lys Lys Thr Val Met Ile 435 440 445Lys Thr Ile Glu Thr Arg Asp Gly Glu Val Val Ser Glu Ala Thr Gln 450 455 460Gln Gln His Glu Val Leu465 4701187878DNAHomo sapiens 118ttttccctgc tctcaccggg cgggggagag aagccctctg gacagcttct agagtgtgca 60ggttctcgta tccctcggcc aagggtatcc tctgcaaacc tctgcaaacc cagcgcaact 120acggtccccc ggtcagaccc aggatggggc cagaacggac aggggccgcg ccgctgccgc 180tgctgctggt gttagcgctc agtcaaggca ttttaaattg ttgtttggcc tacaatgttg 240gtctcccaga agcaaaaata ttttccggtc cttcaagtga acagtttggc tatgcagtgc 300agcagtttat aaatccaaaa ggcaactggt tactggttgg ttcaccctgg agtggctttc 360ctgagaaccg aatgggagat gtgtataaat gtcctgttga cctatccact gccacatgtg 420aaaaactaaa tttgcaaact tcaacaagca ttccaaatgt tactgagatg aaaaccaaca 480tgagcctcgg cttgatcctc accaggaaca tgggaactgg aggttttctc acatgtggtc 540ctctgtgggc acagcaatgt gggaatcagt attacacaac gggtgtgtgt tctgacatca 600gtcctgattt tcagctctca gccagcttct cacctgcaac tcagccctgc ccttccctca 660tagatgttgt ggttgtgtgt gatgaatcaa atagtattta tccttgggat gcagtaaaga 720attttttgga aaaatttgta caaggcctgg atataggccc cacaaagaca caggtggggt 780taattcagta tgccaataat ccaagagttg tgtttaactt gaacacatat aaaaccaaag 840aagaaatgat tgtagcaaca tcccagacat cccaatatgg tggggacctc acaaacacat 900tcggagcaat tcaatatgca agaaaatatg cttattcagc agcttctggt gggcgacgaa 960gtgctacgaa agtaatggta gttgtaactg acggtgaatc acatgatggt tcaatgttga 1020aagctgtgat tgatcaatgc aaccatgaca atatactgag gtttggcata gcagttcttg 1080ggtacttaaa cagaaacgcc cttgatacta aaaatttaat aaaagaaata aaagcaatcg 1140ctagtattcc aacagaaaga tactttttca atgtgtctga tgaagcagct ctactagaaa 1200aggctgggac attaggagaa caaattttca gcattgaagg tactgttcaa ggaggagaca 1260actttcagat ggaaatgtca caagtgggat tcagtgcaga ttactcttct caaaatgata 1320ttctgatgct gggtgcagtg ggagcttttg gctggagtgg gaccattgtc cagaagacat 1380ctcatggcca tttgatcttt cctaaacaag cctttgacca aattctgcag gacagaaatc 1440acagttcata tttaggttac tctgtggctg caatttctac tggagaaagc actcactttg 1500ttgctggtgc tcctcgggca aattataccg gccagatagt gctatatagt gtgaatgaga 1560atggcaatat cacggttatt caggctcacc gaggtgacca gattggctcc tattttggta 1620gtgtgctgtg ttcagttgat gtggataaag acaccattac agacgtgctc ttggtaggtg 1680caccaatgta catgagtgac ctaaagaaag aggaaggaag agtctacctg tttactatca 1740aagagggcat tttgggtcag caccaatttc ttgaaggccc cgagggcatt gaaaacactc 1800gatttggttc agcaattgca gctctttcag acatcaacat ggatggcttt aatgatgtga 1860ttgttggttc accactagaa aatcagaatt ctggagctgt atacatttac aatggtcatc 1920agggcactat ccgcacaaag tattcccaga aaatcttggg atccgatgga gcctttagga 1980gccatctcca gtactttggg aggtccttgg atggctatgg agatttaaat ggggattcca 2040tcaccgatgt gtctattggt gcctttggac aagtggttca actctggtca caaagtattg 2100ctgatgtagc tatagaagct tcattcacac cagaaaaaat cactttggtc aacaagaatg 2160ctcagataat tctcaaactc tgcttcagtg caaagttcag acctactaag caaaacaatc 2220aagtggccat tgtatataac atcacacttg atgcagatgg attttcatcc agagtaacct 2280ccagggggtt atttaaagaa aacaatgaaa ggtgcctgca gaagaatatg gtagtaaatc 2340aagcacagag ttgccccgag cacatcattt atatacagga gccctctgat gttgtcaact 2400ctttggattt gcgtgtggac atcagtctgg aaaaccctgg cactagccct gcccttgaag 2460cctattctga gactgccaag gtcttcagta ttcctttcca caaagactgt ggtgaggacg 2520gactttgcat ttctgatcta gtcctagatg tccgacaaat accagctgct caagaacaac 2580cctttattgt cagcaaccaa aacaaaaggt taacattttc agtaacgctg aaaaataaaa 2640gggaaagtgc atacaacact ggaattgttg ttgatttttc agaaaacttg ttttttgcat 2700cattctccct gccggttgat gggacagaag taacatgcca ggtggctgca tctcagaagt 2760ctgttgcctg cgatgtaggc taccctgctt taaagagaga acaacaggtg acttttacta 2820ttaactttga cttcaatctt caaaaccttc agaatcaggc gtctctcagt ttccaagcct 2880taagtgaaag ccaagaagaa aacaaggctg ataatttggt caacctcaaa attcctctcc 2940tgtatgatgc tgaaattcac ttaacaagat ctaccaacat aaatttttat gaaatctctt 3000cggatgggaa tgttccttca atcgtgcaca gttttgaaga tgttggtcca aaattcatct 3060tctccctgaa ggtaacaaca ggaagtgttc cagtaagcat ggcaactgta atcatccaca 3120tccctcagta taccaaagaa aagaacccac tgatgtacct aactggggtg caaacagaca 3180aggctggtga catcagttgt aatgcagata tcaatccact gaaaatagga caaacatctt 3240cttctgtatc tttcaaaagt gaaaatttca ggcacaccaa agaattgaac tgcagaactg 3300cttcctgtag taatgttacc tgctggttga aagacgttca catgaaagga gaatactttg 3360ttaatgtgac taccagaatt tggaacggga ctttcgcatc atcaacgttc cagacagtac 3420agctaacggc agctgcagaa atcaacacct ataaccctga gatatatgtg attgaagata 3480acactgttac gattcccctg atgataatga aacctgatga gaaagccgaa gtaccaacag 3540gagttataat aggaagtata attgctggaa tccttttgct gttagctctg gttgcaattt 3600tatggaagct cggcttcttc aaaagaaaat atgaaaagat gaccaaaaat ccagatgaga 3660ttgatgagac cacagagctc agtagctgaa ccagcagacc tacctgcagt gggaaccggc 3720agcatcccag ccagggtttg ctgtttgcgt gaatggattt ctttttaaat cccatatttt 3780ttttatcatg tcgtaggtaa actaacctgg tattttaaga gaaaactgca ggtcagtttg 3840gaatgaagaa attgtggggg gtgggggagg tgcggggggc aggtagggaa ataataggga 3900aaatacctat tttatatgat gggggaaaaa aagtaatctt taaactggct ggcccagagt 3960ttacattcta atttgcattg tgtcagaaac atgaaatgct tccaagcatg acaactttta 4020aagaaaaata tgatactctc agattttaag ggggaaaact gttctcttta aaatatttgt 4080ctttaaacag caactacaga agtggaagtg cttgatatgt aagtacttcc acttgtgtat 4140attttaatga atattgatgt taacaagagg ggaaaacaaa acacaggttt tttcaattta 4200tgctgctcat ccaaagttgc cacagatgat acttccaagt gataatttta tttataaact 4260aggtaaaatt tgttgttggt tccttttaga ccacggctgc cccttccaca ccccatcttg 4320ctctaatgat caaaacatgc ttgaataact gagcttagag tatacctcct atatgtccat 4380ttaagttagg agagggggcg atatagagaa taaggcacaa aattttgttt aaaactcaga 4440atataacatg taaaatccca tctgctagaa gcccatcctg tgccagagga aggaaaagga 4500ggaaatttcc tttctctttt aggaggcaca acagttctct tctaggattt gtttggctga 4560ctggcagtaa cctagtgaat ttctgaaaga tgagtaattt ctttggcaac cttcctcctc 4620ccttactgaa ccactctccc acctcctggt ggtaccatta ttatagaagc cctctacagc 4680ctgactttct ctccagcggt ccaaagttat cccctccttt acccctcatc caaagttccc 4740actccttcag gacagctgct gtgcattaga tattaggggg gaaagtcatc tgtttaattt 4800acacacttgc atgaattact gtatataaac tccttaactt cagggagcta ttttcattta 4860gtgctaaaca agtaagaaaa ataagctcga gtgaatttct aaatgttgga atgttatggg 4920atgtaaacaa tgtaaagtaa gacatctcag gatttcacca gaagttacag atgaggcact 4980ggaagccacc aaattagcag gtgcaccttc tgtggctgtc ttgtttctga agtacttaaa 5040cttccacaag agtgaatttg acctaggcaa gtttgttcaa aaggtagatc ctgagatgat 5100ttggtcagat tgggataagg cccagcaatc tgcattttaa caagcacccc agtcactagg 5160atgcagatgg accacacttt gagaaacacc acccatttct actttttgca ccttattttc 5220tctgttcctg agcccccaca ttctctagga gaaacttaga ggaaaagggc acagacacta 5280catatctaaa gctttggaca agtccttgac ctctataaac ttcagagtcc tcattataaa 5340atgggaagac tgagctggag ttcagcagtg atgcttttag ttttaaaagt ctatgatctg 5400gacttcctat aatacaaata cacaatcctc caagaatttg acttggaaaa aaatgtcaaa 5460ggaaaacagg ttatctgccc atgtgcatat ggacaacctt gactaccctg gcctggcccg 5520tggtggcagt ccagggctat ctgtactgtt tacagaatta ctttgtagtt gacaacacaa 5580aacaaacaaa aaaggcataa aatgccagcg gtttatagaa aaaacagcat ggtattctcc 5640agttaggtat gccagagtcc aattctttta acagctgtga gaatttgctg cttcattcca 5700acaaaatttt atttaaaaaa aaaaaaaaaa gactggagaa actagtcatt agcttgataa 5760agaatattta acagctagtg gtgctggtgt gtacctgaag ctccagctac ttgagagact 5820gagacaggaa gatcgcttga gcccaggagt tcaagtccag cctaagcaac atagcaagac 5880cctgtctcaa aaaaatgact atttaaaaag acaatgtggc caggcacggt ggctcacacc 5940tgtaatccca acactttggg aggctgaggc cggtggatca cgaggtcagg agtttgagac 6000tagcctggcc aacatggtga aaccccatct ctaataatat aaaaattagc tgggcgtagt 6060agcaggtgcc tgtaatccca gttactcggg aagctgaggc aggagaatca cttgaacccg 6120ggaggcagag gtttcagtga gccgagatcg cgccactgca ctccagcctg ggtgacaggg 6180caagactctg tctcaaacaa acaaacaaaa aaaaagttag tactgtatat gtaaatacta 6240gcttttcaat gtgctataca aacaattata gcacatcctt ccttttactc tgtctcacct 6300cctttaggtg agtacttcct taaataagtg ctaaacatac atatacggaa cttgaaagct 6360ttggttagcc ttgccttagg taatcagcct agtttacact gtttccaggg agtagttgaa 6420ttactataaa ccattagcca cttgtctctg caccatttat cacaccagga cagggtctct 6480caacctgggc gctactgtca tttggggcca ggtgattctt ccttgcaggg gctgtcctgt 6540accttgtagg acagcagccc tgtcctagaa ggtatgttta gcagcattcc tggcctctag 6600ctacccgatg ccagagcatg ctccccccgc agtcatgaca atcaaaaaat gtctccagac 6660attgtcaaat gcctcctggg gggcagtatt tctcaagcac ttttaagcaa aggtaagtat 6720tcatacaaga aatttagggg gaaaaaacat tgtttaaata aaagctatgt gttcctattc 6780aacaatattt ttgctttaaa agtaagtaga gggcataaaa gatgtcatat tcaaatttcc 6840atttcataaa tggtgtacag acaaggtcta tagaatgtgg taaaaacttg actgcaacac 6900aaggcttata aaatagtaag atagtaaaat agcttatgaa gaaactacag agatttaaaa 6960ttgtgcatga ctcatttcag cagcaaaata agaactccta actgaacaga aatttttcta 7020cctagcaatg ttattcttgt aaaatagtta cctattaaaa ctgtgaagag taaaactaaa 7080gccaatttat tatagtcaca caagtgatta tactaaaaat tattataaag gttataattt 7140tataatgtat ttacctgtcc tgatatatag ctataaccca atatatgaaa atctcaaaaa 7200ttaagacatc atcatacaga aggcaggatt ccttaaactg agatccctga tccatcttta 7260atatttcaat ttgcacacat aaaacaatgc ccttttgtgt acattcaggc atacccattt 7320taatcaattt gaaaggttaa tttaaacctc tagaggtgaa tgagaaacat gggggaaaag 7380tatgaaatag gtgaaaatct taactatttc tttgaactct aaagactgaa actgtagcca 7440ttatgtaaat aaagtttcat atgtacctgt ttattttggc agattaagtc aaaatatgaa 7500tgtatatatt gcataactat gttagaattg tatatatttt aaagaaattg tcttggatat 7560tttcctttat acataataga taagtctttt ttcaaatgtg gtgtttgatg tttttgatta 7620aatgtgtttt gcctctttcc acaaaaactg taaaaataaa tgcatgtttg tacaaaaagt 7680tgcagaattc atttgattta tgagaaacaa aaattaaatt gtagtcaaca gttagtagtt 7740tttctcatat ccaagtataa caaacagaaa agtttcatta ttgtaaccca cttttttcat 7800accacattat tgaatattgt tacaattgtt ttgaaaataa agccattttc tttgggcttt 7860tataagttaa aaaaaaaa 78781191181PRTHomo sapiens 119Met Gly Pro Glu Arg Thr Gly Ala Ala Pro Leu Pro Leu Leu Leu Val1 5 10 15Leu Ala Leu Ser Gln Gly Ile Leu Asn Cys Cys Leu Ala Tyr Asn Val 20 25 30Gly Leu Pro Glu Ala Lys Ile Phe Ser Gly Pro Ser Ser Glu Gln Phe 35 40 45Gly Tyr Ala Val Gln Gln Phe Ile Asn Pro Lys Gly Asn Trp Leu Leu 50 55 60Val Gly Ser Pro Trp Ser Gly Phe Pro Glu Asn Arg Met Gly Asp Val65 70 75 80Tyr Lys Cys Pro Val Asp Leu Ser Thr Ala Thr Cys Glu Lys Leu Asn 85 90 95Leu Gln Thr Ser Thr Ser Ile Pro Asn Val Thr Glu Met Lys Thr Asn 100 105 110Met Ser Leu Gly Leu Ile Leu Thr Arg Asn Met Gly Thr Gly Gly Phe 115 120 125Leu Thr Cys Gly Pro Leu Trp Ala Gln Gln Cys Gly Asn Gln Tyr Tyr 130 135 140Thr Thr Gly Val Cys Ser Asp Ile Ser Pro Asp Phe Gln Leu Ser Ala145 150 155 160Ser Phe Ser Pro Ala Thr Gln Pro Cys Pro Ser Leu Ile Asp Val Val 165 170 175Val Val Cys Asp Glu Ser Asn Ser Ile Tyr Pro Trp Asp Ala Val Lys 180 185 190Asn Phe Leu Glu Lys Phe Val Gln Gly Leu Asp Ile Gly Pro Thr Lys 195 200 205Thr Gln Val Gly Leu Ile Gln Tyr Ala Asn Asn Pro Arg Val Val Phe 210 215 220Asn Leu Asn Thr Tyr Lys Thr Lys Glu Glu Met Ile Val Ala Thr Ser225 230 235 240Gln Thr Ser Gln Tyr Gly Gly Asp Leu Thr Asn Thr Phe Gly Ala Ile 245 250 255Gln Tyr Ala Arg Lys Tyr Ala Tyr Ser Ala Ala Ser Gly Gly Arg Arg 260 265 270Ser Ala Thr Lys Val Met Val Val Val Thr Asp Gly Glu Ser His Asp 275 280 285Gly Ser Met Leu Lys Ala Val Ile Asp Gln Cys Asn His Asp Asn Ile 290 295 300Leu Arg Phe Gly Ile Ala Val Leu Gly Tyr Leu Asn Arg Asn Ala Leu305 310 315 320Asp Thr Lys Asn Leu Ile Lys Glu Ile Lys Ala Ile Ala Ser Ile Pro 325 330 335Thr Glu Arg Tyr Phe Phe Asn Val Ser Asp Glu Ala Ala Leu Leu Glu 340 345 350Lys Ala Gly Thr Leu Gly Glu Gln Ile Phe Ser Ile Glu Gly Thr Val 355 360 365Gln Gly Gly Asp Asn Phe Gln Met Glu Met Ser Gln Val Gly Phe Ser 370 375 380Ala Asp Tyr Ser Ser

Gln Asn Asp Ile Leu Met Leu Gly Ala Val Gly385 390 395 400Ala Phe Gly Trp Ser Gly Thr Ile Val Gln Lys Thr Ser His Gly His 405 410 415Leu Ile Phe Pro Lys Gln Ala Phe Asp Gln Ile Leu Gln Asp Arg Asn 420 425 430His Ser Ser Tyr Leu Gly Tyr Ser Val Ala Ala Ile Ser Thr Gly Glu 435 440 445Ser Thr His Phe Val Ala Gly Ala Pro Arg Ala Asn Tyr Thr Gly Gln 450 455 460Ile Val Leu Tyr Ser Val Asn Glu Asn Gly Asn Ile Thr Val Ile Gln465 470 475 480Ala His Arg Gly Asp Gln Ile Gly Ser Tyr Phe Gly Ser Val Leu Cys 485 490 495Ser Val Asp Val Asp Lys Asp Thr Ile Thr Asp Val Leu Leu Val Gly 500 505 510Ala Pro Met Tyr Met Ser Asp Leu Lys Lys Glu Glu Gly Arg Val Tyr 515 520 525Leu Phe Thr Ile Lys Glu Gly Ile Leu Gly Gln His Gln Phe Leu Glu 530 535 540Gly Pro Glu Gly Ile Glu Asn Thr Arg Phe Gly Ser Ala Ile Ala Ala545 550 555 560Leu Ser Asp Ile Asn Met Asp Gly Phe Asn Asp Val Ile Val Gly Ser 565 570 575Pro Leu Glu Asn Gln Asn Ser Gly Ala Val Tyr Ile Tyr Asn Gly His 580 585 590Gln Gly Thr Ile Arg Thr Lys Tyr Ser Gln Lys Ile Leu Gly Ser Asp 595 600 605Gly Ala Phe Arg Ser His Leu Gln Tyr Phe Gly Arg Ser Leu Asp Gly 610 615 620Tyr Gly Asp Leu Asn Gly Asp Ser Ile Thr Asp Val Ser Ile Gly Ala625 630 635 640Phe Gly Gln Val Val Gln Leu Trp Ser Gln Ser Ile Ala Asp Val Ala 645 650 655Ile Glu Ala Ser Phe Thr Pro Glu Lys Ile Thr Leu Val Asn Lys Asn 660 665 670Ala Gln Ile Ile Leu Lys Leu Cys Phe Ser Ala Lys Phe Arg Pro Thr 675 680 685Lys Gln Asn Asn Gln Val Ala Ile Val Tyr Asn Ile Thr Leu Asp Ala 690 695 700Asp Gly Phe Ser Ser Arg Val Thr Ser Arg Gly Leu Phe Lys Glu Asn705 710 715 720Asn Glu Arg Cys Leu Gln Lys Asn Met Val Val Asn Gln Ala Gln Ser 725 730 735Cys Pro Glu His Ile Ile Tyr Ile Gln Glu Pro Ser Asp Val Val Asn 740 745 750Ser Leu Asp Leu Arg Val Asp Ile Ser Leu Glu Asn Pro Gly Thr Ser 755 760 765Pro Ala Leu Glu Ala Tyr Ser Glu Thr Ala Lys Val Phe Ser Ile Pro 770 775 780Phe His Lys Asp Cys Gly Glu Asp Gly Leu Cys Ile Ser Asp Leu Val785 790 795 800Leu Asp Val Arg Gln Ile Pro Ala Ala Gln Glu Gln Pro Phe Ile Val 805 810 815Ser Asn Gln Asn Lys Arg Leu Thr Phe Ser Val Thr Leu Lys Asn Lys 820 825 830Arg Glu Ser Ala Tyr Asn Thr Gly Ile Val Val Asp Phe Ser Glu Asn 835 840 845Leu Phe Phe Ala Ser Phe Ser Leu Pro Val Asp Gly Thr Glu Val Thr 850 855 860Cys Gln Val Ala Ala Ser Gln Lys Ser Val Ala Cys Asp Val Gly Tyr865 870 875 880Pro Ala Leu Lys Arg Glu Gln Gln Val Thr Phe Thr Ile Asn Phe Asp 885 890 895Phe Asn Leu Gln Asn Leu Gln Asn Gln Ala Ser Leu Ser Phe Gln Ala 900 905 910Leu Ser Glu Ser Gln Glu Glu Asn Lys Ala Asp Asn Leu Val Asn Leu 915 920 925Lys Ile Pro Leu Leu Tyr Asp Ala Glu Ile His Leu Thr Arg Ser Thr 930 935 940Asn Ile Asn Phe Tyr Glu Ile Ser Ser Asp Gly Asn Val Pro Ser Ile945 950 955 960Val His Ser Phe Glu Asp Val Gly Pro Lys Phe Ile Phe Ser Leu Lys 965 970 975Val Thr Thr Gly Ser Val Pro Val Ser Met Ala Thr Val Ile Ile His 980 985 990Ile Pro Gln Tyr Thr Lys Glu Lys Asn Pro Leu Met Tyr Leu Thr Gly 995 1000 1005Val Gln Thr Asp Lys Ala Gly Asp Ile Ser Cys Asn Ala Asp Ile 1010 1015 1020Asn Pro Leu Lys Ile Gly Gln Thr Ser Ser Ser Val Ser Phe Lys 1025 1030 1035Ser Glu Asn Phe Arg His Thr Lys Glu Leu Asn Cys Arg Thr Ala 1040 1045 1050Ser Cys Ser Asn Val Thr Cys Trp Leu Lys Asp Val His Met Lys 1055 1060 1065Gly Glu Tyr Phe Val Asn Val Thr Thr Arg Ile Trp Asn Gly Thr 1070 1075 1080Phe Ala Ser Ser Thr Phe Gln Thr Val Gln Leu Thr Ala Ala Ala 1085 1090 1095Glu Ile Asn Thr Tyr Asn Pro Glu Ile Tyr Val Ile Glu Asp Asn 1100 1105 1110Thr Val Thr Ile Pro Leu Met Ile Met Lys Pro Asp Glu Lys Ala 1115 1120 1125Glu Val Pro Thr Gly Val Ile Ile Gly Ser Ile Ile Ala Gly Ile 1130 1135 1140Leu Leu Leu Leu Ala Leu Val Ala Ile Leu Trp Lys Leu Gly Phe 1145 1150 1155Phe Lys Arg Lys Tyr Glu Lys Met Thr Lys Asn Pro Asp Glu Ile 1160 1165 1170Asp Glu Thr Thr Glu Leu Ser Ser 1175 11801204107DNAHomo sapiens 120gacaagggct cttcttgatg gcttactgta tccactttgt ccccaagacc atagggaaat 60gactagaggt gactgtacta gctagatttt aaatgaaact gaaatgaaag ttcacttcct 120cattttgagt acctcatgtg acaagttcca atttcttttc aagtcaattg aactgaaatc 180tccttgttgc tttgaaatct tagaagagag cccactaatt caaggactct tactgtggga 240gcaactgctg gttctatcac aatgaaacgg ctggtttgtg tgctcttggt gtgctcctct 300gcagtggcac agttgcataa agatcctacc ctggatcacc actggcatct ctggaagaaa 360acctatggca aacaatacaa ggaaaagaat gaagaagcag tacgacgtct catctgggaa 420aagaatctaa agtttgtgat gcttcacaac ctggagcatt caatgggaat gcactcatac 480gatctgggca tgaaccacct gggagacatg accagtgaag aagtgatgtc tttgatgagt 540tccctgagag ttcccagcca gtggcagaga aatatcacat ataagtcaaa ccctaatcgg 600atattgcctg attctgtgga ctggagagag aaagggtgtg ttactgaagt gaaatatcaa 660ggttcttgtg gtgcttgctg ggctttcagt gctgtggggg ccctggaagc acagctgaag 720ctgaaaacag gaaagctggt gtctctcagt gcccagaacc tggtggattg ctcaactgaa 780aaatatggaa acaaaggctg caatggtggc ttcatgacaa cggctttcca gtacatcatt 840gataacaagg gcatcgactc agacgcttcc tatccctaca aagccatgga tcagaaatgt 900caatatgact caaaatatcg tgctgccaca tgttcaaagt acactgaact tccttatggc 960agagaagatg tcctgaaaga agctgtggcc aataaaggcc cagtgtctgt tggtgtagat 1020gcgcgtcatc cttctttctt cctctacaga agtggtgtct actatgaacc atcctgtact 1080cagaatgtga atcatggtgt acttgtggtt ggctatggtg atcttaatgg gaaagaatac 1140tggcttgtga aaaacagctg gggccacaac tttggtgaag aaggatatat tcggatggca 1200agaaataaag gaaatcattg tgggattgct agctttccct cttacccaga aatctagagg 1260atctctcctt tttataacaa atcaagaaat atgaagcact ttctcttaac ttaatttttc 1320ctgctgtatc cagaagaaat aattgtgtca tgattaatgt gtatttactg tactaattag 1380aaaatatagt ttgaggccgg gcacggtggc tcacgcctgt aatcccagta cttgggaggc 1440caaggcaggc atatcaactt gaggccagga gttaaagagc agcctggcta acatggtgaa 1500accccatctc tactaaaaat acaaaaaatt agccgagcac ggtggtgcat gcctgtaatc 1560ccagctactt gggaggctga ggcacgagat tccttgaacc caagaggttg aggctatgtt 1620gagctgagat cacaccactg tactccagcc tggatgacag agtggagact ctgtttcaaa 1680aaaacagaaa agaaaatata gtttgattct tcattttttt aaatttgcaa atctcaggat 1740aaagtttgct aagtaaatta gtaatgtact atagatataa ctgtacaaaa attgttcaac 1800ctaaaacaat ctgtaattgc ttattgtttt attgtatact ctttgtcttt ttaagacccc 1860taatagcctt ttgtaacttg atggcttaaa aatacttaat aaatctgcca tttcaaattt 1920ctatcattgc cacataccat tcttattcct aggcaactat taataatcta tcctgagaat 1980attaattgtg gtattctggt gatggggttt agcaactttg atggaagaaa atattaggct 2040ataaatgtcc taaggactca gattgtatct ttgtacagaa gaggattcaa aacgccacgt 2100gtagtggctc atgcctgtaa tcccaacact ttgggaggct gaagtaggag gatcgtcttg 2160agcccaggag ttcaagacca gcctggacaa catagtgaga ccttgtctcc acaaaaataa 2220aaaagaaact atccaggagt ggtggtgtgt gcctgtggtc cctgctatgc agatgtctaa 2280gacaggagga tcacaagagc ccaggaggtt gagaatgcag tgagcttgta attgcaccac 2340tgcactccag cctgggtgac agagcaagac cctgtcttaa aaaaagagga ttcaacacat 2400atttttatat tatgttaaag taaagaaatg cataaaagac aagcactttg gaagaattat 2460tttaatgatc aacaatttaa tgtattagtc caaattattt ttacgtagtc atcaacaatt 2520tgaccagggc ctttatttgg caaataactg agccaaccag aataaaataa ccaatactcc 2580actgctcata tttttatcta attcagatgg atcttcctta caactgctct agattagtag 2640atgcatctaa gcaggcagca ggaactttaa attttttaag ttcatgtcta tgacatgaac 2700aatgtgtggg ataatgtcat taatatatcc taaattaacc taaacgtatt tcactaactc 2760tggctccttc tccataaagc acattttaag gaacaagaat tgctaaatat aaaaacataa 2820ataataccat aatacatggc tatcatcaaa agtgtataga atattatagt ttaaaagtat 2880ttagttgatt acttttcagt tttgttttgt tttttgagac ggagtctcac tctgttgccc 2940aggctggagt gcagtggcac catctcagtt cactgcaact tctgcctccc gagttcaagc 3000gattctcctg cctcagcctc ccgagtagct ggaattatag gcgtgcacca ccacgcccag 3060ctaatttttg tatttttagt aaagacaggg ttttgccaca ttagccaggc tggtctcaaa 3120ctcctgacct caggtgatcc acccacccca gcctcccaaa gtgctaagat tacaggcgtg 3180agccactgag cccagcctac ttttcagttt ttaacataat ttttgtttta tccacaactt 3240ttcaagtatt gaaagtagaa taaaaacatg ggttcttagt ctttagctat ctgttaaagc 3300ctatgaatgc cttcttaaaa tcatgttttt aaatgcataa aatatatagg attacaaagg 3360aatctaatta tatcgaaata cagttattaa aatgttaaaa gataagtttg ttatatatta 3420atatgcatgc ttctttataa atgcattaaa taagagttaa tagctatcct aaatttgaaa 3480tagtgataag cataatgaaa atagatgcaa aaaactaatg tgatatgaaa atatctgggt 3540ttttcttttg atgatgaagt attgctaata ttaccgtggt ttatgaacta tgttcagaat 3600tgaagaaaat cctaactttc agttagaggt tagtgacggg gttcaggaca ccctacacaa 3660aatacagcac tttgacatat tgaatatttt aagctgaagg catttgagga aattgcagaa 3720gcaggaaggt gactctgacc ttctgcctgc tgttctcccc agaagcagcc ataaaacctg 3780ggaaggattt tctgaccttc ccctgaagta gatcataaga ctgtcatgta agaggtgctc 3840tcctggcacc cagagaaaag gagcatcctt acctccaaaa gcacagggac acaaagagga 3900atctaaacaa acaggcctct cagtttcccc cagtttatta catttagctt gttcacactt 3960tgccctatga catttctaca tcactggctg ctcttcatca aacctactat aaaaaacatt 4020caagttcaac tgtttctttg ggcctttatt tccttatgga gcccctcgtg tcgtgtaaaa 4080cttatattaa ataaatgtgc atgcttt 41071213957DNAHomo sapiens 121gacaagggct cttcttgatg gcttactgta tccactttgt ccccaagacc atagggaaat 60gactagaggt gactgtacta gctagatttt aaatgaaact gaaatgaaag ttcacttcct 120cattttgagt acctcatgtg acaagttcca atttcttttc aagtcaattg aactgaaatc 180tccttgttgc tttgaaatct tagaagagag cccactaatt caaggactct tactgtggga 240gcaactgctg gttctatcac aatgaaacgg ctggtttgtg tgctcttggt gtgctcctct 300gcagtggcac agttgcataa agatcctacc ctggatcacc actggcatct ctggaagaaa 360acctatggca aacaatacaa ggaaaagaat gaagaagcag tacgacgtct catctgggaa 420aagaatctaa agtttgtgat gcttcacaac ctggagcatt caatgggaat gcactcatac 480gatctgggca tgaaccacct gggagacatg ggttcttgtg gtgcttgctg ggctttcagt 540gctgtggggg ccctggaagc acagctgaag ctgaaaacag gaaagctggt gtctctcagt 600gcccagaacc tggtggattg ctcaactgaa aaatatggaa acaaaggctg caatggtggc 660ttcatgacaa cggctttcca gtacatcatt gataacaagg gcatcgactc agacgcttcc 720tatccctaca aagccatgga tcagaaatgt caatatgact caaaatatcg tgctgccaca 780tgttcaaagt acactgaact tccttatggc agagaagatg tcctgaaaga agctgtggcc 840aataaaggcc cagtgtctgt tggtgtagat gcgcgtcatc cttctttctt cctctacaga 900agtggtgtct actatgaacc atcctgtact cagaatgtga atcatggtgt acttgtggtt 960ggctatggtg atcttaatgg gaaagaatac tggcttgtga aaaacagctg gggccacaac 1020tttggtgaag aaggatatat tcggatggca agaaataaag gaaatcattg tgggattgct 1080agctttccct cttacccaga aatctagagg atctctcctt tttataacaa atcaagaaat 1140atgaagcact ttctcttaac ttaatttttc ctgctgtatc cagaagaaat aattgtgtca 1200tgattaatgt gtatttactg tactaattag aaaatatagt ttgaggccgg gcacggtggc 1260tcacgcctgt aatcccagta cttgggaggc caaggcaggc atatcaactt gaggccagga 1320gttaaagagc agcctggcta acatggtgaa accccatctc tactaaaaat acaaaaaatt 1380agccgagcac ggtggtgcat gcctgtaatc ccagctactt gggaggctga ggcacgagat 1440tccttgaacc caagaggttg aggctatgtt gagctgagat cacaccactg tactccagcc 1500tggatgacag agtggagact ctgtttcaaa aaaacagaaa agaaaatata gtttgattct 1560tcattttttt aaatttgcaa atctcaggat aaagtttgct aagtaaatta gtaatgtact 1620atagatataa ctgtacaaaa attgttcaac ctaaaacaat ctgtaattgc ttattgtttt 1680attgtatact ctttgtcttt ttaagacccc taatagcctt ttgtaacttg atggcttaaa 1740aatacttaat aaatctgcca tttcaaattt ctatcattgc cacataccat tcttattcct 1800aggcaactat taataatcta tcctgagaat attaattgtg gtattctggt gatggggttt 1860agcaactttg atggaagaaa atattaggct ataaatgtcc taaggactca gattgtatct 1920ttgtacagaa gaggattcaa aacgccacgt gtagtggctc atgcctgtaa tcccaacact 1980ttgggaggct gaagtaggag gatcgtcttg agcccaggag ttcaagacca gcctggacaa 2040catagtgaga ccttgtctcc acaaaaataa aaaagaaact atccaggagt ggtggtgtgt 2100gcctgtggtc cctgctatgc agatgtctaa gacaggagga tcacaagagc ccaggaggtt 2160gagaatgcag tgagcttgta attgcaccac tgcactccag cctgggtgac agagcaagac 2220cctgtcttaa aaaaagagga ttcaacacat atttttatat tatgttaaag taaagaaatg 2280cataaaagac aagcactttg gaagaattat tttaatgatc aacaatttaa tgtattagtc 2340caaattattt ttacgtagtc atcaacaatt tgaccagggc ctttatttgg caaataactg 2400agccaaccag aataaaataa ccaatactcc actgctcata tttttatcta attcagatgg 2460atcttcctta caactgctct agattagtag atgcatctaa gcaggcagca ggaactttaa 2520attttttaag ttcatgtcta tgacatgaac aatgtgtggg ataatgtcat taatatatcc 2580taaattaacc taaacgtatt tcactaactc tggctccttc tccataaagc acattttaag 2640gaacaagaat tgctaaatat aaaaacataa ataataccat aatacatggc tatcatcaaa 2700agtgtataga atattatagt ttaaaagtat ttagttgatt acttttcagt tttgttttgt 2760tttttgagac ggagtctcac tctgttgccc aggctggagt gcagtggcac catctcagtt 2820cactgcaact tctgcctccc gagttcaagc gattctcctg cctcagcctc ccgagtagct 2880ggaattatag gcgtgcacca ccacgcccag ctaatttttg tatttttagt aaagacaggg 2940ttttgccaca ttagccaggc tggtctcaaa ctcctgacct caggtgatcc acccacccca 3000gcctcccaaa gtgctaagat tacaggcgtg agccactgag cccagcctac ttttcagttt 3060ttaacataat ttttgtttta tccacaactt ttcaagtatt gaaagtagaa taaaaacatg 3120ggttcttagt ctttagctat ctgttaaagc ctatgaatgc cttcttaaaa tcatgttttt 3180aaatgcataa aatatatagg attacaaagg aatctaatta tatcgaaata cagttattaa 3240aatgttaaaa gataagtttg ttatatatta atatgcatgc ttctttataa atgcattaaa 3300taagagttaa tagctatcct aaatttgaaa tagtgataag cataatgaaa atagatgcaa 3360aaaactaatg tgatatgaaa atatctgggt ttttcttttg atgatgaagt attgctaata 3420ttaccgtggt ttatgaacta tgttcagaat tgaagaaaat cctaactttc agttagaggt 3480tagtgacggg gttcaggaca ccctacacaa aatacagcac tttgacatat tgaatatttt 3540aagctgaagg catttgagga aattgcagaa gcaggaaggt gactctgacc ttctgcctgc 3600tgttctcccc agaagcagcc ataaaacctg ggaaggattt tctgaccttc ccctgaagta 3660gatcataaga ctgtcatgta agaggtgctc tcctggcacc cagagaaaag gagcatcctt 3720acctccaaaa gcacagggac acaaagagga atctaaacaa acaggcctct cagtttcccc 3780cagtttatta catttagctt gttcacactt tgccctatga catttctaca tcactggctg 3840ctcttcatca aacctactat aaaaaacatt caagttcaac tgtttctttg ggcctttatt 3900tccttatgga gcccctcgtg tcgtgtaaaa cttatattaa ataaatgtgc atgcttt 3957122331PRTHomo sapiens 122Met Lys Arg Leu Val Cys Val Leu Leu Val Cys Ser Ser Ala Val Ala1 5 10 15Gln Leu His Lys Asp Pro Thr Leu Asp His His Trp His Leu Trp Lys 20 25 30Lys Thr Tyr Gly Lys Gln Tyr Lys Glu Lys Asn Glu Glu Ala Val Arg 35 40 45Arg Leu Ile Trp Glu Lys Asn Leu Lys Phe Val Met Leu His Asn Leu 50 55 60Glu His Ser Met Gly Met His Ser Tyr Asp Leu Gly Met Asn His Leu65 70 75 80Gly Asp Met Thr Ser Glu Glu Val Met Ser Leu Met Ser Ser Leu Arg 85 90 95Val Pro Ser Gln Trp Gln Arg Asn Ile Thr Tyr Lys Ser Asn Pro Asn 100 105 110Arg Ile Leu Pro Asp Ser Val Asp Trp Arg Glu Lys Gly Cys Val Thr 115 120 125Glu Val Lys Tyr Gln Gly Ser Cys Gly Ala Cys Trp Ala Phe Ser Ala 130 135 140Val Gly Ala Leu Glu Ala Gln Leu Lys Leu Lys Thr Gly Lys Leu Val145 150 155 160Ser Leu Ser Ala Gln Asn Leu Val Asp Cys Ser Thr Glu Lys Tyr Gly 165 170 175Asn Lys Gly Cys Asn Gly Gly Phe Met Thr Thr Ala Phe Gln Tyr Ile 180 185 190Ile Asp Asn Lys Gly Ile Asp Ser Asp Ala Ser Tyr Pro Tyr Lys Ala 195 200 205Met Asp Gln Lys Cys Gln Tyr Asp Ser Lys Tyr Arg Ala Ala Thr Cys 210 215 220Ser Lys Tyr Thr Glu Leu Pro Tyr Gly Arg Glu Asp Val Leu Lys Glu225 230 235 240Ala Val Ala Asn Lys Gly Pro Val Ser Val Gly Val Asp Ala Arg His 245 250 255Pro Ser Phe Phe Leu Tyr Arg Ser Gly Val Tyr Tyr Glu Pro Ser Cys 260 265 270Thr Gln Asn Val Asn His Gly Val Leu Val Val Gly Tyr Gly Asp Leu 275 280 285Asn Gly Lys Glu Tyr Trp Leu Val Lys Asn Ser Trp Gly His Asn Phe 290 295 300Gly Glu Glu Gly Tyr Ile Arg Met Ala Arg Asn Lys Gly Asn His Cys305 310 315 320Gly Ile Ala Ser Phe Pro Ser Tyr Pro Glu Ile 325

330123281PRTHomo sapiens 123Met Lys Arg Leu Val Cys Val Leu Leu Val Cys Ser Ser Ala Val Ala1 5 10 15Gln Leu His Lys Asp Pro Thr Leu Asp His His Trp His Leu Trp Lys 20 25 30Lys Thr Tyr Gly Lys Gln Tyr Lys Glu Lys Asn Glu Glu Ala Val Arg 35 40 45Arg Leu Ile Trp Glu Lys Asn Leu Lys Phe Val Met Leu His Asn Leu 50 55 60Glu His Ser Met Gly Met His Ser Tyr Asp Leu Gly Met Asn His Leu65 70 75 80Gly Asp Met Gly Ser Cys Gly Ala Cys Trp Ala Phe Ser Ala Val Gly 85 90 95Ala Leu Glu Ala Gln Leu Lys Leu Lys Thr Gly Lys Leu Val Ser Leu 100 105 110Ser Ala Gln Asn Leu Val Asp Cys Ser Thr Glu Lys Tyr Gly Asn Lys 115 120 125Gly Cys Asn Gly Gly Phe Met Thr Thr Ala Phe Gln Tyr Ile Ile Asp 130 135 140Asn Lys Gly Ile Asp Ser Asp Ala Ser Tyr Pro Tyr Lys Ala Met Asp145 150 155 160Gln Lys Cys Gln Tyr Asp Ser Lys Tyr Arg Ala Ala Thr Cys Ser Lys 165 170 175Tyr Thr Glu Leu Pro Tyr Gly Arg Glu Asp Val Leu Lys Glu Ala Val 180 185 190Ala Asn Lys Gly Pro Val Ser Val Gly Val Asp Ala Arg His Pro Ser 195 200 205Phe Phe Leu Tyr Arg Ser Gly Val Tyr Tyr Glu Pro Ser Cys Thr Gln 210 215 220Asn Val Asn His Gly Val Leu Val Val Gly Tyr Gly Asp Leu Asn Gly225 230 235 240Lys Glu Tyr Trp Leu Val Lys Asn Ser Trp Gly His Asn Phe Gly Glu 245 250 255Glu Gly Tyr Ile Arg Met Ala Arg Asn Lys Gly Asn His Cys Gly Ile 260 265 270Ala Ser Phe Pro Ser Tyr Pro Glu Ile 275 2801241477DNAHomo sapiens 124agaacaactt ttttgacttc ctgcaaagag gacccttaca gtatttttgg agaagttagt 60aaaaccgaat ctgacatcat cacctagcag ttcatgcagc tagcaagtgg tttgttctta 120gggtaacaga ggaggaaatt gttcctcgtc tgataagaca acagtggaga aaggacgcat 180gctgtttctt agggacacgg ctgacttcca gatatgacca tgtatttgtg gcttaaactc 240ttggcatttg gctttgcctt tctggacaca gaagtatttg tgacagggca aagcccaaca 300ccttccccca ctggccatct gcaagctgag gagcaaggaa gccaatccaa gtcaccaaac 360ctcaaaagta gggaagctga cagttcagcc ttcagttggt ggccaaaggc ccgagagccc 420ctcacaaacc actggagtaa gtccaagagt ccaaaagctg aggaacttgg agtctgatgt 480tcaagagcag gaagcagcca gcacgagaga aagatgaaga ccagaagact cagcaagctc 540acttctccta ccttcttgtg cctgcttttt ctagccgtgc tggcagttgc ttggatgatg 600cccactcata ttgggtgggg gtgggggggt tggggagggt ctgcctcccc cagtccactg 660actcaaatgt taatctccct tggcaatacg ctcacaggca cacccaggaa caatactttg 720catccttcaa tccaatcaag ttgacactca atattaacca tcaaatacta ttataaggag 780aatgttgcat gattttcctt ctagtctgtt tgtaattcac atctaatgaa agagtgagag 840tggacgataa agggaacttg ttgaaacatt tctctcaaag caaaagggat cattggaagc 900aggcagacac cagaattggt ttaacctaaa aataacaaat taataattat caagtctata 960atgatgacag tgacttaatg tgaatagaaa gaattctaaa ctctctcctt ccttcctccc 1020tcccttcttt cctactttct ttccactccc tttctcccac ccccttttct tttcctttct 1080tttctcccac cctctctccc tccctttctt ttattcaatg catagtagtt gaaaaaatct 1140aaagttagac ctgattttac actgaagact agaggtagtt actatcctat tactgtactt 1200agttggctat gctggcatgt cattatgggt aaaagtttga tggatttatt tgtgagttat 1260ttggttatga aaatctagag attgaagttt ttcattagaa aataacacac ataacaagtc 1320tatgatcatt ttgcatttct gtaatcacag aatagttctg caatatttca tgtatattgg 1380aattgaagtt caattgaatt ttatctgtat ttagtaaaaa ttaactttag ctttgatact 1440aatgaataaa gctgggtttt ttatttaaaa aaaaaaa 14771255429DNAHomo sapiens 125agaacaactt ttttgacttc ctgcaaagag gacccttaca gtatttttgg agaagttagt 60aaaaccgaat ctgacatcat cacctagcag ttcatgcagc tagcaagtgg tttgttctta 120gggtaacaga ggaggaaatt gttcctcgtc tgataagaca acagtggaga aaggacgcat 180gctgtttctt agggacacgg ctgacttcca gatatgacca tgtatttgtg gcttaaactc 240ttggcatttg gctttgcctt tctggacaca gaagtatttg tgacagggca aagcccaaca 300ccttccccca ctggattgac tacagcaaag atgcccagtg ttccactttc aagtgacccc 360ttacctactc acaccactgc attctcaccc gcaagcacct ttgaaagaga aaatgacttc 420tcagagacca caacttctct tagtccagac aatacttcca cccaagtatc cccggactct 480ttggataatg ctagtgcttt taataccaca ggtgtttcat cagtacagac gcctcacctt 540cccacgcacg cagactcgca gacgccctct gctggaactg acacgcagac attcagcggc 600tccgccgcca atgcaaaact caaccctacc ccaggcagca atgctatctc agatgtccca 660ggagagagga gtacagccag cacctttcct acagacccag tttccccatt gacaaccacc 720ctcagccttg cacaccacag ctctgctgcc ttacctgcac gcacctccaa caccaccatc 780acagcgaaca cctcagatgc ctaccttaat gcctctgaaa caaccactct gagcccttct 840ggaagcgctg tcatttcaac cacaacaata gctactactc catctaagcc aacatgtgat 900gaaaaatatg caaacatcac tgtggattac ttatataaca aggaaactaa attatttaca 960gcaaagctaa atgttaatga gaatgtggaa tgtggaaaca atacttgcac aaacaatgag 1020gtgcataacc ttacagaatg taaaaatgcg tctgtttcca tatctcataa ttcatgtact 1080gctcctgata agacattaat attagatgtg ccaccagggg ttgaaaagtt tcagttacat 1140gattgtacac aagttgaaaa agcagatact actatttgtt taaaatggaa aaatattgaa 1200acctttactt gtgatacaca gaatattacc tacagatttc agtgtggtaa tatgatattt 1260gataataaag aaattaaatt agaaaacctt gaacccgaac atgagtataa gtgtgactca 1320gaaatactct ataataacca caagtttact aacgcaagta aaattattaa aacagatttt 1380gggagtccag gagagcctca gattattttt tgtagaagtg aagctgcaca tcaaggagta 1440attacctgga atccccctca aagatcattt cataatttta ccctctgtta tataaaagag 1500acagaaaaag attgcctcaa tctggataaa aacctgatca aatatgattt gcaaaattta 1560aaaccttata cgaaatatgt tttatcatta catgcctaca tcattgcaaa agtgcaacgt 1620aatggaagtg ctgcaatgtg tcatttcaca actaaaagtg ctcctccaag ccaggtctgg 1680aacatgactg tctccatgac atcagataat agtatgcatg tcaagtgtag gcctcccagg 1740gaccgtaatg gcccccatga acgttaccat ttggaagttg aagctggaaa tactctggtt 1800agaaatgagt cgcataagaa ttgcgatttc cgtgtaaaag atcttcaata ttcaacagac 1860tacactttta aggcctattt tcacaatgga gactatcctg gagaaccctt tattttacat 1920cattcaacat cttataattc taaggcactg atagcatttc tggcatttct gattattgtg 1980acatcaatag ccctgcttgt tgttctctac aaaatctatg atctacataa gaaaagatcc 2040tgcaatttag atgaacagca ggagcttgtt gaaagggatg atgaaaaaca actgatgaat 2100gtggagccaa tccatgcaga tattttgttg gaaacttata agaggaagat tgctgatgaa 2160ggaagacttt ttctggctga atttcagagc atcccgcggg tgttcagcaa gtttcctata 2220aaggaagctc gaaagccctt taaccagaat aaaaaccgtt atgttgacat tcttccttat 2280gattataacc gtgttgaact ctctgagata aacggagatg cagggtcaaa ctacataaat 2340gccagctata ttgatggttt caaagaaccc aggaaataca ttgctgcaca aggtcccagg 2400gatgaaactg ttgatgattt ctggaggatg atttgggaac agaaagccac agttattgtc 2460atggtcactc gatgtgaaga aggaaacagg aacaagtgtg cagaatactg gccgtcaatg 2520gaagagggca ctcgggcttt tggagatgtt gttgtaaaga tcaaccagca caaaagatgt 2580ccagattaca tcattcagaa attgaacatt gtaaataaaa aagaaaaagc aactggaaga 2640gaggtgactc acattcagtt caccagctgg ccagaccacg gggtgcctga ggatcctcac 2700ttgctcctca aactgagaag gagagtgaat gccttcagca atttcttcag tggtcccatt 2760gtggtgcact gcagtgctgg tgttgggcgc acaggaacct atatcggaat tgatgccatg 2820ctagaaggcc tggaagccga gaacaaagtg gatgtttatg gttatgttgt caagctaagg 2880cgacagagat gcctgatggt tcaagtagag gcccagtaca tcttgatcca tcaggctttg 2940gtggaataca atcagtttgg agaaacagaa gtgaatttgt ctgaattaca tccatatcta 3000cataacatga agaaaaggga tccacccagt gagccgtctc cactagaggc tgaattccag 3060agacttcctt catataggag ctggaggaca cagcacattg gaaatcaaga agaaaataaa 3120agtaaaaaca ggaattctaa tgtcatccca tatgactata acagagtgcc acttaaacat 3180gagctggaaa tgagtaaaga gagtgagcat gattcagatg aatcctctga tgatgacagt 3240gattcagagg aaccaagcaa atacatcaat gcatctttta taatgagcta ctggaaacct 3300gaagtgatga ttgctgctca gggaccactg aaggagacca ttggtgactt ttggcagatg 3360atcttccaaa gaaaagtcaa agttattgtt atgctgacag aactgaaaca tggagaccag 3420gaaatctgtg ctcagtactg gggagaagga aagcaaacat atggagatat tgaagttgac 3480ctgaaagaca cagacaaatc ttcaacttat acccttcgtg tctttgaact gagacattcc 3540aagaggaaag actctcgaac tgtgtaccag taccaatata caaactggag tgtggagcag 3600cttcctgcag aacccaagga attaatctct atgattcagg tcgtcaaaca aaaacttccc 3660cagaagaatt cctctgaagg gaacaagcat cacaagagta cacctctact cattcactgc 3720agggatggat ctcagcaaac gggaatattt tgtgctttgt taaatctctt agaaagtgcg 3780gaaacagaag aggtagtgga tatttttcaa gtggtaaaag ctctacgcaa agctaggcca 3840ggcatggttt ccacattcga gcaatatcaa ttcctatatg acgtcattgc cagcacctac 3900cctgctcaga atggacaagt aaagaaaaac aaccatcaag aagataaaat tgaatttgat 3960aatgaagtgg acaaagtaaa gcaggatgct aattgtgtta atccacttgg tgccccagaa 4020aagctccctg aagcaaagga acaggctgaa ggttctgaac ccacgagtgg cactgagggg 4080ccagaacatt ctgtcaatgg tcctgcaagt ccagctttaa atcaaggttc ataggaaaag 4140acataaatga ggaaactcca aacctcctgt tagctgttat ttctattttt gtagaagtag 4200gaagtgaaaa taggtataca gtggattaat taaatgcagc gaaccaatat ttgtagaagg 4260gttatatttt actactgtgg aaaaatattt aagatagttt tgccagaaca gtttgtacag 4320acgtatgctt attttaaaat tttatctctt attcagtaaa aaacaacttc tttgtaatcg 4380ttatgtgtgt atatgtatgt gtgtatgggt gtgtgtttgt gtgagagaca gagaaagaga 4440gagaattctt tcaagtgaat ctaaaagctt ttgcttttcc tttgttttta tgaagaaaaa 4500atacatttta tattagaagt gttaacttag cttgaaggat ctgtttttaa aaatcataaa 4560ctgtgtgcag actcaataaa atcatgtaca tttctgaaat gacctcaaga tgtcctcctt 4620gttctactca tatatatcta tcttatatag tttactattt tacttctaga gatagtacat 4680aaaggtggta tgtgtgtgta tgctactaca aaaaagttgt taactaaatt aacattggga 4740aatcttatat tccatatatt agcatttagt ccaatgtctt tttaagctta tttaattaaa 4800aaatttccag tgagcttatc atgctgtctt tacatggggt tttcaatttt gcatgctcga 4860ttattccctg tacaatattt aaaatttatt gcttgatact tttgacaaca aattaggttt 4920tgtacaattg aacttaaata aatgtcatta aaataaataa atgcaatatg tattaatatt 4980cattgtataa aaatagaaga atacaaacat atttgttaaa tatttacata tgaaatttaa 5040tatagctatt tttatggaat ttttcattga tatgaaaaat atgatattgc atatgcatag 5100ttcccatgtt aaatcccatt cataactttc attaaagcat ttactttgaa tttctccaat 5160gcttagaatg tttttaccag gaatggatgt cgctaatcat aataaaattc aaccattatt 5220tttttcttgt ttataataca ttgtgttata tgttcaaata tgaaatgtgt atgcacctat 5280tgaaatatgt ttaatgcatt tattaacatt tgcaggacac ttttacaggc cccaattatc 5340caatagtcta ataattgttt aagatctaga aaaaaaaaat caagaatagt ggtatttttc 5400atgaagtaat aaaaactcgt tttggtgaa 54291264946DNAHomo sapiens 126agaacaactt ttttgacttc ctgcaaagag gacccttaca gtatttttgg agaagttagt 60aaaaccgaat ctgacatcat cacctagcag ttcatgcagc tagcaagtgg tttgttctta 120gggtaacaga ggaggaaatt gttcctcgtc tgataagaca acagtggaga aaggacgcat 180gctgtttctt agggacacgg ctgacttcca gatatgacca tgtatttgtg gcttaaactc 240ttggcatttg gctttgcctt tctggacaca gaagtatttg tgacagggca aagcccaaca 300ccttccccca ctgatgccta ccttaatgcc tctgaaacaa ccactctgag cccttctgga 360agcgctgtca tttcaaccac aacaatagct actactccat ctaagccaac atgtgatgaa 420aaatatgcaa acatcactgt ggattactta tataacaagg aaactaaatt atttacagca 480aagctaaatg ttaatgagaa tgtggaatgt ggaaacaata cttgcacaaa caatgaggtg 540cataacctta cagaatgtaa aaatgcgtct gtttccatat ctcataattc atgtactgct 600cctgataaga cattaatatt agatgtgcca ccaggggttg aaaagtttca gttacatgat 660tgtacacaag ttgaaaaagc agatactact atttgtttaa aatggaaaaa tattgaaacc 720tttacttgtg atacacagaa tattacctac agatttcagt gtggtaatat gatatttgat 780aataaagaaa ttaaattaga aaaccttgaa cccgaacatg agtataagtg tgactcagaa 840atactctata ataaccacaa gtttactaac gcaagtaaaa ttattaaaac agattttggg 900agtccaggag agcctcagat tattttttgt agaagtgaag ctgcacatca aggagtaatt 960acctggaatc cccctcaaag atcatttcat aattttaccc tctgttatat aaaagagaca 1020gaaaaagatt gcctcaatct ggataaaaac ctgatcaaat atgatttgca aaatttaaaa 1080ccttatacga aatatgtttt atcattacat gcctacatca ttgcaaaagt gcaacgtaat 1140ggaagtgctg caatgtgtca tttcacaact aaaagtgctc ctccaagcca ggtctggaac 1200atgactgtct ccatgacatc agataatagt atgcatgtca agtgtaggcc tcccagggac 1260cgtaatggcc cccatgaacg ttaccatttg gaagttgaag ctggaaatac tctggttaga 1320aatgagtcgc ataagaattg cgatttccgt gtaaaagatc ttcaatattc aacagactac 1380acttttaagg cctattttca caatggagac tatcctggag aaccctttat tttacatcat 1440tcaacatctt ataattctaa ggcactgata gcatttctgg catttctgat tattgtgaca 1500tcaatagccc tgcttgttgt tctctacaaa atctatgatc tacataagaa aagatcctgc 1560aatttagatg aacagcagga gcttgttgaa agggatgatg aaaaacaact gatgaatgtg 1620gagccaatcc atgcagatat tttgttggaa acttataaga ggaagattgc tgatgaagga 1680agactttttc tggctgaatt tcagagcatc ccgcgggtgt tcagcaagtt tcctataaag 1740gaagctcgaa agccctttaa ccagaataaa aaccgttatg ttgacattct tccttatgat 1800tataaccgtg ttgaactctc tgagataaac ggagatgcag ggtcaaacta cataaatgcc 1860agctatattg atggtttcaa agaacccagg aaatacattg ctgcacaagg tcccagggat 1920gaaactgttg atgatttctg gaggatgatt tgggaacaga aagccacagt tattgtcatg 1980gtcactcgat gtgaagaagg aaacaggaac aagtgtgcag aatactggcc gtcaatggaa 2040gagggcactc gggcttttgg agatgttgtt gtaaagatca accagcacaa aagatgtcca 2100gattacatca ttcagaaatt gaacattgta aataaaaaag aaaaagcaac tggaagagag 2160gtgactcaca ttcagttcac cagctggcca gaccacgggg tgcctgagga tcctcacttg 2220ctcctcaaac tgagaaggag agtgaatgcc ttcagcaatt tcttcagtgg tcccattgtg 2280gtgcactgca gtgctggtgt tgggcgcaca ggaacctata tcggaattga tgccatgcta 2340gaaggcctgg aagccgagaa caaagtggat gtttatggtt atgttgtcaa gctaaggcga 2400cagagatgcc tgatggttca agtagaggcc cagtacatct tgatccatca ggctttggtg 2460gaatacaatc agtttggaga aacagaagtg aatttgtctg aattacatcc atatctacat 2520aacatgaaga aaagggatcc acccagtgag ccgtctccac tagaggctga attccagaga 2580cttccttcat ataggagctg gaggacacag cacattggaa atcaagaaga aaataaaagt 2640aaaaacagga attctaatgt catcccatat gactataaca gagtgccact taaacatgag 2700ctggaaatga gtaaagagag tgagcatgat tcagatgaat cctctgatga tgacagtgat 2760tcagaggaac caagcaaata catcaatgca tcttttataa tgagctactg gaaacctgaa 2820gtgatgattg ctgctcaggg accactgaag gagaccattg gtgacttttg gcagatgatc 2880ttccaaagaa aagtcaaagt tattgttatg ctgacagaac tgaaacatgg agaccaggaa 2940atctgtgctc agtactgggg agaaggaaag caaacatatg gagatattga agttgacctg 3000aaagacacag acaaatcttc aacttatacc cttcgtgtct ttgaactgag acattccaag 3060aggaaagact ctcgaactgt gtaccagtac caatatacaa actggagtgt ggagcagctt 3120cctgcagaac ccaaggaatt aatctctatg attcaggtcg tcaaacaaaa acttccccag 3180aagaattcct ctgaagggaa caagcatcac aagagtacac ctctactcat tcactgcagg 3240gatggatctc agcaaacggg aatattttgt gctttgttaa atctcttaga aagtgcggaa 3300acagaagagg tagtggatat ttttcaagtg gtaaaagctc tacgcaaagc taggccaggc 3360atggtttcca cattcgagca atatcaattc ctatatgacg tcattgccag cacctaccct 3420gctcagaatg gacaagtaaa gaaaaacaac catcaagaag ataaaattga atttgataat 3480gaagtggaca aagtaaagca ggatgctaat tgtgttaatc cacttggtgc cccagaaaag 3540ctccctgaag caaaggaaca ggctgaaggt tctgaaccca cgagtggcac tgaggggcca 3600gaacattctg tcaatggtcc tgcaagtcca gctttaaatc aaggttcata ggaaaagaca 3660taaatgagga aactccaaac ctcctgttag ctgttatttc tatttttgta gaagtaggaa 3720gtgaaaatag gtatacagtg gattaattaa atgcagcgaa ccaatatttg tagaagggtt 3780atattttact actgtggaaa aatatttaag atagttttgc cagaacagtt tgtacagacg 3840tatgcttatt ttaaaatttt atctcttatt cagtaaaaaa caacttcttt gtaatcgtta 3900tgtgtgtata tgtatgtgtg tatgggtgtg tgtttgtgtg agagacagag aaagagagag 3960aattctttca agtgaatcta aaagcttttg cttttccttt gtttttatga agaaaaaata 4020cattttatat tagaagtgtt aacttagctt gaaggatctg tttttaaaaa tcataaactg 4080tgtgcagact caataaaatc atgtacattt ctgaaatgac ctcaagatgt cctccttgtt 4140ctactcatat atatctatct tatatagttt actattttac ttctagagat agtacataaa 4200ggtggtatgt gtgtgtatgc tactacaaaa aagttgttaa ctaaattaac attgggaaat 4260cttatattcc atatattagc atttagtcca atgtcttttt aagcttattt aattaaaaaa 4320tttccagtga gcttatcatg ctgtctttac atggggtttt caattttgca tgctcgatta 4380ttccctgtac aatatttaaa atttattgct tgatactttt gacaacaaat taggttttgt 4440acaattgaac ttaaataaat gtcattaaaa taaataaatg caatatgtat taatattcat 4500tgtataaaaa tagaagaata caaacatatt tgttaaatat ttacatatga aatttaatat 4560agctattttt atggaatttt tcattgatat gaaaaatatg atattgcata tgcatagttc 4620ccatgttaaa tcccattcat aactttcatt aaagcattta ctttgaattt ctccaatgct 4680tagaatgttt ttaccaggaa tggatgtcgc taatcataat aaaattcaac cattattttt 4740ttcttgttta taatacattg tgttatatgt tcaaatatga aatgtgtatg cacctattga 4800aatatgttta atgcatttat taacatttgc aggacacttt tacaggcccc aattatccaa 4860tagtctaata attgtttaag atctagaaaa aaaaaatcaa gaatagtggt atttttcatg 4920aagtaataaa aactcgtttt ggtgaa 49461271156DNAHomo sapiens 127agaacaactt ttttgacttc ctgcaaagag gacccttaca gtatttttgg agaagttagt 60aaaaccgaat ctgacatcat cacctagcag ttcatgcagc tagcaagtgg tttgttctta 120gggtaacaga ggaggaaatt gttcctcgtc tgataagaca acagtggaga aaggacgcat 180gctgtttctt agggacacgg ctgacttcca gatatgacca tgtatttgtg gcttaaactc 240ttggcatttg gctttgcctt tctggacaca gaagtatttg tgacagggca aagcccaaca 300ccttccccca ctggtaagaa ttaatattta tatttttact aattttattt tcttgttgca 360aagtttatat atttaactac aattttctat tattaacact gaaattattt ttaaggataa 420attttataat catgagtgat tcttgacatt cacttgttct taaactttct gcttatacgt 480tatagagttt aataactacc taaacatgtt attaaatttg tatatatatt ttgtgtataa 540atagtaactt ttcccaaact tgacagtaaa tcacacaaca ggtttctact ctcttttaat 600attttaagac tataaaaaaa tgcatttaaa ttagataaca aaattttata gtctgaaagc 660aggttaacag ctgtctatgt atgttataga tatgtagata acagatttgc atatgtctat 720atttctttaa gagtatgttg cttttttcaa tggtatgcaa aacctttgag actattgaga 780tatttttaaa taataatttt caaattctac tgaacacttc aatagtcctt ataaatgtct 840taatcatgag ataaatttaa aacacagaga tgctgcaaat aaattcatac atagtacata 900caaaataaga gaaaaaatta aattgcagat ggttaaatat cacatcactt aactgatgtt 960actgaaaatg tattttcctg cataatcata tggttgacag tatgcattaa gaaggtaagt 1020aaaacaatga agacaatttt gatttaatat ggtaatgcac aattccaact aacgtacatt 1080caacagatca tgaaattggg ttattaaaat gaatattttt gtcattaaat aaaaattccg 1140tccaaaaaaa aaaaaa 115612887PRTHomo sapiens 128Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe1 5

10 15Leu Asp Thr Glu Val Phe Val Thr Gly Gln Ser Pro Thr Pro Ser Pro 20 25 30Thr Gly His Leu Gln Ala Glu Glu Gln Gly Ser Gln Ser Lys Ser Pro 35 40 45Asn Leu Lys Ser Arg Glu Ala Asp Ser Ser Ala Phe Ser Trp Trp Pro 50 55 60Lys Ala Arg Glu Pro Leu Thr Asn His Trp Ser Lys Ser Lys Ser Pro65 70 75 80Lys Ala Glu Glu Leu Gly Val 851291306PRTHomo sapiens 129Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe1 5 10 15Leu Asp Thr Glu Val Phe Val Thr Gly Gln Ser Pro Thr Pro Ser Pro 20 25 30Thr Gly Leu Thr Thr Ala Lys Met Pro Ser Val Pro Leu Ser Ser Asp 35 40 45Pro Leu Pro Thr His Thr Thr Ala Phe Ser Pro Ala Ser Thr Phe Glu 50 55 60Arg Glu Asn Asp Phe Ser Glu Thr Thr Thr Ser Leu Ser Pro Asp Asn65 70 75 80Thr Ser Thr Gln Val Ser Pro Asp Ser Leu Asp Asn Ala Ser Ala Phe 85 90 95Asn Thr Thr Gly Val Ser Ser Val Gln Thr Pro His Leu Pro Thr His 100 105 110Ala Asp Ser Gln Thr Pro Ser Ala Gly Thr Asp Thr Gln Thr Phe Ser 115 120 125Gly Ser Ala Ala Asn Ala Lys Leu Asn Pro Thr Pro Gly Ser Asn Ala 130 135 140Ile Ser Asp Val Pro Gly Glu Arg Ser Thr Ala Ser Thr Phe Pro Thr145 150 155 160Asp Pro Val Ser Pro Leu Thr Thr Thr Leu Ser Leu Ala His His Ser 165 170 175Ser Ala Ala Leu Pro Ala Arg Thr Ser Asn Thr Thr Ile Thr Ala Asn 180 185 190Thr Ser Asp Ala Tyr Leu Asn Ala Ser Glu Thr Thr Thr Leu Ser Pro 195 200 205Ser Gly Ser Ala Val Ile Ser Thr Thr Thr Ile Ala Thr Thr Pro Ser 210 215 220Lys Pro Thr Cys Asp Glu Lys Tyr Ala Asn Ile Thr Val Asp Tyr Leu225 230 235 240Tyr Asn Lys Glu Thr Lys Leu Phe Thr Ala Lys Leu Asn Val Asn Glu 245 250 255Asn Val Glu Cys Gly Asn Asn Thr Cys Thr Asn Asn Glu Val His Asn 260 265 270Leu Thr Glu Cys Lys Asn Ala Ser Val Ser Ile Ser His Asn Ser Cys 275 280 285Thr Ala Pro Asp Lys Thr Leu Ile Leu Asp Val Pro Pro Gly Val Glu 290 295 300Lys Phe Gln Leu His Asp Cys Thr Gln Val Glu Lys Ala Asp Thr Thr305 310 315 320Ile Cys Leu Lys Trp Lys Asn Ile Glu Thr Phe Thr Cys Asp Thr Gln 325 330 335Asn Ile Thr Tyr Arg Phe Gln Cys Gly Asn Met Ile Phe Asp Asn Lys 340 345 350Glu Ile Lys Leu Glu Asn Leu Glu Pro Glu His Glu Tyr Lys Cys Asp 355 360 365Ser Glu Ile Leu Tyr Asn Asn His Lys Phe Thr Asn Ala Ser Lys Ile 370 375 380Ile Lys Thr Asp Phe Gly Ser Pro Gly Glu Pro Gln Ile Ile Phe Cys385 390 395 400Arg Ser Glu Ala Ala His Gln Gly Val Ile Thr Trp Asn Pro Pro Gln 405 410 415Arg Ser Phe His Asn Phe Thr Leu Cys Tyr Ile Lys Glu Thr Glu Lys 420 425 430Asp Cys Leu Asn Leu Asp Lys Asn Leu Ile Lys Tyr Asp Leu Gln Asn 435 440 445Leu Lys Pro Tyr Thr Lys Tyr Val Leu Ser Leu His Ala Tyr Ile Ile 450 455 460Ala Lys Val Gln Arg Asn Gly Ser Ala Ala Met Cys His Phe Thr Thr465 470 475 480Lys Ser Ala Pro Pro Ser Gln Val Trp Asn Met Thr Val Ser Met Thr 485 490 495Ser Asp Asn Ser Met His Val Lys Cys Arg Pro Pro Arg Asp Arg Asn 500 505 510Gly Pro His Glu Arg Tyr His Leu Glu Val Glu Ala Gly Asn Thr Leu 515 520 525Val Arg Asn Glu Ser His Lys Asn Cys Asp Phe Arg Val Lys Asp Leu 530 535 540Gln Tyr Ser Thr Asp Tyr Thr Phe Lys Ala Tyr Phe His Asn Gly Asp545 550 555 560Tyr Pro Gly Glu Pro Phe Ile Leu His His Ser Thr Ser Tyr Asn Ser 565 570 575Lys Ala Leu Ile Ala Phe Leu Ala Phe Leu Ile Ile Val Thr Ser Ile 580 585 590Ala Leu Leu Val Val Leu Tyr Lys Ile Tyr Asp Leu His Lys Lys Arg 595 600 605Ser Cys Asn Leu Asp Glu Gln Gln Glu Leu Val Glu Arg Asp Asp Glu 610 615 620Lys Gln Leu Met Asn Val Glu Pro Ile His Ala Asp Ile Leu Leu Glu625 630 635 640Thr Tyr Lys Arg Lys Ile Ala Asp Glu Gly Arg Leu Phe Leu Ala Glu 645 650 655Phe Gln Ser Ile Pro Arg Val Phe Ser Lys Phe Pro Ile Lys Glu Ala 660 665 670Arg Lys Pro Phe Asn Gln Asn Lys Asn Arg Tyr Val Asp Ile Leu Pro 675 680 685Tyr Asp Tyr Asn Arg Val Glu Leu Ser Glu Ile Asn Gly Asp Ala Gly 690 695 700Ser Asn Tyr Ile Asn Ala Ser Tyr Ile Asp Gly Phe Lys Glu Pro Arg705 710 715 720Lys Tyr Ile Ala Ala Gln Gly Pro Arg Asp Glu Thr Val Asp Asp Phe 725 730 735Trp Arg Met Ile Trp Glu Gln Lys Ala Thr Val Ile Val Met Val Thr 740 745 750Arg Cys Glu Glu Gly Asn Arg Asn Lys Cys Ala Glu Tyr Trp Pro Ser 755 760 765Met Glu Glu Gly Thr Arg Ala Phe Gly Asp Val Val Val Lys Ile Asn 770 775 780Gln His Lys Arg Cys Pro Asp Tyr Ile Ile Gln Lys Leu Asn Ile Val785 790 795 800Asn Lys Lys Glu Lys Ala Thr Gly Arg Glu Val Thr His Ile Gln Phe 805 810 815Thr Ser Trp Pro Asp His Gly Val Pro Glu Asp Pro His Leu Leu Leu 820 825 830Lys Leu Arg Arg Arg Val Asn Ala Phe Ser Asn Phe Phe Ser Gly Pro 835 840 845Ile Val Val His Cys Ser Ala Gly Val Gly Arg Thr Gly Thr Tyr Ile 850 855 860Gly Ile Asp Ala Met Leu Glu Gly Leu Glu Ala Glu Asn Lys Val Asp865 870 875 880Val Tyr Gly Tyr Val Val Lys Leu Arg Arg Gln Arg Cys Leu Met Val 885 890 895Gln Val Glu Ala Gln Tyr Ile Leu Ile His Gln Ala Leu Val Glu Tyr 900 905 910Asn Gln Phe Gly Glu Thr Glu Val Asn Leu Ser Glu Leu His Pro Tyr 915 920 925Leu His Asn Met Lys Lys Arg Asp Pro Pro Ser Glu Pro Ser Pro Leu 930 935 940Glu Ala Glu Phe Gln Arg Leu Pro Ser Tyr Arg Ser Trp Arg Thr Gln945 950 955 960His Ile Gly Asn Gln Glu Glu Asn Lys Ser Lys Asn Arg Asn Ser Asn 965 970 975Val Ile Pro Tyr Asp Tyr Asn Arg Val Pro Leu Lys His Glu Leu Glu 980 985 990Met Ser Lys Glu Ser Glu His Asp Ser Asp Glu Ser Ser Asp Asp Asp 995 1000 1005Ser Asp Ser Glu Glu Pro Ser Lys Tyr Ile Asn Ala Ser Phe Ile 1010 1015 1020Met Ser Tyr Trp Lys Pro Glu Val Met Ile Ala Ala Gln Gly Pro 1025 1030 1035Leu Lys Glu Thr Ile Gly Asp Phe Trp Gln Met Ile Phe Gln Arg 1040 1045 1050Lys Val Lys Val Ile Val Met Leu Thr Glu Leu Lys His Gly Asp 1055 1060 1065Gln Glu Ile Cys Ala Gln Tyr Trp Gly Glu Gly Lys Gln Thr Tyr 1070 1075 1080Gly Asp Ile Glu Val Asp Leu Lys Asp Thr Asp Lys Ser Ser Thr 1085 1090 1095Tyr Thr Leu Arg Val Phe Glu Leu Arg His Ser Lys Arg Lys Asp 1100 1105 1110Ser Arg Thr Val Tyr Gln Tyr Gln Tyr Thr Asn Trp Ser Val Glu 1115 1120 1125Gln Leu Pro Ala Glu Pro Lys Glu Leu Ile Ser Met Ile Gln Val 1130 1135 1140Val Lys Gln Lys Leu Pro Gln Lys Asn Ser Ser Glu Gly Asn Lys 1145 1150 1155His His Lys Ser Thr Pro Leu Leu Ile His Cys Arg Asp Gly Ser 1160 1165 1170Gln Gln Thr Gly Ile Phe Cys Ala Leu Leu Asn Leu Leu Glu Ser 1175 1180 1185Ala Glu Thr Glu Glu Val Val Asp Ile Phe Gln Val Val Lys Ala 1190 1195 1200Leu Arg Lys Ala Arg Pro Gly Met Val Ser Thr Phe Glu Gln Tyr 1205 1210 1215Gln Phe Leu Tyr Asp Val Ile Ala Ser Thr Tyr Pro Ala Gln Asn 1220 1225 1230Gly Gln Val Lys Lys Asn Asn His Gln Glu Asp Lys Ile Glu Phe 1235 1240 1245Asp Asn Glu Val Asp Lys Val Lys Gln Asp Ala Asn Cys Val Asn 1250 1255 1260Pro Leu Gly Ala Pro Glu Lys Leu Pro Glu Ala Lys Glu Gln Ala 1265 1270 1275Glu Gly Ser Glu Pro Thr Ser Gly Thr Glu Gly Pro Glu His Ser 1280 1285 1290Val Asn Gly Pro Ala Ser Pro Ala Leu Asn Gln Gly Ser 1295 1300 13051301145PRTHomo sapiens 130Met Thr Met Tyr Leu Trp Leu Lys Leu Leu Ala Phe Gly Phe Ala Phe1 5 10 15Leu Asp Thr Glu Val Phe Val Thr Gly Gln Ser Pro Thr Pro Ser Pro 20 25 30Thr Asp Ala Tyr Leu Asn Ala Ser Glu Thr Thr Thr Leu Ser Pro Ser 35 40 45Gly Ser Ala Val Ile Ser Thr Thr Thr Ile Ala Thr Thr Pro Ser Lys 50 55 60Pro Thr Cys Asp Glu Lys Tyr Ala Asn Ile Thr Val Asp Tyr Leu Tyr65 70 75 80Asn Lys Glu Thr Lys Leu Phe Thr Ala Lys Leu Asn Val Asn Glu Asn 85 90 95Val Glu Cys Gly Asn Asn Thr Cys Thr Asn Asn Glu Val His Asn Leu 100 105 110Thr Glu Cys Lys Asn Ala Ser Val Ser Ile Ser His Asn Ser Cys Thr 115 120 125Ala Pro Asp Lys Thr Leu Ile Leu Asp Val Pro Pro Gly Val Glu Lys 130 135 140Phe Gln Leu His Asp Cys Thr Gln Val Glu Lys Ala Asp Thr Thr Ile145 150 155 160Cys Leu Lys Trp Lys Asn Ile Glu Thr Phe Thr Cys Asp Thr Gln Asn 165 170 175Ile Thr Tyr Arg Phe Gln Cys Gly Asn Met Ile Phe Asp Asn Lys Glu 180 185 190Ile Lys Leu Glu Asn Leu Glu Pro Glu His Glu Tyr Lys Cys Asp Ser 195 200 205Glu Ile Leu Tyr Asn Asn His Lys Phe Thr Asn Ala Ser Lys Ile Ile 210 215 220Lys Thr Asp Phe Gly Ser Pro Gly Glu Pro Gln Ile Ile Phe Cys Arg225 230 235 240Ser Glu Ala Ala His Gln Gly Val Ile Thr Trp Asn Pro Pro Gln Arg 245 250 255Ser Phe His Asn Phe Thr Leu Cys Tyr Ile Lys Glu Thr Glu Lys Asp 260 265 270Cys Leu Asn Leu Asp Lys Asn Leu Ile Lys Tyr Asp Leu Gln Asn Leu 275 280 285Lys Pro Tyr Thr Lys Tyr Val Leu Ser Leu His Ala Tyr Ile Ile Ala 290 295 300Lys Val Gln Arg Asn Gly Ser Ala Ala Met Cys His Phe Thr Thr Lys305 310 315 320Ser Ala Pro Pro Ser Gln Val Trp Asn Met Thr Val Ser Met Thr Ser 325 330 335Asp Asn Ser Met His Val Lys Cys Arg Pro Pro Arg Asp Arg Asn Gly 340 345 350Pro His Glu Arg Tyr His Leu Glu Val Glu Ala Gly Asn Thr Leu Val 355 360 365Arg Asn Glu Ser His Lys Asn Cys Asp Phe Arg Val Lys Asp Leu Gln 370 375 380Tyr Ser Thr Asp Tyr Thr Phe Lys Ala Tyr Phe His Asn Gly Asp Tyr385 390 395 400Pro Gly Glu Pro Phe Ile Leu His His Ser Thr Ser Tyr Asn Ser Lys 405 410 415Ala Leu Ile Ala Phe Leu Ala Phe Leu Ile Ile Val Thr Ser Ile Ala 420 425 430Leu Leu Val Val Leu Tyr Lys Ile Tyr Asp Leu His Lys Lys Arg Ser 435 440 445Cys Asn Leu Asp Glu Gln Gln Glu Leu Val Glu Arg Asp Asp Glu Lys 450 455 460Gln Leu Met Asn Val Glu Pro Ile His Ala Asp Ile Leu Leu Glu Thr465 470 475 480Tyr Lys Arg Lys Ile Ala Asp Glu Gly Arg Leu Phe Leu Ala Glu Phe 485 490 495Gln Ser Ile Pro Arg Val Phe Ser Lys Phe Pro Ile Lys Glu Ala Arg 500 505 510Lys Pro Phe Asn Gln Asn Lys Asn Arg Tyr Val Asp Ile Leu Pro Tyr 515 520 525Asp Tyr Asn Arg Val Glu Leu Ser Glu Ile Asn Gly Asp Ala Gly Ser 530 535 540Asn Tyr Ile Asn Ala Ser Tyr Ile Asp Gly Phe Lys Glu Pro Arg Lys545 550 555 560Tyr Ile Ala Ala Gln Gly Pro Arg Asp Glu Thr Val Asp Asp Phe Trp 565 570 575Arg Met Ile Trp Glu Gln Lys Ala Thr Val Ile Val Met Val Thr Arg 580 585 590Cys Glu Glu Gly Asn Arg Asn Lys Cys Ala Glu Tyr Trp Pro Ser Met 595 600 605Glu Glu Gly Thr Arg Ala Phe Gly Asp Val Val Val Lys Ile Asn Gln 610 615 620His Lys Arg Cys Pro Asp Tyr Ile Ile Gln Lys Leu Asn Ile Val Asn625 630 635 640Lys Lys Glu Lys Ala Thr Gly Arg Glu Val Thr His Ile Gln Phe Thr 645 650 655Ser Trp Pro Asp His Gly Val Pro Glu Asp Pro His Leu Leu Leu Lys 660 665 670Leu Arg Arg Arg Val Asn Ala Phe Ser Asn Phe Phe Ser Gly Pro Ile 675 680 685Val Val His Cys Ser Ala Gly Val Gly Arg Thr Gly Thr Tyr Ile Gly 690 695 700Ile Asp Ala Met Leu Glu Gly Leu Glu Ala Glu Asn Lys Val Asp Val705 710 715 720Tyr Gly Tyr Val Val Lys Leu Arg Arg Gln Arg Cys Leu Met Val Gln 725 730 735Val Glu Ala Gln Tyr Ile Leu Ile His Gln Ala Leu Val Glu Tyr Asn 740 745 750Gln Phe Gly Glu Thr Glu Val Asn Leu Ser Glu Leu His Pro Tyr Leu 755 760 765His Asn Met Lys Lys Arg Asp Pro Pro Ser Glu Pro Ser Pro Leu Glu 770 775 780Ala Glu Phe Gln Arg Leu Pro Ser Tyr Arg Ser Trp Arg Thr Gln His785 790 795 800Ile Gly Asn Gln Glu Glu Asn Lys Ser Lys Asn Arg Asn Ser Asn Val 805 810 815Ile Pro Tyr Asp Tyr Asn Arg Val Pro Leu Lys His Glu Leu Glu Met 820 825 830Ser Lys Glu Ser Glu His Asp Ser Asp Glu Ser Ser Asp Asp Asp Ser 835 840 845Asp Ser Glu Glu Pro Ser Lys Tyr Ile Asn Ala Ser Phe Ile Met Ser 850 855 860Tyr Trp Lys Pro Glu Val Met Ile Ala Ala Gln Gly Pro Leu Lys Glu865 870 875 880Thr Ile Gly Asp Phe Trp Gln Met Ile Phe Gln Arg Lys Val Lys Val 885 890 895Ile Val Met Leu Thr Glu Leu Lys His Gly Asp Gln Glu Ile Cys Ala 900 905 910Gln Tyr Trp Gly Glu Gly Lys Gln Thr Tyr Gly Asp Ile Glu Val Asp 915 920 925Leu Lys Asp Thr Asp Lys Ser Ser Thr Tyr Thr Leu Arg Val Phe Glu 930 935 940Leu Arg His Ser Lys Arg Lys Asp Ser Arg Thr Val Tyr Gln Tyr Gln945 950 955 960Tyr Thr Asn Trp Ser Val Glu Gln Leu Pro Ala Glu Pro Lys Glu Leu 965 970 975Ile Ser Met Ile Gln Val Val Lys Gln Lys Leu Pro Gln Lys Asn Ser 980 985 990Ser Glu Gly Asn Lys His His Lys Ser Thr Pro Leu Leu Ile His Cys 995 1000 1005Arg Asp Gly Ser Gln Gln Thr Gly Ile Phe Cys Ala Leu Leu Asn 1010 1015 1020Leu Leu Glu Ser Ala Glu Thr Glu Glu Val Val Asp Ile Phe Gln 1025 1030 1035Val Val Lys Ala Leu Arg Lys Ala Arg Pro Gly Met Val Ser Thr 1040 1045 1050Phe Glu Gln Tyr Gln Phe Leu Tyr Asp Val Ile Ala Ser Thr Tyr 1055 1060 1065Pro Ala Gln Asn Gly Gln Val Lys Lys Asn Asn His Gln Glu Asp 1070

1075 1080Lys Ile Glu Phe Asp Asn Glu Val Asp Lys Val Lys Gln Asp Ala 1085 1090 1095Asn Cys Val Asn Pro Leu Gly Ala Pro Glu Lys Leu Pro Glu Ala 1100 1105 1110Lys Glu Gln Ala Glu Gly Ser Glu Pro Thr Ser Gly Thr Glu Gly 1115 1120 1125Pro Glu His Ser Val Asn Gly Pro Ala Ser Pro Ala Leu Asn Gln 1130 1135 1140Gly Ser 11451313740DNAHomo sapiens 131gggacggcgg cggcgcagct cggaacccgc cagggtccag ggtccaggtt ccagcgcccg 60gcggcccagg caccccccga gcccagctcc acacaccgtt cctggatctc ctctccccag 120gcggagcgtg cccctgccca gtccagtgac cttcgcctgt tggagccctg gttaattttt 180gcccagtctg cctgttgtgg ggctcctccc ctttggggat ataagcccgg cctggggctg 240ctccgttctc tgcctggcct gaggctccct gagccgcctc cccaccatca ccatggccaa 300gggcttctat atttccaagt ccctgggcat cctggggatc ctcctgggcg tggcagccgt 360gtgcacaatc atcgcactgt cagtggtgta ctcccaggag aagaacaaga acgccaacag 420ctcccccgtg gcctccacca ccccgtccgc ctcagccacc accaaccccg cctcggccac 480caccttggac caaagtaaag cgtggaatcg ttaccgcctc cccaacacgc tgaaacccga 540ttcctaccgg gtgacgctga gaccgtacct cacccccaat gacaggggcc tgtacgtttt 600taagggctcc agcaccgtcc gtttcacctg caaggaggcc actgacgtca tcatcatcca 660cagcaagaag ctcaactaca ccctcagcca ggggcacagg gtggtcctgc gtggtgtggg 720aggctcccag ccccccgaca ttgacaagac tgagctggtg gagcccaccg agtacctggt 780ggtgcacctc aagggctccc tggtgaagga cagccagtat gagatggaca gcgagttcga 840gggggagttg gcagatgacc tggcgggctt ctaccgcagc gagtacatgg agggcaatgt 900cagaaaggtg gtggccacta cacagatgca ggctgcagat gcccggaagt ccttcccatg 960cttcgatgag ccggccatga aggccgagtt caacatcacg cttatccacc ccaaggacct 1020gacagccctg tccaacatgc ttcccaaagg tcccagcacc ccacttccag aagaccccaa 1080ctggaatgtc actgagttcc acaccacgcc caagatgtcc acgtacttgc tggccttcat 1140tgtcagtgag ttcgactacg tggagaagca ggcatccaat ggtgtcttga tccggatctg 1200ggcccggccc agtgccattg cggcgggcca cggcgattat gccctgaacg tgacgggccc 1260catccttaac ttctttgctg gtcattatga cacaccctac ccactcccaa aatcagacca 1320gattggcctg ccagacttca acgccggcgc catggagaac tggggactgg tgacctaccg 1380ggagaactcc ctgctgttcg accccctgtc ctcctccagc agcaacaagg agcgggtggt 1440cactgtgatt gctcatgagc tggcccacca gtggttcggg aacctggtga ccatagagtg 1500gtggaatgac ctgtggctga acgagggctt cgcctcctac gtggagtacc tgggtgctga 1560ctatgcggag cccacctgga acttgaaaga cctcatggtg ctgaatgatg tgtaccgcgt 1620gatggcagtg gatgcactgg cctcctccca cccgctgtcc acacccgcct cggagatcaa 1680cacgccggcc cagatcagtg agctgtttga cgccatctcc tacagcaagg gcgcctcagt 1740cctcaggatg ctctccagct tcctgtccga ggacgtattc aagcagggcc tggcgtccta 1800cctccacacc tttgcctacc agaacaccat ctacctgaac ctgtgggacc acctgcagga 1860ggctgtgaac aaccggtcca tccaactccc caccaccgtg cgggacatca tgaaccgctg 1920gaccctgcag atgggcttcc cggtcatcac ggtggatacc agcacgggga ccctttccca 1980ggagcacttc ctccttgacc ccgattccaa tgttacccgc ccctcagaat tcaactacgt 2040gtggattgtg cccatcacat ccatcagaga tggcagacag cagcaggact actggctgat 2100agatgtaaga gcccagaacg atctcttcag cacatcaggc aatgagtggg tcctgctgaa 2160cctcaatgtg acgggctatt accgggtgaa ctacgacgaa gagaactgga ggaagattca 2220gactcagctg cagagagacc actcggccat ccctgtcatc aatcgggcac agatcattaa 2280tgacgccttc aacctggcca gtgcccataa ggtccctgtc actctggcgc tgaacaacac 2340cctcttcctg attgaagaga gacagtacat gccctgggag gccgccctga gcagcctgag 2400ctacttcaag ctcatgtttg accgctccga ggtctatggc cccatgaaga actacctgaa 2460gaagcaggtc acacccctct tcattcactt cagaaataat accaacaact ggagggagat 2520cccagaaaac ctgatggacc agtacagcga ggttaatgcc atcagcaccg cctgctccaa 2580cggagttcca gagtgtgagg agatggtctc tggccttttc aagcagtgga tggagaaccc 2640caataataac ccgatccacc ccaacctgcg gtccaccgtc tactgcaacg ctatcgccca 2700gggcggggag gaggagtggg acttcgcctg ggagcagttc cgaaatgcca cactggtcaa 2760tgaggctgac aagctccggg cagccctggc ctgcagcaaa gagttgtgga tcctgaacag 2820gtacctgagc tacaccctga acccggactt aatccggaag caggacgcca cctctaccat 2880catcagcatt accaacaacg tcattgggca aggtctggtc tgggactttg tccagagcaa 2940ctggaagaag ctttttaacg attatggtgg tggctcgttc tccttctcca acctcatcca 3000ggcagtgaca cgacgattct ccaccgagta tgagctgcag cagctggagc agttcaagaa 3060ggacaacgag gaaacaggct tcggctcagg cacccgggcc ctggagcaag ccctggagaa 3120gacgaaagcc aacatcaagt gggtgaagga gaacaaggag gtggtgctcc agtggttcac 3180agaaaacagc aaatagtccc cagcccttga agtcacccgg cccccatgca aggtgcccac 3240atgtgtccat cccagcggct ggtgcagggc ctccattcct ggagcccgag gcaccagtgt 3300cctcccctca aggacaaagt ctccagccca cgttctctct gcctgtgagc cagtctagtt 3360cctgatgacc caggctgcct gagcacctcc cagcccctgc ccctcatgcc aaccccgccc 3420taggcctggc atggcacctg tcgcccagtg ccctggggct gatctcaggg aagcccagct 3480ccagggccag atgagcagaa gctctcgatg gacaatgaac ggccttgctg ggggccgccc 3540tgtaccctct ttcacctttc cctaaagacc ctaaatctga ggaatcaaca gggcagcaga 3600tctgtatatt tttttctaag agaaaatgta aataaaggat ttctagatga aaaaaaaaaa 3660aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3720aaaaaaaaaa aaaaaaaaaa 3740132967PRTHomo sapiens 132Met Ala Lys Gly Phe Tyr Ile Ser Lys Ser Leu Gly Ile Leu Gly Ile1 5 10 15Leu Leu Gly Val Ala Ala Val Cys Thr Ile Ile Ala Leu Ser Val Val 20 25 30Tyr Ser Gln Glu Lys Asn Lys Asn Ala Asn Ser Ser Pro Val Ala Ser 35 40 45Thr Thr Pro Ser Ala Ser Ala Thr Thr Asn Pro Ala Ser Ala Thr Thr 50 55 60Leu Asp Gln Ser Lys Ala Trp Asn Arg Tyr Arg Leu Pro Asn Thr Leu65 70 75 80Lys Pro Asp Ser Tyr Arg Val Thr Leu Arg Pro Tyr Leu Thr Pro Asn 85 90 95Asp Arg Gly Leu Tyr Val Phe Lys Gly Ser Ser Thr Val Arg Phe Thr 100 105 110Cys Lys Glu Ala Thr Asp Val Ile Ile Ile His Ser Lys Lys Leu Asn 115 120 125Tyr Thr Leu Ser Gln Gly His Arg Val Val Leu Arg Gly Val Gly Gly 130 135 140Ser Gln Pro Pro Asp Ile Asp Lys Thr Glu Leu Val Glu Pro Thr Glu145 150 155 160Tyr Leu Val Val His Leu Lys Gly Ser Leu Val Lys Asp Ser Gln Tyr 165 170 175Glu Met Asp Ser Glu Phe Glu Gly Glu Leu Ala Asp Asp Leu Ala Gly 180 185 190Phe Tyr Arg Ser Glu Tyr Met Glu Gly Asn Val Arg Lys Val Val Ala 195 200 205Thr Thr Gln Met Gln Ala Ala Asp Ala Arg Lys Ser Phe Pro Cys Phe 210 215 220Asp Glu Pro Ala Met Lys Ala Glu Phe Asn Ile Thr Leu Ile His Pro225 230 235 240Lys Asp Leu Thr Ala Leu Ser Asn Met Leu Pro Lys Gly Pro Ser Thr 245 250 255Pro Leu Pro Glu Asp Pro Asn Trp Asn Val Thr Glu Phe His Thr Thr 260 265 270Pro Lys Met Ser Thr Tyr Leu Leu Ala Phe Ile Val Ser Glu Phe Asp 275 280 285Tyr Val Glu Lys Gln Ala Ser Asn Gly Val Leu Ile Arg Ile Trp Ala 290 295 300Arg Pro Ser Ala Ile Ala Ala Gly His Gly Asp Tyr Ala Leu Asn Val305 310 315 320Thr Gly Pro Ile Leu Asn Phe Phe Ala Gly His Tyr Asp Thr Pro Tyr 325 330 335Pro Leu Pro Lys Ser Asp Gln Ile Gly Leu Pro Asp Phe Asn Ala Gly 340 345 350Ala Met Glu Asn Trp Gly Leu Val Thr Tyr Arg Glu Asn Ser Leu Leu 355 360 365Phe Asp Pro Leu Ser Ser Ser Ser Ser Asn Lys Glu Arg Val Val Thr 370 375 380Val Ile Ala His Glu Leu Ala His Gln Trp Phe Gly Asn Leu Val Thr385 390 395 400Ile Glu Trp Trp Asn Asp Leu Trp Leu Asn Glu Gly Phe Ala Ser Tyr 405 410 415Val Glu Tyr Leu Gly Ala Asp Tyr Ala Glu Pro Thr Trp Asn Leu Lys 420 425 430Asp Leu Met Val Leu Asn Asp Val Tyr Arg Val Met Ala Val Asp Ala 435 440 445Leu Ala Ser Ser His Pro Leu Ser Thr Pro Ala Ser Glu Ile Asn Thr 450 455 460Pro Ala Gln Ile Ser Glu Leu Phe Asp Ala Ile Ser Tyr Ser Lys Gly465 470 475 480Ala Ser Val Leu Arg Met Leu Ser Ser Phe Leu Ser Glu Asp Val Phe 485 490 495Lys Gln Gly Leu Ala Ser Tyr Leu His Thr Phe Ala Tyr Gln Asn Thr 500 505 510Ile Tyr Leu Asn Leu Trp Asp His Leu Gln Glu Ala Val Asn Asn Arg 515 520 525Ser Ile Gln Leu Pro Thr Thr Val Arg Asp Ile Met Asn Arg Trp Thr 530 535 540Leu Gln Met Gly Phe Pro Val Ile Thr Val Asp Thr Ser Thr Gly Thr545 550 555 560Leu Ser Gln Glu His Phe Leu Leu Asp Pro Asp Ser Asn Val Thr Arg 565 570 575Pro Ser Glu Phe Asn Tyr Val Trp Ile Val Pro Ile Thr Ser Ile Arg 580 585 590Asp Gly Arg Gln Gln Gln Asp Tyr Trp Leu Ile Asp Val Arg Ala Gln 595 600 605Asn Asp Leu Phe Ser Thr Ser Gly Asn Glu Trp Val Leu Leu Asn Leu 610 615 620Asn Val Thr Gly Tyr Tyr Arg Val Asn Tyr Asp Glu Glu Asn Trp Arg625 630 635 640Lys Ile Gln Thr Gln Leu Gln Arg Asp His Ser Ala Ile Pro Val Ile 645 650 655Asn Arg Ala Gln Ile Ile Asn Asp Ala Phe Asn Leu Ala Ser Ala His 660 665 670Lys Val Pro Val Thr Leu Ala Leu Asn Asn Thr Leu Phe Leu Ile Glu 675 680 685Glu Arg Gln Tyr Met Pro Trp Glu Ala Ala Leu Ser Ser Leu Ser Tyr 690 695 700Phe Lys Leu Met Phe Asp Arg Ser Glu Val Tyr Gly Pro Met Lys Asn705 710 715 720Tyr Leu Lys Lys Gln Val Thr Pro Leu Phe Ile His Phe Arg Asn Asn 725 730 735Thr Asn Asn Trp Arg Glu Ile Pro Glu Asn Leu Met Asp Gln Tyr Ser 740 745 750Glu Val Asn Ala Ile Ser Thr Ala Cys Ser Asn Gly Val Pro Glu Cys 755 760 765Glu Glu Met Val Ser Gly Leu Phe Lys Gln Trp Met Glu Asn Pro Asn 770 775 780Asn Asn Pro Ile His Pro Asn Leu Arg Ser Thr Val Tyr Cys Asn Ala785 790 795 800Ile Ala Gln Gly Gly Glu Glu Glu Trp Asp Phe Ala Trp Glu Gln Phe 805 810 815Arg Asn Ala Thr Leu Val Asn Glu Ala Asp Lys Leu Arg Ala Ala Leu 820 825 830Ala Cys Ser Lys Glu Leu Trp Ile Leu Asn Arg Tyr Leu Ser Tyr Thr 835 840 845Leu Asn Pro Asp Leu Ile Arg Lys Gln Asp Ala Thr Ser Thr Ile Ile 850 855 860Ser Ile Thr Asn Asn Val Ile Gly Gln Gly Leu Val Trp Asp Phe Val865 870 875 880Gln Ser Asn Trp Lys Lys Leu Phe Asn Asp Tyr Gly Gly Gly Ser Phe 885 890 895Ser Phe Ser Asn Leu Ile Gln Ala Val Thr Arg Arg Phe Ser Thr Glu 900 905 910Tyr Glu Leu Gln Gln Leu Glu Gln Phe Lys Lys Asp Asn Glu Glu Thr 915 920 925Gly Phe Gly Ser Gly Thr Arg Ala Leu Glu Gln Ala Leu Glu Lys Thr 930 935 940Lys Ala Asn Ile Lys Trp Val Lys Glu Asn Lys Glu Val Val Leu Gln945 950 955 960Trp Phe Thr Glu Asn Ser Lys 9651333962DNAHomo sapiens 133acacacacac agacgtgctc acggagcctg tgcctgcctc tacttgtctg ctctgcgcag 60atggttcctg gcttttgggt cacctcatcc tgcagcccag tccagttaga acctttcttc 120cacagagact ggcaagctgt ggggtaagag ttttggtaag gctgcctgtc ttcagagcat 180gaaggacact gcccggagag ggaagagggc aatatttagt gtttgggcct acttgttgtt 240gggctcccca ctgcctctcc tttgcagagc tatcactggc ccctggttgc aaactctcgg 300tggctttcaa gcctacaaaa caaaaactga gagggtgtcc aaaaagagaa gaagaaaacg 360ttgttgttgg tcctggattc cactgttgga ttttggtggg gatgagaaga aggaattacc 420aggtgtgatc aacacctgca cggtacctgc acggctttaa agaatgcgtt ccagaggcag 480tgataccgag ggctcagccc aaaagaaatt tccaagacat actaaaggcc acagtttcca 540agggcctaaa aacatgaagc atagacagca agacaaagac tcccccagtg agtcggatgt 600aatacttccg tgtcccaagg cagagaagcc acacagtggt aatggccacc aagcagaaga 660cctctcaaga gatgacctgt tatttctcct cagcattctg gagggagaac tgcaggctcg 720agatgaggtc ataggcattt taaaggctga aaaaatggac ctggctttgc tggaagctca 780gtatgggttt gtcactccaa aaaaggtgtt agaggctctc cagagagatg cttttcaagc 840gaaatctacc ccttggcagg aggacatcta tgagaaacca atgaatgagt tggacaaagt 900tgtggaaaaa cataaagaat cttacagacg aatcctggga cagcttttag tggcagaaaa 960atcccgtagg caaaccatat tggagttgga ggaagaaaag agaaaacata aagaatacat 1020ggagaagagt gatgaattca tatgcctact agaacaggaa tgtgaaagat taaagaagct 1080aattgatcaa gaaatcaagt ctcaggagga gaaggagcaa gaaaaggaga aaagggtcac 1140caccctgaaa gaggagctga ccaagctgaa gtcttttgct ttgatggtgg tggatgaaca 1200gcaaaggctg acggcacagc tcacccttca aagacagaaa atccaagagc tgaccacaaa 1260tgcaaaggaa acacatacca aactagccct tgctgaagcc agagttcagg aggaagagca 1320gaaggcaacc agactagaga aggaactgca aacgcagacc acaaagtttc accaagacca 1380agacacaatt atggcgaagc tcaccaatga ggacagtcaa aatcgccagc ttcaacaaaa 1440gctggcagca ctcagccggc agattgatga gttagaagag acaaacaggt ctttacgaaa 1500agcagaagag gagctgcaag atataaaaga aaaaatcagt aagggagaat atggaaacgc 1560tggtatcatg gctgaagtgg aagagctcag gaaacgtgtg ctagatatgg aagggaaaga 1620tgaagagctc ataaaaatgg aggagcagtg cagagatctc aataagaggc ttgaaaggga 1680gacgttacag agtaaagact ttaaactaga ggttgaaaaa ctcagtaaaa gaattatggc 1740tctggaaaag ttagaagacg ctttcaacaa aagcaaacaa gaatgctact ctctgaaatg 1800caatttagaa aaagaaagga tgaccacaaa gcagttgtct caagaactgg agagtttaaa 1860agtaaggatc aaagagctag aagccattga aagtcggcta gaaaagacag aattcactct 1920aaaagaggat ttaactaaac tgaaaacatt aactgtgatg tttgtagatg aacggaaaac 1980aatgagtgaa aaattaaaga aaactgaaga taaattacaa gctgcttctt ctcagcttca 2040agtggagcaa aataaagtaa caacagttac tgagaagtta attgaggaaa ctaaaagggc 2100gctcaagtcc aaaaccgatg tagaagaaaa gatgtacagc gtaaccaagg agagagatga 2160tttaaaaaac aaattgaaag cggaagaaga gaaaggaaat gatctcctgt caagagttaa 2220tatgttgaaa aataggcttc aatcattgga agcaattgag aaagatttcc taaaaaacaa 2280attaaatcaa gactctggga aatccacaac agcattacac caagaaaaca ataagattaa 2340ggagctctct caagaagtgg aaagactgaa actgaagcta aaggacatga aagccattga 2400ggatgacctc atgaaaacag aagatgaata tgagactcta gaacgaaggt atgctaatga 2460acgagacaaa gctcaatttt tatctaaaga gctagaacat gttaaaatgg aacttgctaa 2520gtacaagtta gcagaaaaga cagagaccag ccatgaacaa tggcttttca aaaggcttca 2580agaagaagaa gctaagtcag ggcacctctc aagagaagtg gatgcattaa aagagaaaat 2640tcatgaatac atggcaactg aagacctaat atgtcacctc cagggagatc actcagtcct 2700gcaaaaaaaa ctaaatcaac aagaaaacag gaacagagat ttaggaagag agattgaaaa 2760cctcactaag gagttagaga ggtaccggca tttcagtaag agcctcaggc ctagtctcaa 2820tggaagaaga atttccgatc ctcaagtatt ttctaaagaa gttcagacag aagcagtaga 2880caatgaacca cctgattaca agagcctcat tcctctggaa cgtgcagtca tcaatggtca 2940gttatatgag gagagtgaga atcaagacga ggaccctaat gatgagggat ctgtgctgtc 3000cttcaaatgc agccagtcta ctccatgtcc tgttaacaga aagctatgga ttccctggat 3060gaaatccaag gagggccatc ttcagaatgg aaaaatgcaa actaaaccca atgccaactt 3120tgtgcaacct ggagatctag tcctaagcca cacacctggg cagccacttc atataaaggt 3180tactccagac catgtacaaa acacagccac tcttgaaatc acaagtccaa ccacagagag 3240tcctcactct tacacgagta ctgcagtgat accgaactgt ggcacgccaa agcaaaggat 3300aaccatcctc caaaacgcct ccataacacc agtaaagtcc aaaacctcta ccgaagacct 3360catgaattta gaacaaggca tgtccccaat taccatggca acctttgcca gagcacagac 3420cccagagtct tgtggttctc taactccaga aaggacaatg tcccctattc aggttttggc 3480tgtgactggt tcagctagct ctcctgagca gggacgctcc ccagaaccaa cagaaatcag 3540tgccaagcat gcgatattca gagtctcccc agaccggcag tcatcatggc agtttcagcg 3600ttcaaacagc aatagctcaa gtgtgataac tactgaggat aataaaatcc acattcactt 3660aggaagtcct tacatgcaag ctgtagccag ccctgtgaga cctgccagcc cttcagcacc 3720actgcaggat aaccgaactc aaggcttaat taacggggca ctaaacaaaa caaccaataa 3780agtcaccagc agtattacta tcacaccaac agccacacct cttcctcgac aatcacaaat 3840tacagtggaa ccacttcttc tgcctcattg aactcaacat ccttcagact tttaaggcat 3900tccaaatccc agtcttcatg ttgaactggg ttaagcattt attaaaaaat cgttttcttc 3960ta 39621343274DNAHomo sapiens 134ataggccggg cgcgctcagc gccccgctcg cattgttcgg gcgactctcg gagcgcgcac 60agtcggctcg cagcgcggca ctacagcggc cccggcccgg cccccgcccg gccccggcgc 120aggcagttca gattaaagaa gctaattgat caagaaatca agtctcagga ggagaaggag 180caagaaaagg agaaaagggt caccaccctg aaagaggagc tgaccaagct gaagtctttt 240gctttgatgg tggtggatga acagcaaagg ctgacggcac agctcaccct tcaaagacag 300aaaatccaag agctgaccac aaatgcaaag gaaacacata ccaaactagc ccttgctgaa 360gccagagttc aggaggaaga gcagaaggca accagactag agaaggaact gcaaacgcag 420accacaaagt ttcaccaaga ccaagacaca attatggcga agctcaccaa tgaggacagt 480caaaatcgcc agcttcaaca aaagctggca gcactcagcc ggcagattga tgagttagaa 540gagacaaaca ggtctttacg aaaagcagaa gaggagctgc aagatataaa agaaaaaatc 600agtaagggag aatatggaaa cgctggtatc atggctgaag tggaagagct caggaaacgt 660gtgctagata tggaagggaa agatgaagag ctcataaaaa tggaggagca gtgcagagat 720ctcaataaga ggcttgaaag ggagacgtta cagagtaaag actttaaact agaggttgaa 780aaactcagta aaagaattat ggctctggaa aagttagaag acgctttcaa caaaagcaaa 840caagaatgct actctctgaa atgcaattta gaaaaagaaa ggatgaccac

aaagcagttg 900tctcaagaac tggagagttt aaaagtaagg atcaaagagc tagaagccat tgaaagtcgg 960ctagaaaaga cagaattcac tctaaaagag gatttaacta aactgaaaac attaactgtg 1020atgtttgtag atgaacggaa aacaatgagt gaaaaattaa agaaaactga agataaatta 1080caagctgctt cttctcagct tcaagtggag caaaataaag taacaacagt tactgagaag 1140ttaattgagg aaactaaaag ggcgctcaag tccaaaaccg atgtagaaga aaagatgtac 1200agcgtaacca aggagagaga tgatttaaaa aacaaattga aagcggaaga agagaaagga 1260aatgatctcc tgtcaagagt taatatgttg aaaaataggc ttcaatcatt ggaagcaatt 1320gagaaagatt tcctaaaaaa caaattaaat caagactctg ggaaatccac aacagcatta 1380caccaagaaa acaataagat taaggagctc tctcaagaag tggaaagact gaaactgaag 1440ctaaaggaca tgaaagccat tgaggatgac ctcatgaaaa cagaagatga atatgagact 1500ctagaacgaa ggtatgctaa tgaacgagac aaagctcaat ttttatctaa agagctagaa 1560catgttaaaa tggaacttgc taagtacaag ttagcagaaa agacagagac cagccatgaa 1620caatggcttt tcaaaaggct tcaagaagaa gaagctaagt cagggcacct ctcaagagaa 1680gtggatgcat taaaagagaa aattcatgaa tacatggcaa ctgaagacct aatatgtcac 1740ctccagggag atcactcagt cctgcaaaaa aaactaaatc aacaagaaaa caggaacaga 1800gatttaggaa gagagattga aaacctcact aaggagttag agaggtaccg gcatttcagt 1860aagagcctca ggcctagtct caatggaaga agaatttccg atcctcaagt attttctaaa 1920gaagttcaga cagaagcagt agacaatgaa ccacctgatt acaagagcct cattcctctg 1980gaacgtgcag tcatcaatgg tcagttatat gaggagagtg agaatcaaga cgaggaccct 2040aatgatgagg gatctgtgct gtccttcaaa tgcagccagt ctactccatg tcctgttaac 2100agaaagctat ggattccctg gatgaaatcc aaggagggcc atcttcagaa tggaaaaatg 2160caaactaaac ccaatgccaa ctttgtgcaa cctggagatc tagtcctaag ccacacacct 2220gggcagccac ttcatataaa ggttactcca gaccatgtac aaaacacagc cactcttgaa 2280atcacaagtc caaccacaga gagtcctcac tcttacacga gtactgcagt gataccgaac 2340tgtggcacgc caaagcaaag gataaccatc ctccaaaacg cctccataac accagtaaag 2400tccaaaacct ctaccgaaga cctcatgaat ttagaacaag gcatgtcccc aattaccatg 2460gcaacctttg ccagagcaca gaccccagag tcttgtggtt ctctaactcc agaaaggaca 2520atgtccccta ttcaggtttt ggctgtgact ggttcagcta gctctcctga gcagggacgc 2580tccccagaac caacagaaat cagtgccaag catgcgatat tcagagtctc cccagaccgg 2640cagtcatcat ggcagtttca gcgttcaaac agcaatagct caagtgtgat aactactgag 2700gataataaaa tccacattca cttaggaagt ccttacatgc aagctgtagc cagccctgtg 2760agacctgcca gcccttcagc accactgcag gataaccgaa ctcaaggctt aattaacggg 2820gcactaaaca aaacaaccaa taaagtcacc agcagtatta ctatcacacc aacagccaca 2880cctcttcctc gacaatcaca aattacagta agtaatatat ataactgacc acgctcaccc 2940tcatccagtc catactgata tttttgcaag gaactcaatc cttttttaat catccctcca 3000tatcccccaa gactgactga actcgtactt tgggaaggtt tgtgcatgaa ctatacaaga 3060gtatctgaaa ctaactgttg cctgcatagt catatcgagt gtgcacttac tgtatatctt 3120ttcatttaca tacttgtatg gaaaatattt agtctgcact tgtataaata catctttatg 3180tatttcattt tccataactc actttaattt gactgcaact tgtcttggtg aaatacttta 3240acattataaa acagtaaata atttgttatt ttta 32741354211DNAHomo sapiens 135acacacacac agacgtgctc acggagcctg tgcctgcctc tacttgtctg ctctgcgcag 60atggttcctg gcttttgggt cacctcatcc tgcagcccag tccagttaga acctttcttc 120cacagagact ggcaagctgt ggggtaagag ttttggtaag gctgcctgtc ttcagagcat 180gaaggacact gcccggagag ggaagagggc aatatttagt gtttgggcct acttgttgtt 240gggctcccca ctgcctctcc tttgcagagc tatcactggc ccctggttgc aaactctcgg 300tggctttcaa gcctacaaaa caaaaactga gagggtgtcc aaaaagagaa gaagaaaacg 360ttgttgttgg tcctggattc cactgttgga ttttggtggg gatgagaaga aggaattacc 420aggtgtgatc aacacctgca cggtacctgc acggctttaa agaatgcgtt ccagaggcag 480tgataccgag ggctcagccc aaaagaaatt tccaagacat actaaaggcc acagtttcca 540agggcctaaa aacatgaagc atagacagca agacaaagac tcccccagtg agtcggatgt 600aatacttccg tgtcccaagg cagagaagcc acacagtggt aatggccacc aagcagaaga 660cctctcaaga gatgacctgt tatttctcct cagcattctg gagggagaac tgcaggctcg 720agatgaggtc ataggcattt taaaggctga aaaaatggac ctggctttgc tggaagctca 780gtatgggttt gtcactccaa aaaaggtgtt agaggctctc cagagagatg cttttcaagc 840gaaatctacc ccttggcagg aggacatcta tgagaaacca atgaatgagt tggacaaagt 900tgtggaaaaa cataaagaat cttacagacg aatcctggga cagcttttag tggcagaaaa 960atcccgtagg caaaccatat tggagttgga ggaagaaaag agaaaacata aagaatacat 1020ggagaagagt gatgaattca tatgcctact agaacaggaa tgtgaaagat taaagaagct 1080aattgatcaa gaaatcaagt ctcaggagga gaaggagcaa gaaaaggaga aaagggtcac 1140caccctgaaa gaggagctga ccaagctgaa gtcttttgct ttgatggtgg tggatgaaca 1200gcaaaggctg acggcacagc tcacccttca aagacagaaa atccaagagc tgaccacaaa 1260tgcaaaggaa acacatacca aactagccct tgctgaagcc agagttcagg aggaagagca 1320gaaggcaacc agactagaga aggaactgca aacgcagacc acaaagtttc accaagacca 1380agacacaatt atggcgaagc tcaccaatga ggacagtcaa aatcgccagc ttcaacaaaa 1440gctggcagca ctcagccggc agattgatga gttagaagag acaaacaggt ctttacgaaa 1500agcagaagag gagctgcaag atataaaaga aaaaatcagt aagggagaat atggaaacgc 1560tggtatcatg gctgaagtgg aagagctcag gaaacgtgtg ctagatatgg aagggaaaga 1620tgaagagctc ataaaaatgg aggagcagtg cagagatctc aataagaggc ttgaaaggga 1680gacgttacag agtaaagact ttaaactaga ggttgaaaaa ctcagtaaaa gaattatggc 1740tctggaaaag ttagaagacg ctttcaacaa aagcaaacaa gaatgctact ctctgaaatg 1800caatttagaa aaagaaagga tgaccacaaa gcagttgtct caagaactgg agagtttaaa 1860agtaaggatc aaagagctag aagccattga aagtcggcta gaaaagacag aattcactct 1920aaaagaggat ttaactaaac tgaaaacatt aactgtgatg tttgtagatg aacggaaaac 1980aatgagtgaa aaattaaaga aaactgaaga taaattacaa gctgcttctt ctcagcttca 2040agtggagcaa aataaagtaa caacagttac tgagaagtta attgaggaaa ctaaaagggc 2100gctcaagtcc aaaaccgatg tagaagaaaa gatgtacagc gtaaccaagg agagagatga 2160tttaaaaaac aaattgaaag cggaagaaga gaaaggaaat gatctcctgt caagagttaa 2220tatgttgaaa aataggcttc aatcattgga agcaattgag aaagatttcc taaaaaacaa 2280attaaatcaa gactctggga aatccacaac agcattacac caagaaaaca ataagattaa 2340ggagctctct caagaagtgg aaagactgaa actgaagcta aaggacatga aagccattga 2400ggatgacctc atgaaaacag aagatgaata tgagactcta gaacgaaggt atgctaatga 2460acgagacaaa gctcaatttt tatctaaaga gctagaacat gttaaaatgg aacttgctaa 2520gtacaagtta gcagaaaaga cagagaccag ccatgaacaa tggcttttca aaaggcttca 2580agaagaagaa gctaagtcag ggcacctctc aagagaagtg gatgcattaa aagagaaaat 2640tcatgaatac atggcaactg aagacctaat atgtcacctc cagggagatc actcagtcct 2700gcaaaaaaaa ctaaatcaac aagaaaacag gaacagagat ttaggaagag agattgaaaa 2760cctcactaag gagttagaga ggtaccggca tttcagtaag agcctcaggc ctagtctcaa 2820tggaagaaga atttccgatc ctcaagtatt ttctaaagaa gttcagacag aagcagtaga 2880caatgaacca cctgattaca agagcctcat tcctctggaa cgtgcagtca tcaatggtca 2940gttatatgag gagagtgaga atcaagacga ggaccctaat gatgagggat ctgtgctgtc 3000cttcaaatgc agccagtcta ctccatgtcc tgttaacaga aagctatgga ttccctggat 3060gaaatccaag gagggccatc ttcagaatgg aaaaatgcaa actaaaccca atgccaactt 3120tgtgcaacct ggagatctag tcctaagcca cacacctggg cagccacttc atataaaggt 3180tactccagac catgtacaaa acacagccac tcttgaaatc acaagtccaa ccacagagag 3240tcctcactct tacacgagta ctgcagtgat accgaactgt ggcacgccaa agcaaaggat 3300aaccatcctc caaaacgcct ccataacacc agtaaagtcc aaaacctcta ccgaagacct 3360catgaattta gaacaaggca tgtccccaat taccatggca acctttgcca gagcacagac 3420cccagagtct tgtggttctc taactccaga aaggacaatg tcccctattc aggttttggc 3480tgtgactggt tcagctagct ctcctgagca gggacgctcc ccagaaccaa cagaaatcag 3540tgccaagcat gcgatattca gagtctcccc agaccggcag tcatcatggc agtttcagcg 3600ttcaaacagc aatagctcaa gtgtgataac tactgaggat aataaaatcc acattcactt 3660aggaagtcct tacatgcaag ctgtagccag ccctgtgaga cctgccagcc cttcagcacc 3720actgcaggat aaccgaactc aaggcttaat taacggggca ctaaacaaaa caaccaataa 3780agtcaccagc agtattacta tcacaccaac agccacacct cttcctcgac aatcacaaat 3840tacagtaagt aatatatata actgaccacg ctcaccctca tccagtccat actgatattt 3900ttgcaaggaa ctcaatcctt ttttaatcat ccctccatat cccccaagac tgactgaact 3960cgtactttgg gaaggtttgt gcatgaacta tacaagagta tctgaaacta actgttgcct 4020gcatagtcat atcgagtgtg cacttactgt atatcttttc atttacatac ttgtatggaa 4080aatatttagt ctgcacttgt ataaatacat ctttatgtat ttcattttcc ataactcact 4140ttaatttgac tgcaacttgt cttggtgaaa tactttaaca ttataaaaca gtaaataatt 4200tgttattttt a 42111361135PRTHomo sapiens 136Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala Gln Lys Lys Phe1 5 10 15Pro Arg His Thr Lys Gly His Ser Phe Gln Gly Pro Lys Asn Met Lys 20 25 30His Arg Gln Gln Asp Lys Asp Ser Pro Ser Glu Ser Asp Val Ile Leu 35 40 45Pro Cys Pro Lys Ala Glu Lys Pro His Ser Gly Asn Gly His Gln Ala 50 55 60Glu Asp Leu Ser Arg Asp Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu65 70 75 80Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly Ile Leu Lys Ala Glu 85 90 95Lys Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro 100 105 110Lys Lys Val Leu Glu Ala Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser 115 120 125Thr Pro Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu Leu Asp 130 135 140Lys Val Val Glu Lys His Lys Glu Ser Tyr Arg Arg Ile Leu Gly Gln145 150 155 160Leu Leu Val Ala Glu Lys Ser Arg Arg Gln Thr Ile Leu Glu Leu Glu 165 170 175Glu Glu Lys Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe 180 185 190Ile Cys Leu Leu Glu Gln Glu Cys Glu Arg Leu Lys Lys Leu Ile Asp 195 200 205Gln Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu Lys Arg 210 215 220Val Thr Thr Leu Lys Glu Glu Leu Thr Lys Leu Lys Ser Phe Ala Leu225 230 235 240Met Val Val Asp Glu Gln Gln Arg Leu Thr Ala Gln Leu Thr Leu Gln 245 250 255Arg Gln Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr 260 265 270Lys Leu Ala Leu Ala Glu Ala Arg Val Gln Glu Glu Glu Gln Lys Ala 275 280 285Thr Arg Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys Phe His Gln 290 295 300Asp Gln Asp Thr Ile Met Ala Lys Leu Thr Asn Glu Asp Ser Gln Asn305 310 315 320Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu Ser Arg Gln Ile Asp Glu 325 330 335Leu Glu Glu Thr Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu Leu Gln 340 345 350Asp Ile Lys Glu Lys Ile Ser Lys Gly Glu Tyr Gly Asn Ala Gly Ile 355 360 365Met Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp Met Glu Gly 370 375 380Lys Asp Glu Glu Leu Ile Lys Met Glu Glu Gln Cys Arg Asp Leu Asn385 390 395 400Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp Phe Lys Leu Glu 405 410 415Val Glu Lys Leu Ser Lys Arg Ile Met Ala Leu Glu Lys Leu Glu Asp 420 425 430Ala Phe Asn Lys Ser Lys Gln Glu Cys Tyr Ser Leu Lys Cys Asn Leu 435 440 445Glu Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln Glu Leu Glu Ser 450 455 460Leu Lys Val Arg Ile Lys Glu Leu Glu Ala Ile Glu Ser Arg Leu Glu465 470 475 480Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys Leu Lys Thr Leu 485 490 495Thr Val Met Phe Val Asp Glu Arg Lys Thr Met Ser Glu Lys Leu Lys 500 505 510Lys Thr Glu Asp Lys Leu Gln Ala Ala Ser Ser Gln Leu Gln Val Glu 515 520 525Gln Asn Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu Thr Lys 530 535 540Arg Ala Leu Lys Ser Lys Thr Asp Val Glu Glu Lys Met Tyr Ser Val545 550 555 560Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys Ala Glu Glu Glu 565 570 575Lys Gly Asn Asp Leu Leu Ser Arg Val Asn Met Leu Lys Asn Arg Leu 580 585 590Gln Ser Leu Glu Ala Ile Glu Lys Asp Phe Leu Lys Asn Lys Leu Asn 595 600 605Gln Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu Asn Asn Lys 610 615 620Ile Lys Glu Leu Ser Gln Glu Val Glu Arg Leu Lys Leu Lys Leu Lys625 630 635 640Asp Met Lys Ala Ile Glu Asp Asp Leu Met Lys Thr Glu Asp Glu Tyr 645 650 655Glu Thr Leu Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala Gln Phe 660 665 670Leu Ser Lys Glu Leu Glu His Val Lys Met Glu Leu Ala Lys Tyr Lys 675 680 685Leu Ala Glu Lys Thr Glu Thr Ser His Glu Gln Trp Leu Phe Lys Arg 690 695 700Leu Gln Glu Glu Glu Ala Lys Ser Gly His Leu Ser Arg Glu Val Asp705 710 715 720Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr Glu Asp Leu Ile 725 730 735Cys His Leu Gln Gly Asp His Ser Val Leu Gln Lys Lys Leu Asn Gln 740 745 750Gln Glu Asn Arg Asn Arg Asp Leu Gly Arg Glu Ile Glu Asn Leu Thr 755 760 765Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu Arg Pro Ser 770 775 780Leu Asn Gly Arg Arg Ile Ser Asp Pro Gln Val Phe Ser Lys Glu Val785 790 795 800Gln Thr Glu Ala Val Asp Asn Glu Pro Pro Asp Tyr Lys Ser Leu Ile 805 810 815Pro Leu Glu Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu Glu Ser Glu 820 825 830Asn Gln Asp Glu Asp Pro Asn Asp Glu Gly Ser Val Leu Ser Phe Lys 835 840 845Cys Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys Leu Trp Ile Pro 850 855 860Trp Met Lys Ser Lys Glu Gly His Leu Gln Asn Gly Lys Met Gln Thr865 870 875 880Lys Pro Asn Ala Asn Phe Val Gln Pro Gly Asp Leu Val Leu Ser His 885 890 895Thr Pro Gly Gln Pro Leu His Ile Lys Val Thr Pro Asp His Val Gln 900 905 910Asn Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu Ser Pro His 915 920 925Ser Tyr Thr Ser Thr Ala Val Ile Pro Asn Cys Gly Thr Pro Lys Gln 930 935 940Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile Thr Pro Val Lys Ser Lys945 950 955 960Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly Met Ser Pro Ile 965 970 975Thr Met Ala Thr Phe Ala Arg Ala Gln Thr Pro Glu Ser Cys Gly Ser 980 985 990Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu Ala Val Thr 995 1000 1005Gly Ser Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu Pro Thr 1010 1015 1020Glu Ile Ser Ala Lys His Ala Ile Phe Arg Val Ser Pro Asp Arg 1025 1030 1035Gln Ser Ser Trp Gln Phe Gln Arg Ser Asn Ser Asn Ser Ser Ser 1040 1045 1050Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile His Leu Gly Ser 1055 1060 1065Pro Tyr Met Gln Ala Val Ala Ser Pro Val Arg Pro Ala Ser Pro 1070 1075 1080Ser Ala Pro Leu Gln Asp Asn Arg Thr Gln Gly Leu Ile Asn Gly 1085 1090 1095Ala Leu Asn Lys Thr Thr Asn Lys Val Thr Ser Ser Ile Thr Ile 1100 1105 1110Thr Pro Thr Ala Thr Pro Leu Pro Arg Gln Ser Gln Ile Thr Val 1115 1120 1125Glu Pro Leu Leu Leu Pro His 1130 1135137893PRTHomo sapiens 137Met Val Val Asp Glu Gln Gln Arg Leu Thr Ala Gln Leu Thr Leu Gln1 5 10 15Arg Gln Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr 20 25 30Lys Leu Ala Leu Ala Glu Ala Arg Val Gln Glu Glu Glu Gln Lys Ala 35 40 45Thr Arg Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys Phe His Gln 50 55 60Asp Gln Asp Thr Ile Met Ala Lys Leu Thr Asn Glu Asp Ser Gln Asn65 70 75 80Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu Ser Arg Gln Ile Asp Glu 85 90 95Leu Glu Glu Thr Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu Leu Gln 100 105 110Asp Ile Lys Glu Lys Ile Ser Lys Gly Glu Tyr Gly Asn Ala Gly Ile 115 120 125Met Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp Met Glu Gly 130 135 140Lys Asp Glu Glu Leu Ile Lys Met Glu Glu Gln Cys Arg Asp Leu Asn145 150 155 160Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp Phe Lys Leu Glu 165 170 175Val Glu Lys Leu Ser Lys Arg Ile Met Ala Leu Glu Lys Leu Glu Asp 180 185 190Ala Phe Asn Lys Ser Lys Gln Glu Cys Tyr Ser Leu Lys Cys Asn Leu 195 200 205Glu Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln Glu Leu Glu Ser 210 215 220Leu Lys Val Arg Ile Lys Glu Leu Glu Ala Ile Glu Ser Arg Leu Glu225

230 235 240Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys Leu Lys Thr Leu 245 250 255Thr Val Met Phe Val Asp Glu Arg Lys Thr Met Ser Glu Lys Leu Lys 260 265 270Lys Thr Glu Asp Lys Leu Gln Ala Ala Ser Ser Gln Leu Gln Val Glu 275 280 285Gln Asn Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu Thr Lys 290 295 300Arg Ala Leu Lys Ser Lys Thr Asp Val Glu Glu Lys Met Tyr Ser Val305 310 315 320Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys Ala Glu Glu Glu 325 330 335Lys Gly Asn Asp Leu Leu Ser Arg Val Asn Met Leu Lys Asn Arg Leu 340 345 350Gln Ser Leu Glu Ala Ile Glu Lys Asp Phe Leu Lys Asn Lys Leu Asn 355 360 365Gln Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu Asn Asn Lys 370 375 380Ile Lys Glu Leu Ser Gln Glu Val Glu Arg Leu Lys Leu Lys Leu Lys385 390 395 400Asp Met Lys Ala Ile Glu Asp Asp Leu Met Lys Thr Glu Asp Glu Tyr 405 410 415Glu Thr Leu Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala Gln Phe 420 425 430Leu Ser Lys Glu Leu Glu His Val Lys Met Glu Leu Ala Lys Tyr Lys 435 440 445Leu Ala Glu Lys Thr Glu Thr Ser His Glu Gln Trp Leu Phe Lys Arg 450 455 460Leu Gln Glu Glu Glu Ala Lys Ser Gly His Leu Ser Arg Glu Val Asp465 470 475 480Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr Glu Asp Leu Ile 485 490 495Cys His Leu Gln Gly Asp His Ser Val Leu Gln Lys Lys Leu Asn Gln 500 505 510Gln Glu Asn Arg Asn Arg Asp Leu Gly Arg Glu Ile Glu Asn Leu Thr 515 520 525Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu Arg Pro Ser 530 535 540Leu Asn Gly Arg Arg Ile Ser Asp Pro Gln Val Phe Ser Lys Glu Val545 550 555 560Gln Thr Glu Ala Val Asp Asn Glu Pro Pro Asp Tyr Lys Ser Leu Ile 565 570 575Pro Leu Glu Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu Glu Ser Glu 580 585 590Asn Gln Asp Glu Asp Pro Asn Asp Glu Gly Ser Val Leu Ser Phe Lys 595 600 605Cys Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys Leu Trp Ile Pro 610 615 620Trp Met Lys Ser Lys Glu Gly His Leu Gln Asn Gly Lys Met Gln Thr625 630 635 640Lys Pro Asn Ala Asn Phe Val Gln Pro Gly Asp Leu Val Leu Ser His 645 650 655Thr Pro Gly Gln Pro Leu His Ile Lys Val Thr Pro Asp His Val Gln 660 665 670Asn Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu Ser Pro His 675 680 685Ser Tyr Thr Ser Thr Ala Val Ile Pro Asn Cys Gly Thr Pro Lys Gln 690 695 700Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile Thr Pro Val Lys Ser Lys705 710 715 720Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly Met Ser Pro Ile 725 730 735Thr Met Ala Thr Phe Ala Arg Ala Gln Thr Pro Glu Ser Cys Gly Ser 740 745 750Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu Ala Val Thr 755 760 765Gly Ser Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu Pro Thr Glu 770 775 780Ile Ser Ala Lys His Ala Ile Phe Arg Val Ser Pro Asp Arg Gln Ser785 790 795 800Ser Trp Gln Phe Gln Arg Ser Asn Ser Asn Ser Ser Ser Val Ile Thr 805 810 815Thr Glu Asp Asn Lys Ile His Ile His Leu Gly Ser Pro Tyr Met Gln 820 825 830Ala Val Ala Ser Pro Val Arg Pro Ala Ser Pro Ser Ala Pro Leu Gln 835 840 845Asp Asn Arg Thr Gln Gly Leu Ile Asn Gly Ala Leu Asn Lys Thr Thr 850 855 860Asn Lys Val Thr Ser Ser Ile Thr Ile Thr Pro Thr Ala Thr Pro Leu865 870 875 880Pro Arg Gln Ser Gln Ile Thr Val Ser Asn Ile Tyr Asn 885 8901381133PRTHomo sapiens 138Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala Gln Lys Lys Phe1 5 10 15Pro Arg His Thr Lys Gly His Ser Phe Gln Gly Pro Lys Asn Met Lys 20 25 30His Arg Gln Gln Asp Lys Asp Ser Pro Ser Glu Ser Asp Val Ile Leu 35 40 45Pro Cys Pro Lys Ala Glu Lys Pro His Ser Gly Asn Gly His Gln Ala 50 55 60Glu Asp Leu Ser Arg Asp Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu65 70 75 80Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly Ile Leu Lys Ala Glu 85 90 95Lys Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro 100 105 110Lys Lys Val Leu Glu Ala Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser 115 120 125Thr Pro Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu Leu Asp 130 135 140Lys Val Val Glu Lys His Lys Glu Ser Tyr Arg Arg Ile Leu Gly Gln145 150 155 160Leu Leu Val Ala Glu Lys Ser Arg Arg Gln Thr Ile Leu Glu Leu Glu 165 170 175Glu Glu Lys Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe 180 185 190Ile Cys Leu Leu Glu Gln Glu Cys Glu Arg Leu Lys Lys Leu Ile Asp 195 200 205Gln Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu Lys Arg 210 215 220Val Thr Thr Leu Lys Glu Glu Leu Thr Lys Leu Lys Ser Phe Ala Leu225 230 235 240Met Val Val Asp Glu Gln Gln Arg Leu Thr Ala Gln Leu Thr Leu Gln 245 250 255Arg Gln Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr 260 265 270Lys Leu Ala Leu Ala Glu Ala Arg Val Gln Glu Glu Glu Gln Lys Ala 275 280 285Thr Arg Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys Phe His Gln 290 295 300Asp Gln Asp Thr Ile Met Ala Lys Leu Thr Asn Glu Asp Ser Gln Asn305 310 315 320Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu Ser Arg Gln Ile Asp Glu 325 330 335Leu Glu Glu Thr Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu Leu Gln 340 345 350Asp Ile Lys Glu Lys Ile Ser Lys Gly Glu Tyr Gly Asn Ala Gly Ile 355 360 365Met Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp Met Glu Gly 370 375 380Lys Asp Glu Glu Leu Ile Lys Met Glu Glu Gln Cys Arg Asp Leu Asn385 390 395 400Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp Phe Lys Leu Glu 405 410 415Val Glu Lys Leu Ser Lys Arg Ile Met Ala Leu Glu Lys Leu Glu Asp 420 425 430Ala Phe Asn Lys Ser Lys Gln Glu Cys Tyr Ser Leu Lys Cys Asn Leu 435 440 445Glu Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln Glu Leu Glu Ser 450 455 460Leu Lys Val Arg Ile Lys Glu Leu Glu Ala Ile Glu Ser Arg Leu Glu465 470 475 480Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys Leu Lys Thr Leu 485 490 495Thr Val Met Phe Val Asp Glu Arg Lys Thr Met Ser Glu Lys Leu Lys 500 505 510Lys Thr Glu Asp Lys Leu Gln Ala Ala Ser Ser Gln Leu Gln Val Glu 515 520 525Gln Asn Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu Thr Lys 530 535 540Arg Ala Leu Lys Ser Lys Thr Asp Val Glu Glu Lys Met Tyr Ser Val545 550 555 560Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys Ala Glu Glu Glu 565 570 575Lys Gly Asn Asp Leu Leu Ser Arg Val Asn Met Leu Lys Asn Arg Leu 580 585 590Gln Ser Leu Glu Ala Ile Glu Lys Asp Phe Leu Lys Asn Lys Leu Asn 595 600 605Gln Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu Asn Asn Lys 610 615 620Ile Lys Glu Leu Ser Gln Glu Val Glu Arg Leu Lys Leu Lys Leu Lys625 630 635 640Asp Met Lys Ala Ile Glu Asp Asp Leu Met Lys Thr Glu Asp Glu Tyr 645 650 655Glu Thr Leu Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala Gln Phe 660 665 670Leu Ser Lys Glu Leu Glu His Val Lys Met Glu Leu Ala Lys Tyr Lys 675 680 685Leu Ala Glu Lys Thr Glu Thr Ser His Glu Gln Trp Leu Phe Lys Arg 690 695 700Leu Gln Glu Glu Glu Ala Lys Ser Gly His Leu Ser Arg Glu Val Asp705 710 715 720Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr Glu Asp Leu Ile 725 730 735Cys His Leu Gln Gly Asp His Ser Val Leu Gln Lys Lys Leu Asn Gln 740 745 750Gln Glu Asn Arg Asn Arg Asp Leu Gly Arg Glu Ile Glu Asn Leu Thr 755 760 765Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu Arg Pro Ser 770 775 780Leu Asn Gly Arg Arg Ile Ser Asp Pro Gln Val Phe Ser Lys Glu Val785 790 795 800Gln Thr Glu Ala Val Asp Asn Glu Pro Pro Asp Tyr Lys Ser Leu Ile 805 810 815Pro Leu Glu Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu Glu Ser Glu 820 825 830Asn Gln Asp Glu Asp Pro Asn Asp Glu Gly Ser Val Leu Ser Phe Lys 835 840 845Cys Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys Leu Trp Ile Pro 850 855 860Trp Met Lys Ser Lys Glu Gly His Leu Gln Asn Gly Lys Met Gln Thr865 870 875 880Lys Pro Asn Ala Asn Phe Val Gln Pro Gly Asp Leu Val Leu Ser His 885 890 895Thr Pro Gly Gln Pro Leu His Ile Lys Val Thr Pro Asp His Val Gln 900 905 910Asn Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu Ser Pro His 915 920 925Ser Tyr Thr Ser Thr Ala Val Ile Pro Asn Cys Gly Thr Pro Lys Gln 930 935 940Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile Thr Pro Val Lys Ser Lys945 950 955 960Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly Met Ser Pro Ile 965 970 975Thr Met Ala Thr Phe Ala Arg Ala Gln Thr Pro Glu Ser Cys Gly Ser 980 985 990Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu Ala Val Thr 995 1000 1005Gly Ser Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu Pro Thr 1010 1015 1020Glu Ile Ser Ala Lys His Ala Ile Phe Arg Val Ser Pro Asp Arg 1025 1030 1035Gln Ser Ser Trp Gln Phe Gln Arg Ser Asn Ser Asn Ser Ser Ser 1040 1045 1050Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile His Leu Gly Ser 1055 1060 1065Pro Tyr Met Gln Ala Val Ala Ser Pro Val Arg Pro Ala Ser Pro 1070 1075 1080Ser Ala Pro Leu Gln Asp Asn Arg Thr Gln Gly Leu Ile Asn Gly 1085 1090 1095Ala Leu Asn Lys Thr Thr Asn Lys Val Thr Ser Ser Ile Thr Ile 1100 1105 1110Thr Pro Thr Ala Thr Pro Leu Pro Arg Gln Ser Gln Ile Thr Val 1115 1120 1125Ser Asn Ile Tyr Asn 11301394653DNAHomo sapiens 139cccaaaccaa cttgtcccca tcaactccat ctttctagtc cccaccttcc ccggtgcaga 60cacccggcga agcccacccg gttttcccag cggcatttcc gatgacagct tcggggctac 120gtgtcctgtg ctgtcggaga cgcacaggaa gcaaagtttg tgagaagcct tgggggcgac 180tttgccttgg gcacccgcat ttgtgcgtct gcgaggtgcc tcggtgtgcg cggagctagt 240ttcccagttt cccgggcccc tcccttctcc gagcccctct agcgatttgt ttaggaaaag 300tgatgacatg aactagtagt ggagaatcgc agcgccgctc cccgccctgg ggagggaggg 360gagccccgga gagcctgccg gtgggagctg gaagcaggct cccggctgag cgccccagcc 420cgaaaggcag ggtctgggtg cgggaagagg gctcggagct gccttcctgc tgccttgggg 480ccgcccagat gagggaacag cccgatttgc ctggttctga ttctccaggc tgtcgtggtt 540gtggaatgca aacgccagca cataatggaa acaggacctg aagacccttc cagcatgcca 600gaggaaagtt cccccaggcg gaccccgcag agcattccct accaggacct ccctcacctg 660gtcaatgcag acggacagta cctcttctgc aggtactgga aacccacagg cacacccaag 720gccctcatct ttgtgtccca tggagccgga gagcacagtg gccgctatga agagctggct 780cggatgctga tggggctgga cctgctggtg ttcgcccacg accatgttgg ccacggacag 840agcgaagggg agaggatggt agtgtctgac ttccacgttt tcgtcaggga tgtgttgcag 900catgtggatt ccatgcagaa agactaccct gggcttcctg tcttccttct gggccactcc 960atgggaggcg ccatcgccat cctcacggcc gcagagaggc cgggccactt cgccggcatg 1020gtactcattt cgcctctggt tcttgccaat cctgaatctg caacaacttt caaggtcctt 1080gctgcgaaag tgctcaacct tgtgctgcca aacttgtccc tcgggcccat cgactccagc 1140gtgctctctc ggaataagac agaggtcgac atttataact cagaccccct gatctgccgg 1200gcagggctga aggtgtgctt cggcatccaa ctgctgaatg ccgtctcacg ggtggagcgc 1260gccctcccca agctgactgt gcccttcctg ctgctccagg gctctgccga tcgcctatgt 1320gacagcaaag gggcctacct gctcatggag ttagccaaga gccaggacaa gactctcaag 1380atttatgaag gtgcctacca tgttctccac aaggagcttc ctgaagtcac caactccgtc 1440ttccatgaaa taaacatgtg ggtctctcaa aggacagcca cggcaggaac tgcgtcccca 1500ccctgaatgc attggccggt gcccggctca tggtctgggg gatgcaggca ggggaagggc 1560agagatggct tctcagatat ggcttgccaa aaaaaaaaaa aaaaaaaaat cagaaattgg 1620agaaatcctt agcacaattt tctaaaaaat aacagacatt tttgttatac attagactat 1680cagacactgg acctacctta atggttagac actttatgca aaaaaagaga aaggtcccag 1740gtgattttcc acaaagaatg tgctaaaatg tccactgaaa acaaagccaa gcctctgccc 1800tgcctctccc agctcccaca agggttccag gaattcctgg tgttcccagg acaccagact 1860gcaataactg gaggcgcctc cttcctgccc acccttcgct cacgccccag cgccctctct 1920gaccagcctc cgcttggtgg ccttcctctg gccgtgtgat gaggtggttg ctgtctccat 1980aggggccagc tccccagggc agactcacgt gcccctctga ggctcagaaa atgcccagcc 2040cttcctcaaa atgagcagcc acccatgact ttgtgggctc cttgttagcc tgagaccagg 2100ctttgcagag gggcgggggg tgaggcttag cccagaagga gaactgagca ggaaaccaag 2160gctcttctct gtcccctgcc cttcccctcc tgccaggggg aggctcaggt tggtccccga 2220gtgccgcctg tactcacaaa ggctgccttt cctctagagt cactaatttt acctgatgct 2280atgagagaat catattgaag atgaaatgtc taatatataa tgtatatttt aaagcagaga 2340ctattttggt ggataggtgg gagggagcaa ggggagtttg agggaatcag agcttgatgc 2400tactgtacag aactggacag gttgggccgg cagtggtggg gccagagggc tctgtgctct 2460aggagctaag ccagcagccc ccgagagggg acttggctgg gcctttccta tgggcaaggc 2520ccagtgctct tcctgcccac cagggaccat ggagcagtgg caccctatgg ggctatgatc 2580cctaggcctg ggcctgggcc tgcctatggc ccagagctac cctgggagtg tcagtgctag 2640cagcacagct acctctggtg gcaggagaag agaggcccag cacagcagca ggccaggcct 2700tcctgtccag gtctgcatgg agcactcggt gacccagagc agggactgga ggcaccccca 2760gccctgcccc aggccacagc aggacaggcc gggacaggcc tcacccaagg ccaaggctgg 2820catcagccaa tcattcagag ctgaggccct gggcctagcc tgcccttctc aggtgccaat 2880accaccccag ccctgccctt ggcctcactt tttcccagca ataagtgggg ttcaccaccc 2940gcctcgggaa tactttcccc ttctaaatgg gacttgctgt tacctcagga ggctccttag 3000tgcaaatatg accctggtca gggctttgcc accgttgaag ccctgcagaa ggtgcaatgt 3060aggggttctg gggccacaga ggagaggcca cttcccacca ggacccccaa catgaagtct 3120aggcctcagg ggctcccgcc cttcttcctc cagcagcggg aactgccact gctctcccag 3180gccctgttct ggaggctaac cttggttcct ggagagtgtg cccctccacc ctccctccag 3240cagccctgat cacaccatga gagccaggaa cgggtcaccc tgctgaagat cactctgtgc 3300cctgggggag gagccaagcc ctcaccccac aaggggcagg tgggggcttg gttgctgacc 3360cggcccaagt ccccacagag caccttctgt agctccagct tgtctccctg gcttctcttt 3420gaaggagaaa aatgtaaaat atgcactgag aaagccagcc ccgcctgctt agtcagcccc 3480ggcagcaggg cagccatggg aactcaggaa aagcaggaac cctttccaaa agcccagaga 3540tgccctgggc tcagatctgt aattctccca ggagctgtga tagagcaggc cacacaaagt 3600ccctacgcct ccctgctgcc tcccccagat gcatgtggtg gcatcaccat tccccaaatt 3660gaatatcagc atgcggcctg accagggact ctttagatgc atgaatttat ttatatgaag 3720gctctcacag agacacacac agcacttcag tagcatttgc attcctggtt aaagaatcac 3780caatatttaa aataaaaact ttcctgaaat tgggactgtc atgttatcca gaagggctgg 3840tacatccgcc caccatgtcc ccctgctggg tcaggagcca acacaggacc ctgcgtgtga 3900gcgtgcctga catctcacgc acggccactc cagagccggt ccctgtcctt ggaaagctgt 3960gaagccttgc gttgagttcc ttctcgatac tgacggctcc gtgctgacat tctgagctct 4020ggagtcacac cagcgcaggg gcgtggagga actgaggttt ggaaggaatg ccaggtctcg 4080cacagcttgg cctcgagaag

gtgagaggaa ggcaaaggcc agggagggga cccagagagg 4140cctggcacac aaggcccaag caccaccgtc aacacagccc agtccataca gaaatgggtt 4200tcatgcctga aaagcttttt acagaaagat gccgcctgta gccagtgaca gccgcaaccc 4260tacaggcctc agttccttgc agaggtgagg ggtagagagt cagcctccct cccttccagc 4320agcgacccag cttccctcca cttccaggtg gtgctgggct caccgaggga gcactggtgg 4380gtgctctgaa aacccacagg atcccacctc caggcccacc tgggtcccat ctcactctct 4440tcttctttca ccaattgcta acatagacct tgttgggatc acgatggctt cacaagccag 4500ctgttgggtt tgctatgtca ctgtggctca gtcacatccc tgcgtgtata ctgtctgcgg 4560ggcacatatg tatccattta gagctaaagg aatcagtgta cactacagct aatcctaata 4620aatccgatgt tttcggaatg gcaaaaaaaa aaa 46531404246DNAHomo sapiens 140acctcgggcc gcccccgccg ccgagccggc ccagggataa agtggcggcg cagacgccgc 60accctgtcgc cgcgaagccg gtcgcgcgca gctcgtcccg gccctggccc gccgcaaacg 120aggatccgct gcgctcgggg aacgcgacag cggcgctcgt ggccccggac ctgaagaccc 180ttccagcatg ccagaggaaa gttcccccag gcggaccccg cagagcattc cctaccagga 240cctccctcac ctggtcaatg cagacggaca gtacctcttc tgcaggtact ggaaacccac 300aggcacaccc aaggccctca tctttgtgtc ccatggagcc ggagagcaca gtggccgcta 360tgaagagctg gctcggatgc tgatggggct ggacctgctg gtgttcgccc acgaccatgt 420tggccacgga cagagcgaag gggagaggat ggtagtgtct gacttccacg ttttcgtcag 480ggatgtgttg cagcatgtgg attccatgca gaaagactac cctgggcttc ctgtcttcct 540tctgggccac tccatgggag gcgccatcgc catcctcacg gccgcagaga ggccgggcca 600cttcgccggc atggtactca tttcgcctct ggttcttgcc aatcctgaat ctgcaacaac 660tttcaaggtc cttgctgcga aagtgctcaa ccttgtgctg ccaaacttgt ccctcgggcc 720catcgactcc agcgtgctct ctcggaataa gacagaggtc gacatttata actcagaccc 780cctgatctgc cgggcagggc tgaaggtgtg cttcggcatc caactgctga atgccgtctc 840acgggtggag cgcgccctcc ccaagctgac tgtgcccttc ctgctgctcc agggctctgc 900cgatcgccta tgtgacagca aaggggccta cctgctcatg gagttagcca agagccagga 960caagactctc aagatttatg aaggtgccta ccatgttctc cacaaggagc ttcctgaagt 1020caccaactcc gtcttccatg aaataaacat gtgggtctct caaaggacag ccacggcagg 1080aactgcgtcc ccaccctgaa tgcattggcc ggtgcccggc tcatggtctg ggggatgcag 1140gcaggggaag ggcagagatg gcttctcaga tatggcttgc caaaaaaaaa aaaaaaaaaa 1200aatcagaaat tggagaaatc cttagcacaa ttttctaaaa aataacagac atttttgtta 1260tacattagac tatcagacac tggacctacc ttaatggtta gacactttat gcaaaaaaag 1320agaaaggtcc caggtgattt tccacaaaga atgtgctaaa atgtccactg aaaacaaagc 1380caagcctctg ccctgcctct cccagctccc acaagggttc caggaattcc tggtgttccc 1440aggacaccag actgcaataa ctggaggcgc ctccttcctg cccacccttc gctcacgccc 1500cagcgccctc tctgaccagc ctccgcttgg tggccttcct ctggccgtgt gatgaggtgg 1560ttgctgtctc cataggggcc agctccccag ggcagactca cgtgcccctc tgaggctcag 1620aaaatgccca gcccttcctc aaaatgagca gccacccatg actttgtggg ctccttgtta 1680gcctgagacc aggctttgca gaggggcggg gggtgaggct tagcccagaa ggagaactga 1740gcaggaaacc aaggctcttc tctgtcccct gcccttcccc tcctgccagg gggaggctca 1800ggttggtccc cgagtgccgc ctgtactcac aaaggctgcc tttcctctag agtcactaat 1860tttacctgat gctatgagag aatcatattg aagatgaaat gtctaatata taatgtatat 1920tttaaagcag agactatttt ggtggatagg tgggagggag caaggggagt ttgagggaat 1980cagagcttga tgctactgta cagaactgga caggttgggc cggcagtggt ggggccagag 2040ggctctgtgc tctaggagct aagccagcag cccccgagag gggacttggc tgggcctttc 2100ctatgggcaa ggcccagtgc tcttcctgcc caccagggac catggagcag tggcacccta 2160tggggctatg atccctaggc ctgggcctgg gcctgcctat ggcccagagc taccctggga 2220gtgtcagtgc tagcagcaca gctacctctg gtggcaggag aagagaggcc cagcacagca 2280gcaggccagg ccttcctgtc caggtctgca tggagcactc ggtgacccag agcagggact 2340ggaggcaccc ccagccctgc cccaggccac agcaggacag gccgggacag gcctcaccca 2400aggccaaggc tggcatcagc caatcattca gagctgaggc cctgggccta gcctgccctt 2460ctcaggtgcc aataccaccc cagccctgcc cttggcctca ctttttccca gcaataagtg 2520gggttcacca cccgcctcgg gaatactttc cccttctaaa tgggacttgc tgttacctca 2580ggaggctcct tagtgcaaat atgaccctgg tcagggcttt gccaccgttg aagccctgca 2640gaaggtgcaa tgtaggggtt ctggggccac agaggagagg ccacttccca ccaggacccc 2700caacatgaag tctaggcctc aggggctccc gcccttcttc ctccagcagc gggaactgcc 2760actgctctcc caggccctgt tctggaggct aaccttggtt cctggagagt gtgcccctcc 2820accctccctc cagcagccct gatcacacca tgagagccag gaacgggtca ccctgctgaa 2880gatcactctg tgccctgggg gaggagccaa gccctcaccc cacaaggggc aggtgggggc 2940ttggttgctg acccggccca agtccccaca gagcaccttc tgtagctcca gcttgtctcc 3000ctggcttctc tttgaaggag aaaaatgtaa aatatgcact gagaaagcca gccccgcctg 3060cttagtcagc cccggcagca gggcagccat gggaactcag gaaaagcagg aaccctttcc 3120aaaagcccag agatgccctg ggctcagatc tgtaattctc ccaggagctg tgatagagca 3180ggccacacaa agtccctacg cctccctgct gcctccccca gatgcatgtg gtggcatcac 3240cattccccaa attgaatatc agcatgcggc ctgaccaggg actctttaga tgcatgaatt 3300tatttatatg aaggctctca cagagacaca cacagcactt cagtagcatt tgcattcctg 3360gttaaagaat caccaatatt taaaataaaa actttcctga aattgggact gtcatgttat 3420ccagaagggc tggtacatcc gcccaccatg tccccctgct gggtcaggag ccaacacagg 3480accctgcgtg tgagcgtgcc tgacatctca cgcacggcca ctccagagcc ggtccctgtc 3540cttggaaagc tgtgaagcct tgcgttgagt tccttctcga tactgacggc tccgtgctga 3600cattctgagc tctggagtca caccagcgca ggggcgtgga ggaactgagg tttggaagga 3660atgccaggtc tcgcacagct tggcctcgag aaggtgagag gaaggcaaag gccagggagg 3720ggacccagag aggcctggca cacaaggccc aagcaccacc gtcaacacag cccagtccat 3780acagaaatgg gtttcatgcc tgaaaagctt tttacagaaa gatgccgcct gtagccagtg 3840acagccgcaa ccctacaggc ctcagttcct tgcagaggtg aggggtagag agtcagcctc 3900cctcccttcc agcagcgacc cagcttccct ccacttccag gtggtgctgg gctcaccgag 3960ggagcactgg tgggtgctct gaaaacccac aggatcccac ctccaggccc acctgggtcc 4020catctcactc tcttcttctt tcaccaattg ctaacataga ccttgttggg atcacgatgg 4080cttcacaagc cagctgttgg gtttgctatg tcactgtggc tcagtcacat ccctgcgtgt 4140atactgtctg cggggcacat atgtatccat ttagagctaa aggaatcagt gtacactaca 4200gctaatccta ataaatccga tgttttcgga atggcaaaaa aaaaaa 42461414563DNAHomo sapiens 141cccaaaccaa cttgtcccca tcaactccat ctttctagtc cccaccttcc ccggtgcaga 60cacccggcga agcccacccg gttttcccag cggcatttcc gatgacagct tcggggctac 120gtgtcctgtg ctgtcggaga cgcacaggaa gcaaagtttg tgagaagcct tgggggcgac 180tttgccttgg gcacccgcat ttgtgcgtct gcgaggtgcc tcggtgtgcg cggagctagt 240ttcccagttt cccgggcccc tcccttctcc gagcccctct agcgatttgt ttaggaaaag 300tgatgacatg aactagtagt ggagaatcgc agcgccgctc cccgccctgg ggagggaggg 360gagccccgga gagcctgccg gtgggagctg gaagcaggct cccggctgag cgccccagcc 420cgaaaggcag ggtctgggtg cgggaagagg gctcggagct gccttcctgc tgccttgggg 480ccgcccagat gagggaacag cccgatttgc ctggttctga ttctccaggc tgtcgtggtt 540gtggaatgca aacgccagca cataatggaa acaggacctg aagacccttc cagcatgcca 600gaggaaagtt cccccaggcg gaccccgcag agcattccct accaggacct ccctcacctg 660gtcaatgcag acggacagta cctcttctgc aggtactgga aacccacagg cacacccaag 720gccctcatct ttgtgtccca tggagccgga gagcacagtg gccgctatga agagctggct 780cggatgctga tggggctgga cctgctggtg ttcgcccacg accatgttgg ccacggacag 840agcgaagggg agaggatggt agtgtctgac ttccacgttt tcgtcaggga tgtgttgcag 900catgtggatt ccatgcagaa agactaccct gggcttcctg tcttccttct gggccactcc 960atgggaggcg ccatcgccat cctcacggcc gcagagaggc cgggccactt cgccggcatg 1020gtactcattt cgcctctggt tcttgccaat cctgaatctg caacaacttt caaggtcgac 1080atttataact cagaccccct gatctgccgg gcagggctga aggtgtgctt cggcatccaa 1140ctgctgaatg ccgtctcacg ggtggagcgc gccctcccca agctgactgt gcccttcctg 1200ctgctccagg gctctgccga tcgcctatgt gacagcaaag gggcctacct gctcatggag 1260ttagccaaga gccaggacaa gactctcaag atttatgaag gtgcctacca tgttctccac 1320aaggagcttc ctgaagtcac caactccgtc ttccatgaaa taaacatgtg ggtctctcaa 1380aggacagcca cggcaggaac tgcgtcccca ccctgaatgc attggccggt gcccggctca 1440tggtctgggg gatgcaggca ggggaagggc agagatggct tctcagatat ggcttgccaa 1500aaaaaaaaaa aaaaaaaaat cagaaattgg agaaatcctt agcacaattt tctaaaaaat 1560aacagacatt tttgttatac attagactat cagacactgg acctacctta atggttagac 1620actttatgca aaaaaagaga aaggtcccag gtgattttcc acaaagaatg tgctaaaatg 1680tccactgaaa acaaagccaa gcctctgccc tgcctctccc agctcccaca agggttccag 1740gaattcctgg tgttcccagg acaccagact gcaataactg gaggcgcctc cttcctgccc 1800acccttcgct cacgccccag cgccctctct gaccagcctc cgcttggtgg ccttcctctg 1860gccgtgtgat gaggtggttg ctgtctccat aggggccagc tccccagggc agactcacgt 1920gcccctctga ggctcagaaa atgcccagcc cttcctcaaa atgagcagcc acccatgact 1980ttgtgggctc cttgttagcc tgagaccagg ctttgcagag gggcgggggg tgaggcttag 2040cccagaagga gaactgagca ggaaaccaag gctcttctct gtcccctgcc cttcccctcc 2100tgccaggggg aggctcaggt tggtccccga gtgccgcctg tactcacaaa ggctgccttt 2160cctctagagt cactaatttt acctgatgct atgagagaat catattgaag atgaaatgtc 2220taatatataa tgtatatttt aaagcagaga ctattttggt ggataggtgg gagggagcaa 2280ggggagtttg agggaatcag agcttgatgc tactgtacag aactggacag gttgggccgg 2340cagtggtggg gccagagggc tctgtgctct aggagctaag ccagcagccc ccgagagggg 2400acttggctgg gcctttccta tgggcaaggc ccagtgctct tcctgcccac cagggaccat 2460ggagcagtgg caccctatgg ggctatgatc cctaggcctg ggcctgggcc tgcctatggc 2520ccagagctac cctgggagtg tcagtgctag cagcacagct acctctggtg gcaggagaag 2580agaggcccag cacagcagca ggccaggcct tcctgtccag gtctgcatgg agcactcggt 2640gacccagagc agggactgga ggcaccccca gccctgcccc aggccacagc aggacaggcc 2700gggacaggcc tcacccaagg ccaaggctgg catcagccaa tcattcagag ctgaggccct 2760gggcctagcc tgcccttctc aggtgccaat accaccccag ccctgccctt ggcctcactt 2820tttcccagca ataagtgggg ttcaccaccc gcctcgggaa tactttcccc ttctaaatgg 2880gacttgctgt tacctcagga ggctccttag tgcaaatatg accctggtca gggctttgcc 2940accgttgaag ccctgcagaa ggtgcaatgt aggggttctg gggccacaga ggagaggcca 3000cttcccacca ggacccccaa catgaagtct aggcctcagg ggctcccgcc cttcttcctc 3060cagcagcggg aactgccact gctctcccag gccctgttct ggaggctaac cttggttcct 3120ggagagtgtg cccctccacc ctccctccag cagccctgat cacaccatga gagccaggaa 3180cgggtcaccc tgctgaagat cactctgtgc cctgggggag gagccaagcc ctcaccccac 3240aaggggcagg tgggggcttg gttgctgacc cggcccaagt ccccacagag caccttctgt 3300agctccagct tgtctccctg gcttctcttt gaaggagaaa aatgtaaaat atgcactgag 3360aaagccagcc ccgcctgctt agtcagcccc ggcagcaggg cagccatggg aactcaggaa 3420aagcaggaac cctttccaaa agcccagaga tgccctgggc tcagatctgt aattctccca 3480ggagctgtga tagagcaggc cacacaaagt ccctacgcct ccctgctgcc tcccccagat 3540gcatgtggtg gcatcaccat tccccaaatt gaatatcagc atgcggcctg accagggact 3600ctttagatgc atgaatttat ttatatgaag gctctcacag agacacacac agcacttcag 3660tagcatttgc attcctggtt aaagaatcac caatatttaa aataaaaact ttcctgaaat 3720tgggactgtc atgttatcca gaagggctgg tacatccgcc caccatgtcc ccctgctggg 3780tcaggagcca acacaggacc ctgcgtgtga gcgtgcctga catctcacgc acggccactc 3840cagagccggt ccctgtcctt ggaaagctgt gaagccttgc gttgagttcc ttctcgatac 3900tgacggctcc gtgctgacat tctgagctct ggagtcacac cagcgcaggg gcgtggagga 3960actgaggttt ggaaggaatg ccaggtctcg cacagcttgg cctcgagaag gtgagaggaa 4020ggcaaaggcc agggagggga cccagagagg cctggcacac aaggcccaag caccaccgtc 4080aacacagccc agtccataca gaaatgggtt tcatgcctga aaagcttttt acagaaagat 4140gccgcctgta gccagtgaca gccgcaaccc tacaggcctc agttccttgc agaggtgagg 4200ggtagagagt cagcctccct cccttccagc agcgacccag cttccctcca cttccaggtg 4260gtgctgggct caccgaggga gcactggtgg gtgctctgaa aacccacagg atcccacctc 4320caggcccacc tgggtcccat ctcactctct tcttctttca ccaattgcta acatagacct 4380tgttgggatc acgatggctt cacaagccag ctgttgggtt tgctatgtca ctgtggctca 4440gtcacatccc tgcgtgtata ctgtctgcgg ggcacatatg tatccattta gagctaaagg 4500aatcagtgta cactacagct aatcctaata aatccgatgt tttcggaatg gcaaaaaaaa 4560aaa 4563142313PRTHomo sapiens 142Met Glu Thr Gly Pro Glu Asp Pro Ser Ser Met Pro Glu Glu Ser Ser1 5 10 15Pro Arg Arg Thr Pro Gln Ser Ile Pro Tyr Gln Asp Leu Pro His Leu 20 25 30Val Asn Ala Asp Gly Gln Tyr Leu Phe Cys Arg Tyr Trp Lys Pro Thr 35 40 45Gly Thr Pro Lys Ala Leu Ile Phe Val Ser His Gly Ala Gly Glu His 50 55 60Ser Gly Arg Tyr Glu Glu Leu Ala Arg Met Leu Met Gly Leu Asp Leu65 70 75 80Leu Val Phe Ala His Asp His Val Gly His Gly Gln Ser Glu Gly Glu 85 90 95Arg Met Val Val Ser Asp Phe His Val Phe Val Arg Asp Val Leu Gln 100 105 110His Val Asp Ser Met Gln Lys Asp Tyr Pro Gly Leu Pro Val Phe Leu 115 120 125Leu Gly His Ser Met Gly Gly Ala Ile Ala Ile Leu Thr Ala Ala Glu 130 135 140Arg Pro Gly His Phe Ala Gly Met Val Leu Ile Ser Pro Leu Val Leu145 150 155 160Ala Asn Pro Glu Ser Ala Thr Thr Phe Lys Val Leu Ala Ala Lys Val 165 170 175Leu Asn Leu Val Leu Pro Asn Leu Ser Leu Gly Pro Ile Asp Ser Ser 180 185 190Val Leu Ser Arg Asn Lys Thr Glu Val Asp Ile Tyr Asn Ser Asp Pro 195 200 205Leu Ile Cys Arg Ala Gly Leu Lys Val Cys Phe Gly Ile Gln Leu Leu 210 215 220Asn Ala Val Ser Arg Val Glu Arg Ala Leu Pro Lys Leu Thr Val Pro225 230 235 240Phe Leu Leu Leu Gln Gly Ser Ala Asp Arg Leu Cys Asp Ser Lys Gly 245 250 255Ala Tyr Leu Leu Met Glu Leu Ala Lys Ser Gln Asp Lys Thr Leu Lys 260 265 270Ile Tyr Glu Gly Ala Tyr His Val Leu His Lys Glu Leu Pro Glu Val 275 280 285Thr Asn Ser Val Phe His Glu Ile Asn Met Trp Val Ser Gln Arg Thr 290 295 300Ala Thr Ala Gly Thr Ala Ser Pro Pro305 310143303PRTHomo sapiens 143Met Pro Glu Glu Ser Ser Pro Arg Arg Thr Pro Gln Ser Ile Pro Tyr1 5 10 15Gln Asp Leu Pro His Leu Val Asn Ala Asp Gly Gln Tyr Leu Phe Cys 20 25 30Arg Tyr Trp Lys Pro Thr Gly Thr Pro Lys Ala Leu Ile Phe Val Ser 35 40 45His Gly Ala Gly Glu His Ser Gly Arg Tyr Glu Glu Leu Ala Arg Met 50 55 60Leu Met Gly Leu Asp Leu Leu Val Phe Ala His Asp His Val Gly His65 70 75 80Gly Gln Ser Glu Gly Glu Arg Met Val Val Ser Asp Phe His Val Phe 85 90 95Val Arg Asp Val Leu Gln His Val Asp Ser Met Gln Lys Asp Tyr Pro 100 105 110Gly Leu Pro Val Phe Leu Leu Gly His Ser Met Gly Gly Ala Ile Ala 115 120 125Ile Leu Thr Ala Ala Glu Arg Pro Gly His Phe Ala Gly Met Val Leu 130 135 140Ile Ser Pro Leu Val Leu Ala Asn Pro Glu Ser Ala Thr Thr Phe Lys145 150 155 160Val Leu Ala Ala Lys Val Leu Asn Leu Val Leu Pro Asn Leu Ser Leu 165 170 175Gly Pro Ile Asp Ser Ser Val Leu Ser Arg Asn Lys Thr Glu Val Asp 180 185 190Ile Tyr Asn Ser Asp Pro Leu Ile Cys Arg Ala Gly Leu Lys Val Cys 195 200 205Phe Gly Ile Gln Leu Leu Asn Ala Val Ser Arg Val Glu Arg Ala Leu 210 215 220Pro Lys Leu Thr Val Pro Phe Leu Leu Leu Gln Gly Ser Ala Asp Arg225 230 235 240Leu Cys Asp Ser Lys Gly Ala Tyr Leu Leu Met Glu Leu Ala Lys Ser 245 250 255Gln Asp Lys Thr Leu Lys Ile Tyr Glu Gly Ala Tyr His Val Leu His 260 265 270Lys Glu Leu Pro Glu Val Thr Asn Ser Val Phe His Glu Ile Asn Met 275 280 285Trp Val Ser Gln Arg Thr Ala Thr Ala Gly Thr Ala Ser Pro Pro 290 295 300144283PRTHomo sapiens 144Met Glu Thr Gly Pro Glu Asp Pro Ser Ser Met Pro Glu Glu Ser Ser1 5 10 15Pro Arg Arg Thr Pro Gln Ser Ile Pro Tyr Gln Asp Leu Pro His Leu 20 25 30Val Asn Ala Asp Gly Gln Tyr Leu Phe Cys Arg Tyr Trp Lys Pro Thr 35 40 45Gly Thr Pro Lys Ala Leu Ile Phe Val Ser His Gly Ala Gly Glu His 50 55 60Ser Gly Arg Tyr Glu Glu Leu Ala Arg Met Leu Met Gly Leu Asp Leu65 70 75 80Leu Val Phe Ala His Asp His Val Gly His Gly Gln Ser Glu Gly Glu 85 90 95Arg Met Val Val Ser Asp Phe His Val Phe Val Arg Asp Val Leu Gln 100 105 110His Val Asp Ser Met Gln Lys Asp Tyr Pro Gly Leu Pro Val Phe Leu 115 120 125Leu Gly His Ser Met Gly Gly Ala Ile Ala Ile Leu Thr Ala Ala Glu 130 135 140Arg Pro Gly His Phe Ala Gly Met Val Leu Ile Ser Pro Leu Val Leu145 150 155 160Ala Asn Pro Glu Ser Ala Thr Thr Phe Lys Val Asp Ile Tyr Asn Ser 165 170 175Asp Pro Leu Ile Cys Arg Ala Gly Leu Lys Val Cys Phe Gly Ile Gln 180 185 190Leu Leu Asn Ala Val Ser Arg Val Glu Arg Ala Leu Pro Lys Leu Thr 195 200 205Val Pro Phe Leu Leu Leu Gln Gly Ser Ala Asp Arg Leu Cys Asp Ser 210 215 220Lys Gly Ala Tyr Leu Leu Met Glu Leu Ala Lys Ser Gln Asp Lys Thr225 230 235 240Leu Lys Ile Tyr Glu Gly Ala Tyr His Val Leu His Lys Glu Leu Pro 245 250 255Glu Val Thr Asn Ser Val Phe His Glu Ile Asn Met Trp Val Ser Gln 260 265 270Arg Thr Ala Thr Ala Gly Thr Ala Ser Pro Pro 275 2801455556DNAHomo sapiens 145gcgcttgccc cgcagctgat tcatagcccc ggcccgggcc

gcctctgcac gtccgccccg 60gagcccgcac ccgcgcccca cgcgccgccg aggactcggc ccggctcgtg gagcccttcg 120cccgcggcgt gagtaccccc gacccgcccg tccccgctct gctcgcgccc tgccgctgcg 180ccgccctcgg tggcttttcc gacgggcgag ccccgtgctg tgcgggaaag aatccgacaa 240cttcgcagcc catcccggct ggacgcgacc gggagtgcag cagcccgttc ccctcctcgg 300tgccgcctct gcccagcgtt tgcttggctg ggctaccacc tgcgctcgga cggcgctcgg 360agggtcctcg cccccggcct gcctacctga aaaccagaac tgatggctct atttgcagtc 420tttcagacaa cattcttctt aacattgctg tccttgagga cttaccagag tgaagtcttg 480gctgaacgtt taccattgac tcctgtatca cttaaagttt ccaccaattc tacgcgtcag 540agtttgcact tacaatggac tgtccacaac cttccttatc atcaggaatt gaaaatggta 600tttcagatcc agatcagtag gattgaaaca tccaatgtca tctgggtggg gaattacagc 660accactgtga agtggaacca ggttctgcat tggagctggg aatctgagct ccctttggaa 720tgtgccacac actttgtaag aataaagagt ttggtggacg atgccaagtt ccctgagcca 780aatttctgga gcaactggag ttcctgggag gaagtcagtg tacaagattc tactggacag 840gatatattgt tcgttttccc taaagataag ctggtggaag aaggcaccaa tgttaccatt 900tgttacgttt ctaggaacat tcaaaataat gtatcctgtt atttggaagg gaaacagatt 960catggagaac aacttgatcc acatgtaact gcattcaact tgaatagtgt gcctttcatt 1020aggaataaag ggacaaatat ctattgtgag gcaagtcaag gaaatgtcag tgaaggcatg 1080aaaggcatcg ttctttttgt ctcaaaagta cttgaggagc ccaaggactt ttcttgtgaa 1140accgaggact tcaagacttt gcactgtact tgggatcctg ggacggacac tgccttgggg 1200tggtctaaac aaccttccca aagctacact ttatttgaat cattttctgg ggaaaagaaa 1260ctttgtacac acaaaaactg gtgtaattgg caaataactc aagactcaca agaaacctat 1320aacttcacac tcatagctga aaattactta aggaagagaa gtgtcaatat cctttttaac 1380ctgactcatc gagtttattt aatgaatcct tttagtgtca actttgaaaa tgtaaatgcc 1440acaaatgcca tcatgacctg gaaggtgcac tccataagga ataatttcac atatttgtgt 1500cagattgaac tccatggtga aggaaaaatg atgcaataca atgtttccat caaggtgaac 1560ggtgagtact tcttaagtga actggaacct gccacagagt acatggcgcg agtacggtgt 1620gctgatgcca gccacttctg gaaatggagt gaatggagtg gtcagaactt caccacactt 1680gaagctgctc cctcagaggc ccctgatgtc tggagaattg tgagcttgga gccaggaaat 1740catactgtga ccttattctg gaagccatta tcaaaactgc atgccaatgg aaagatcctg 1800ttctataatg tagttgtaga aaacctagac aaaccatcca gttcagagct ccattccatt 1860ccagcaccag ccaacagcac aaaactaatc cttgacaggt gttcctacca aatctgcgtc 1920atagccaaca acagtgtggg tgcttctcct gcttctgtaa tagtcatctc tgcagacccc 1980gaaaacaaag aggttgagga agaaagaatt gcaggcacag agggtggatt ctctctgtct 2040tggaaacccc aacctggaga tgttataggc tatgttgtgg actggtgtga ccatacccag 2100gatgtgctcg gtgatttcca gtggaagaat gtaggtccca ataccacaag cacagtcatt 2160agcacagatg cttttaggcc aggagttcga tatgacttca gaatttatgg gttatctaca 2220aaaaggattg cttgtttatt agagaaaaaa acaggatact ctcaggaact tgctccttca 2280gacaaccctc acgtgctggt ggatacattg acatcccact ccttcactct gagttggaaa 2340gattactcta ctgaatctca acctggtttt atacaagggt accatgtcta tctgaaatcc 2400aaggcgaggc agtgccaccc acgatttgaa aaggcagttc tttcagatgg ttcagaatgt 2460tgcaaataca aaattgacaa cccggaagaa aaggcattga ttgtggacaa cctaaagcca 2520gaatccttct atgagttttt catcactcca ttcactagtg ctggtgaagg ccccagtgct 2580acgttcacga aggtcacgac tccggatgaa cactcctcga tgctgattca tatcctactg 2640cccatggttt tctgcgtctt gctcatcatg gtcatgtgct acttgaaaag tcagtggatc 2700aaggagacct gttatcctga catccctgac ccttacaaga gcagcatcct gtcattaata 2760aaattcaagg agaaccctca cctaataata atgaatgtca gtgactgtat cccagatgct 2820attgaagttg taagcaagcc agaagggaca aagatacagt tcctaggcac taggaagtca 2880ctcacagaaa ccgagttgac taagcctaac tacctttatc tccttccaac agaaaagaat 2940cactctggcc ctggcccctg catctgtttt gagaacttga cctataacca ggcagcttct 3000gactctggct cttgtggcca tgttccagta tccccaaaag ccccaagtat gctgggacta 3060atgacctcac ctgaaaatgt actaaaggca ctagaaaaaa actacatgaa ctccctggga 3120gaaatcccag ctggagaaac aagtttgaat tatgtgtccc agttggcttc acccatgttt 3180ggagacaagg acagtctccc aacaaaccca gtagaggcac cacactgttc agagtataaa 3240atgcaaatgg cagtctccct gcgtcttgcc ttgcctcccc cgaccgagaa tagcagcctc 3300tcctcaatta cccttttaga tccaggtgaa cactactgct aaccagcatg ccgatttcat 3360accttatgct acacagacat taagaagagc agagctggca ccctgtcatc accagtggcc 3420ttggtcctta atcccagtac gatttgcagg tctggtttat ataagaccac tacagtctgg 3480ctaggttaaa ggccagaggc tatggaactt aacactcccc attggagcaa gcttgcccta 3540gagacggcag gatcatggga gcatgcttac cttctgctgt ttgttccagg ctcaccttta 3600gaacaggaga cttgagcttg acctaaggat atgcattaac cactctacag actcccactc 3660agtactgtac agggtggctg tggtcctaga agttcagttt ttactgagga aatatttcca 3720ttaacagcaa ttattatatt gaaggcttta ataaaggcca caggagacat tactatagca 3780tagattgtca aatgtaaatt tactgagcgt gttttataaa aaactcacag gtgtttgagg 3840ccaaaacaga ttttagactt accttgaacg gataagaatc tatagttcac tgacacagta 3900aaattaactc tgtgggtggg ggcggggggc atagctctaa tctaatatat aaaatgtgtg 3960atgaatcaac aagatttcca caattcttct gtcaagctta ctacagtgaa agaatgggat 4020tggcaagtaa cttctgactt actgtcagtt gtacttctgc tccatagaca tcagtattct 4080gccatcattt ttgatgacta cctcagaaca taaaaaggaa cgtatatcac ataattccag 4140tcacagtttt tggttcctct tttctttcaa gaactatata taaatgacct gttttcactt 4200agcatccttt ggactctgca gtaggttgtc tgggtcaaga taactctcag tcacatttat 4260attcatatta tgctaaaata gtaaaatgaa acctcattgt tggacataat ttagatataa 4320ctaaaaagtt ctatgaagtg ggaaattccg tgttggctct ggagcagctt tgtctcctct 4380gaaccaatat atcccaaacc aatatatgca aagcacctgg tacacaactg gtattttagt 4440acatgttggt tcttttggtg caatctcagc tcactgcagc ttccgcctcc tagattcaaa 4500caaacagttc tcctgcccca gcctccagag cacctaggac tccaggtgca tgctaccaca 4560cctgactagt ttttatattt ttagtagaga ttgggtttta ccatattggc caggctggtc 4620tcaaactcct gaccgcaggt gatccacctg cctcagcttc cccaagggct gggattacag 4680gtgtgagcca ccatgcccag cctatttgtc acattatttg tcacatttat tttactttta 4740tttatttttt gagatgaaat ttcgctcttg ttgcccaggc tggagtgcaa tggtgcagcc 4800ttggctcact gcaacctccg cctcccaggg tcaagcaatt ctcctgcctc agcctcctga 4860gtagctggga ttacaggcat gcaccaccac acccaggtaa ttttgtatct ttagtagaga 4920tggggtttca ccatgttggt caggctgttc tcgaactcct gacctcaggt gatctgcctg 4980ccttggcctc ccaaagtgct gggattacag gcgtgagcca ctgcgcctag ccgtcacatt 5040tctaaacaag catgaaaggg gttcattttt gtcttcttct tgcctgccgt cagcatggtg 5100gaaatggctc tgcctatgct catgcttctg gtgcccaatg ccttgcactg tgccattcaa 5160cactatgaag agaaacaagt agccacacct caaaataatg tggctgtcaa caactggcct 5220aaataaacct acacaaacca gtacttgcct tttgctggaa acattgatta tgtgctcctc 5280acgtagtaga aagcggtatc ctgattagtc taacagttgt gttagacttt agggccagta 5340ttgtcagcat ttatttattt atgtaccttt gttatgatgg gatatttttc atttgaaact 5400tgttcataaa aatgtcaatg acattgatga ctgatttgta catatttttc atatagtttt 5460gtttaaaaaa taattcacgc aaaatcttga agtcattttt gctattgaaa taaaccttaa 5520ttaaaatatt tcatcatcaa aaaaaaaaaa aaaaaa 55561461765DNAHomo sapiens 146gcggccgcct ccccccggga ctgaagggag ggaattcctg tgggtcccag gagtgccaag 60agtgcgcagc aagacgggaa attgcaaaag acctcacccc tctgccctcc cccgcggttt 120tccagtaact cccgcccctc cgcgcttgcc ccgcagctga ttcatagccc cggcccgggc 180cgcctctgca cgtccgcccc ggagcccgca cccgcgcccc acgcgccgcc gaggactcgg 240cccggctcgt ggagcccttc gcccgcggca aaaccagaac tgatggctct atttgcagtc 300tttcagacaa cattcttctt aacattgctg tccttgagga cttaccagag tgaagtcttg 360gctgaacgtt taccattgac tcctgtatca cttaaagttt ccaccaattc tacgcgtcag 420agtttgcact tacaatggac tgtccacaac cttccttatc atcaggaatt gaaaatggta 480tttcagatcc agatcagtag gattgaaaca tccaatgtca tctgggtggg gaattacagc 540accactgtga agtggaacca ggttctgcat tggagctggg aatctgagct ccctttggaa 600tgtgccacac actttgtaag aataaagagt ttggtggacg atgccaagtt ccctgagcca 660aatttctgga gcaactggag ttcctgggag gaagtcagtg tacaagattc tactggacag 720gatatattgt tcgttttccc taaagataag ctggtggaag aaggcaccaa tgttaccatt 780tgttacgttt ctaggaacat tcaaaataat gtatcctgtt atttggaagg gaaacagatt 840catggagaac aacttgatcc acatgtaact gcattcaact tgaatagtgt gcctttcatt 900aggaataaag ggacaaatat ctattgtgag gcaagtcaag gaaatgtcag tgaaggcatg 960aaaggcatcg ttctttttgt ctcaaaagta cttgaggagc ccaaggactt ttcttgtgaa 1020accgaggact tcaagacttt gcactgtact tgggatcctg ggacggacac tgccttgggg 1080tggtctaaac aaccttccca aagctacact ttatttgaat cattttctgg ggaaaagaaa 1140ctttgtacac acaaaaactg gtgtaattgg caaataactc aagactcaca agaaacctat 1200aacttcacac tcatagctga aaattactta aggaagagaa gtgtcaatat cctttttaac 1260ctgactcatc gaggtgagac tagagttgtc acagcccacc gtggccacta acgtgtcttt 1320gtttcacaga ctgtgtgatc aagtaaatgt gctgtagatc tttgcctcat tcacagcgga 1380ggtgagagtt agaatttata cctattgttc atgccacgtt tctcctcatg gatgcacgca 1440tcccctatta tttgtttctt ttaataatgt cacgagcacc aatgagctta ctacccaact 1500tcaaaactag gactctaaca ataacttctg tcatatctca tcctgtaacg cccccacctt 1560cgctccttcc gccaagataa ttatcacttt aaattgtgtg cgtgtgtatt ctcatttctt 1620atgtgatggt aaaaatgcct ttattttgtt tggttttaat gcatagaaag gacatcaagc 1680tgtatgtaat aattcagtaa ttatgtttat ataatattaa attgctaata tttgcccata 1740aaaaaaaaaa aaaaaaaaaa aaaaa 1765147979PRTHomo sapiens 147Met Ala Leu Phe Ala Val Phe Gln Thr Thr Phe Phe Leu Thr Leu Leu1 5 10 15Ser Leu Arg Thr Tyr Gln Ser Glu Val Leu Ala Glu Arg Leu Pro Leu 20 25 30Thr Pro Val Ser Leu Lys Val Ser Thr Asn Ser Thr Arg Gln Ser Leu 35 40 45His Leu Gln Trp Thr Val His Asn Leu Pro Tyr His Gln Glu Leu Lys 50 55 60Met Val Phe Gln Ile Gln Ile Ser Arg Ile Glu Thr Ser Asn Val Ile65 70 75 80Trp Val Gly Asn Tyr Ser Thr Thr Val Lys Trp Asn Gln Val Leu His 85 90 95Trp Ser Trp Glu Ser Glu Leu Pro Leu Glu Cys Ala Thr His Phe Val 100 105 110Arg Ile Lys Ser Leu Val Asp Asp Ala Lys Phe Pro Glu Pro Asn Phe 115 120 125Trp Ser Asn Trp Ser Ser Trp Glu Glu Val Ser Val Gln Asp Ser Thr 130 135 140Gly Gln Asp Ile Leu Phe Val Phe Pro Lys Asp Lys Leu Val Glu Glu145 150 155 160Gly Thr Asn Val Thr Ile Cys Tyr Val Ser Arg Asn Ile Gln Asn Asn 165 170 175Val Ser Cys Tyr Leu Glu Gly Lys Gln Ile His Gly Glu Gln Leu Asp 180 185 190Pro His Val Thr Ala Phe Asn Leu Asn Ser Val Pro Phe Ile Arg Asn 195 200 205Lys Gly Thr Asn Ile Tyr Cys Glu Ala Ser Gln Gly Asn Val Ser Glu 210 215 220Gly Met Lys Gly Ile Val Leu Phe Val Ser Lys Val Leu Glu Glu Pro225 230 235 240Lys Asp Phe Ser Cys Glu Thr Glu Asp Phe Lys Thr Leu His Cys Thr 245 250 255Trp Asp Pro Gly Thr Asp Thr Ala Leu Gly Trp Ser Lys Gln Pro Ser 260 265 270Gln Ser Tyr Thr Leu Phe Glu Ser Phe Ser Gly Glu Lys Lys Leu Cys 275 280 285Thr His Lys Asn Trp Cys Asn Trp Gln Ile Thr Gln Asp Ser Gln Glu 290 295 300Thr Tyr Asn Phe Thr Leu Ile Ala Glu Asn Tyr Leu Arg Lys Arg Ser305 310 315 320Val Asn Ile Leu Phe Asn Leu Thr His Arg Val Tyr Leu Met Asn Pro 325 330 335Phe Ser Val Asn Phe Glu Asn Val Asn Ala Thr Asn Ala Ile Met Thr 340 345 350Trp Lys Val His Ser Ile Arg Asn Asn Phe Thr Tyr Leu Cys Gln Ile 355 360 365Glu Leu His Gly Glu Gly Lys Met Met Gln Tyr Asn Val Ser Ile Lys 370 375 380Val Asn Gly Glu Tyr Phe Leu Ser Glu Leu Glu Pro Ala Thr Glu Tyr385 390 395 400Met Ala Arg Val Arg Cys Ala Asp Ala Ser His Phe Trp Lys Trp Ser 405 410 415Glu Trp Ser Gly Gln Asn Phe Thr Thr Leu Glu Ala Ala Pro Ser Glu 420 425 430Ala Pro Asp Val Trp Arg Ile Val Ser Leu Glu Pro Gly Asn His Thr 435 440 445Val Thr Leu Phe Trp Lys Pro Leu Ser Lys Leu His Ala Asn Gly Lys 450 455 460Ile Leu Phe Tyr Asn Val Val Val Glu Asn Leu Asp Lys Pro Ser Ser465 470 475 480Ser Glu Leu His Ser Ile Pro Ala Pro Ala Asn Ser Thr Lys Leu Ile 485 490 495Leu Asp Arg Cys Ser Tyr Gln Ile Cys Val Ile Ala Asn Asn Ser Val 500 505 510Gly Ala Ser Pro Ala Ser Val Ile Val Ile Ser Ala Asp Pro Glu Asn 515 520 525Lys Glu Val Glu Glu Glu Arg Ile Ala Gly Thr Glu Gly Gly Phe Ser 530 535 540Leu Ser Trp Lys Pro Gln Pro Gly Asp Val Ile Gly Tyr Val Val Asp545 550 555 560Trp Cys Asp His Thr Gln Asp Val Leu Gly Asp Phe Gln Trp Lys Asn 565 570 575Val Gly Pro Asn Thr Thr Ser Thr Val Ile Ser Thr Asp Ala Phe Arg 580 585 590Pro Gly Val Arg Tyr Asp Phe Arg Ile Tyr Gly Leu Ser Thr Lys Arg 595 600 605Ile Ala Cys Leu Leu Glu Lys Lys Thr Gly Tyr Ser Gln Glu Leu Ala 610 615 620Pro Ser Asp Asn Pro His Val Leu Val Asp Thr Leu Thr Ser His Ser625 630 635 640Phe Thr Leu Ser Trp Lys Asp Tyr Ser Thr Glu Ser Gln Pro Gly Phe 645 650 655Ile Gln Gly Tyr His Val Tyr Leu Lys Ser Lys Ala Arg Gln Cys His 660 665 670Pro Arg Phe Glu Lys Ala Val Leu Ser Asp Gly Ser Glu Cys Cys Lys 675 680 685Tyr Lys Ile Asp Asn Pro Glu Glu Lys Ala Leu Ile Val Asp Asn Leu 690 695 700Lys Pro Glu Ser Phe Tyr Glu Phe Phe Ile Thr Pro Phe Thr Ser Ala705 710 715 720Gly Glu Gly Pro Ser Ala Thr Phe Thr Lys Val Thr Thr Pro Asp Glu 725 730 735His Ser Ser Met Leu Ile His Ile Leu Leu Pro Met Val Phe Cys Val 740 745 750Leu Leu Ile Met Val Met Cys Tyr Leu Lys Ser Gln Trp Ile Lys Glu 755 760 765Thr Cys Tyr Pro Asp Ile Pro Asp Pro Tyr Lys Ser Ser Ile Leu Ser 770 775 780Leu Ile Lys Phe Lys Glu Asn Pro His Leu Ile Ile Met Asn Val Ser785 790 795 800Asp Cys Ile Pro Asp Ala Ile Glu Val Val Ser Lys Pro Glu Gly Thr 805 810 815Lys Ile Gln Phe Leu Gly Thr Arg Lys Ser Leu Thr Glu Thr Glu Leu 820 825 830Thr Lys Pro Asn Tyr Leu Tyr Leu Leu Pro Thr Glu Lys Asn His Ser 835 840 845Gly Pro Gly Pro Cys Ile Cys Phe Glu Asn Leu Thr Tyr Asn Gln Ala 850 855 860Ala Ser Asp Ser Gly Ser Cys Gly His Val Pro Val Ser Pro Lys Ala865 870 875 880Pro Ser Met Leu Gly Leu Met Thr Ser Pro Glu Asn Val Leu Lys Ala 885 890 895Leu Glu Lys Asn Tyr Met Asn Ser Leu Gly Glu Ile Pro Ala Gly Glu 900 905 910Thr Ser Leu Asn Tyr Val Ser Gln Leu Ala Ser Pro Met Phe Gly Asp 915 920 925Lys Asp Ser Leu Pro Thr Asn Pro Val Glu Ala Pro His Cys Ser Glu 930 935 940Tyr Lys Met Gln Met Ala Val Ser Leu Arg Leu Ala Leu Pro Pro Pro945 950 955 960Thr Glu Asn Ser Ser Leu Ser Ser Ile Thr Leu Leu Asp Pro Gly Glu 965 970 975His Tyr Cys148342PRTHomo sapiens 148Met Ala Leu Phe Ala Val Phe Gln Thr Thr Phe Phe Leu Thr Leu Leu1 5 10 15Ser Leu Arg Thr Tyr Gln Ser Glu Val Leu Ala Glu Arg Leu Pro Leu 20 25 30Thr Pro Val Ser Leu Lys Val Ser Thr Asn Ser Thr Arg Gln Ser Leu 35 40 45His Leu Gln Trp Thr Val His Asn Leu Pro Tyr His Gln Glu Leu Lys 50 55 60Met Val Phe Gln Ile Gln Ile Ser Arg Ile Glu Thr Ser Asn Val Ile65 70 75 80Trp Val Gly Asn Tyr Ser Thr Thr Val Lys Trp Asn Gln Val Leu His 85 90 95Trp Ser Trp Glu Ser Glu Leu Pro Leu Glu Cys Ala Thr His Phe Val 100 105 110Arg Ile Lys Ser Leu Val Asp Asp Ala Lys Phe Pro Glu Pro Asn Phe 115 120 125Trp Ser Asn Trp Ser Ser Trp Glu Glu Val Ser Val Gln Asp Ser Thr 130 135 140Gly Gln Asp Ile Leu Phe Val Phe Pro Lys Asp Lys Leu Val Glu Glu145 150 155 160Gly Thr Asn Val Thr Ile Cys Tyr Val Ser Arg Asn Ile Gln Asn Asn 165 170 175Val Ser Cys Tyr Leu Glu Gly Lys Gln Ile His Gly Glu Gln Leu Asp 180 185 190Pro His Val Thr Ala Phe Asn Leu Asn Ser Val Pro Phe Ile Arg Asn 195 200 205Lys Gly Thr Asn Ile Tyr Cys Glu Ala Ser Gln Gly Asn Val Ser Glu 210 215 220Gly Met Lys Gly Ile Val Leu Phe Val Ser Lys Val Leu Glu Glu Pro225 230 235 240Lys Asp Phe Ser Cys Glu Thr Glu Asp Phe Lys Thr Leu His Cys Thr 245 250 255Trp Asp Pro Gly Thr Asp Thr Ala Leu Gly Trp Ser Lys Gln Pro Ser 260 265 270Gln Ser Tyr Thr Leu Phe Glu Ser Phe Ser Gly Glu Lys Lys Leu Cys

275 280 285Thr His Lys Asn Trp Cys Asn Trp Gln Ile Thr Gln Asp Ser Gln Glu 290 295 300Thr Tyr Asn Phe Thr Leu Ile Ala Glu Asn Tyr Leu Arg Lys Arg Ser305 310 315 320Val Asn Ile Leu Phe Asn Leu Thr His Arg Gly Glu Thr Arg Val Val 325 330 335Thr Ala His Arg Gly His 3401492397DNAHomo sapiens 149gcaagaactg aaacgaatgg ggattgaact gctttgcctg ttctttctat ttctaggaag 60gaatgatcac gtacaaggtg gctgtgccct gggaggtgca gaaacctgtg aagactgcct 120gcttattgga cctcagtgtg cctggtgtgc tcaggagaat tttactcatc catctggagt 180tggcgaaagg tgtgataccc cagcaaacct tttagctaaa ggatgtcaat taaacttcat 240cgaaaaccct gtctcccaag tagaaatact taaaaataag cctctcagtg taggcagaca 300gaaaaatagt tctgacattg ttcagattgc gcctcaaagc ttgatcctta agttgagacc 360aggtggtgcg cagactctgc aggtgcatgt ccgccagact gaggactacc cggtggattt 420gtattacctc atggacctct ccgcctccat ggatgacgac ctcaacacaa taaaggagct 480gggctcccgg ctttccaaag agatgtctaa attaaccagc aactttagac tgggcttcgg 540atcttttgtg gaaaaacctg tatccccttt cgtgaaaaca acaccagaag aaattgccaa 600cccttgcagt agtattccat acttctgttt acctacattt ggattcaagc acattttgcc 660attgacaaat gatgctgaaa gattcaatga aattgtgaag aatcagaaaa tttctgctaa 720tattgacaca cccgaaggtg gatttgatgc aattatgcaa gctgctgtgt gtaaggaaaa 780aattggctgg cggaatgact ccctccacct cctggtcttt gtgagtgatg ctgattctca 840ttttggaatg gacagcaaac tagcaggcat cgtcattcct aatgacgggc tctgtcactt 900ggacagcaag aatgaatact ccatgtcaac tgtcttggaa tatccaacaa ttggacaact 960cattgataaa ctggtacaaa acaacgtgtt attgatcttc gctgtaaccc aagaacaagt 1020tcatttatat gagaattacg caaaacttat tcctggagct acagtaggtc tacttcagaa 1080ggactccgga aacattctcc agctgatcat ctcagcttat gaagaactgc ggtctgaggt 1140ggaactggaa gtattaggag acactgaagg actcaacttg tcatttacag ccatctgtaa 1200caacggtacc ctcttccaac accaaaagaa atgctctcac atgaaagtgg gagacacagc 1260ttccttcagc gtgactgtga atatcccaca ctgcgagaga agaagcaggc acattatcat 1320aaagcctgtg gggctggggg atgccctgga attacttgtc agcccagaat gcaactgcga 1380ctgtcagaaa gaagtggaag tgaacagctc caaatgtcac cacgggaacg gctctttcca 1440gtgtggggtg tgtgcctgcc accctggcca catggggcct cgctgtgagt gtggcgagga 1500catgctgagc acagattcct gcaaggaggc cccagatcat ccctcctgca gcggaagggg 1560tgactgctac tgtgggcagt gtatctgcca cttgtctccc tatggaaaca tttatgggcc 1620ttattgccag tgtgacaatt tctcctgcgt gagacacaaa gggctgctct gcggaggtaa 1680cggcgactgt gactgtggtg aatgtgtgtg caggagcggc tggactggcg agtactgcaa 1740ctgcaccacc agcacggact cctgcgtctc tgaagatgga gtgctctgca gcgggcgcgg 1800ggactgtgtt tgtggcaagt gtgtttgcac aaaccctgga gcctcaggac caacctgtga 1860acgatgtcct acctgtggtg acccctgtaa ctctaaacgg agctgcattg agtgccacct 1920gtcagcagct ggccaagccc gagaagaatg tgtggacaag tgcaaactag ctggtgcgac 1980catcagtgaa gaagaagatt tctcaaagga tggttctgtt tcctgctctc tgcaaggaga 2040aaatgaatgt cttattacat tcctaataac tacagataat gaggggaaaa ccatcattca 2100cagcatcaat gaaaaagatt gtccgaagcc tccaaacatt cccatgatca tgttaggggt 2160ttccctggct attcttctca tcggggttgt cctactgtgc atctggaagc tactggtgtc 2220atttcatgat cgtaaagaag ttgccaaatt tgaagcagaa cgatcaaaag ccaagtggca 2280aacgggaacc aatccactct acagaggatc cacaagtact tttaaaaatg taacttataa 2340acacagggaa aaacaaaagg tagacctttc cacagattgc tagaactact ttatgca 2397150788PRTHomo sapiens 150Met Gly Ile Glu Leu Leu Cys Leu Phe Phe Leu Phe Leu Gly Arg Asn1 5 10 15Asp His Val Gln Gly Gly Cys Ala Leu Gly Gly Ala Glu Thr Cys Glu 20 25 30Asp Cys Leu Leu Ile Gly Pro Gln Cys Ala Trp Cys Ala Gln Glu Asn 35 40 45Phe Thr His Pro Ser Gly Val Gly Glu Arg Cys Asp Thr Pro Ala Asn 50 55 60Leu Leu Ala Lys Gly Cys Gln Leu Asn Phe Ile Glu Asn Pro Val Ser65 70 75 80Gln Val Glu Ile Leu Lys Asn Lys Pro Leu Ser Val Gly Arg Gln Lys 85 90 95Asn Ser Ser Asp Ile Val Gln Ile Ala Pro Gln Ser Leu Ile Leu Lys 100 105 110Leu Arg Pro Gly Gly Ala Gln Thr Leu Gln Val His Val Arg Gln Thr 115 120 125Glu Asp Tyr Pro Val Asp Leu Tyr Tyr Leu Met Asp Leu Ser Ala Ser 130 135 140Met Asp Asp Asp Leu Asn Thr Ile Lys Glu Leu Gly Ser Arg Leu Ser145 150 155 160Lys Glu Met Ser Lys Leu Thr Ser Asn Phe Arg Leu Gly Phe Gly Ser 165 170 175Phe Val Glu Lys Pro Val Ser Pro Phe Val Lys Thr Thr Pro Glu Glu 180 185 190Ile Ala Asn Pro Cys Ser Ser Ile Pro Tyr Phe Cys Leu Pro Thr Phe 195 200 205Gly Phe Lys His Ile Leu Pro Leu Thr Asn Asp Ala Glu Arg Phe Asn 210 215 220Glu Ile Val Lys Asn Gln Lys Ile Ser Ala Asn Ile Asp Thr Pro Glu225 230 235 240Gly Gly Phe Asp Ala Ile Met Gln Ala Ala Val Cys Lys Glu Lys Ile 245 250 255Gly Trp Arg Asn Asp Ser Leu His Leu Leu Val Phe Val Ser Asp Ala 260 265 270Asp Ser His Phe Gly Met Asp Ser Lys Leu Ala Gly Ile Val Ile Pro 275 280 285Asn Asp Gly Leu Cys His Leu Asp Ser Lys Asn Glu Tyr Ser Met Ser 290 295 300Thr Val Leu Glu Tyr Pro Thr Ile Gly Gln Leu Ile Asp Lys Leu Val305 310 315 320Gln Asn Asn Val Leu Leu Ile Phe Ala Val Thr Gln Glu Gln Val His 325 330 335Leu Tyr Glu Asn Tyr Ala Lys Leu Ile Pro Gly Ala Thr Val Gly Leu 340 345 350Leu Gln Lys Asp Ser Gly Asn Ile Leu Gln Leu Ile Ile Ser Ala Tyr 355 360 365Glu Glu Leu Arg Ser Glu Val Glu Leu Glu Val Leu Gly Asp Thr Glu 370 375 380Gly Leu Asn Leu Ser Phe Thr Ala Ile Cys Asn Asn Gly Thr Leu Phe385 390 395 400Gln His Gln Lys Lys Cys Ser His Met Lys Val Gly Asp Thr Ala Ser 405 410 415Phe Ser Val Thr Val Asn Ile Pro His Cys Glu Arg Arg Ser Arg His 420 425 430Ile Ile Ile Lys Pro Val Gly Leu Gly Asp Ala Leu Glu Leu Leu Val 435 440 445Ser Pro Glu Cys Asn Cys Asp Cys Gln Lys Glu Val Glu Val Asn Ser 450 455 460Ser Lys Cys His His Gly Asn Gly Ser Phe Gln Cys Gly Val Cys Ala465 470 475 480Cys His Pro Gly His Met Gly Pro Arg Cys Glu Cys Gly Glu Asp Met 485 490 495Leu Ser Thr Asp Ser Cys Lys Glu Ala Pro Asp His Pro Ser Cys Ser 500 505 510Gly Arg Gly Asp Cys Tyr Cys Gly Gln Cys Ile Cys His Leu Ser Pro 515 520 525Tyr Gly Asn Ile Tyr Gly Pro Tyr Cys Gln Cys Asp Asn Phe Ser Cys 530 535 540Val Arg His Lys Gly Leu Leu Cys Gly Gly Asn Gly Asp Cys Asp Cys545 550 555 560Gly Glu Cys Val Cys Arg Ser Gly Trp Thr Gly Glu Tyr Cys Asn Cys 565 570 575Thr Thr Ser Thr Asp Ser Cys Val Ser Glu Asp Gly Val Leu Cys Ser 580 585 590Gly Arg Gly Asp Cys Val Cys Gly Lys Cys Val Cys Thr Asn Pro Gly 595 600 605Ala Ser Gly Pro Thr Cys Glu Arg Cys Pro Thr Cys Gly Asp Pro Cys 610 615 620Asn Ser Lys Arg Ser Cys Ile Glu Cys His Leu Ser Ala Ala Gly Gln625 630 635 640Ala Arg Glu Glu Cys Val Asp Lys Cys Lys Leu Ala Gly Ala Thr Ile 645 650 655Ser Glu Glu Glu Asp Phe Ser Lys Asp Gly Ser Val Ser Cys Ser Leu 660 665 670Gln Gly Glu Asn Glu Cys Leu Ile Thr Phe Leu Ile Thr Thr Asp Asn 675 680 685Glu Gly Lys Thr Ile Ile His Ser Ile Asn Glu Lys Asp Cys Pro Lys 690 695 700Pro Pro Asn Ile Pro Met Ile Met Leu Gly Val Ser Leu Ala Ile Leu705 710 715 720Leu Ile Gly Val Val Leu Leu Cys Ile Trp Lys Leu Leu Val Ser Phe 725 730 735His Asp Arg Lys Glu Val Ala Lys Phe Glu Ala Glu Arg Ser Lys Ala 740 745 750Lys Trp Gln Thr Gly Thr Asn Pro Leu Tyr Arg Gly Ser Thr Ser Thr 755 760 765Phe Lys Asn Val Thr Tyr Lys His Arg Glu Lys Gln Lys Val Asp Leu 770 775 780Ser Thr Asp Cys7851517889DNAHomo sapiens 151atgggtggag tctcgctttt tctttccagt gttggctgac ttacagctct tataaactag 60tggcaatttc tgaacccagc cggctccatc tcagcttctg gtttctaagt ccatgtgcca 120aaggctgcca ggaaggagac gccttcctga gtcctggatc tttcttcctt ctggaaatct 180ttgactgtgg gtagttattt atttctgaat aagagcgtcc acgcatcatg gacctcgcgg 240gactgctgaa gtctcagttc ctgtgccacc tggtcttctg ctacgtcttt attgcctcag 300ggctaatcat caacaccatt cagctcttca ctctcctcct ctggcccatt aacaagcagc 360tcttccggaa gatcaactgc agactgtcct attgcatctc aagccagctg gtgatgctgc 420tggagtggtg gtcgggcacg gaatgcacca tcttcacgga cccgcgcgcc tacctcaagt 480atgggaagga aaatgccatc gtggttctca accacaagtt tgaaattgac tttctgtgtg 540gctggagcct gtccgaacgc tttgggctgt tagggggctc caaggtcctg gccaagaaag 600agctggccta tgtcccaatt atcggctgga tgtggtactt caccgagatg gtcttctgtt 660cgcgcaagtg ggagcaggat cgcaagacgg ttgccaccag tttgcagcac ctccgggact 720accccgagaa gtattttttc ctgattcact gtgagggcac acggttcacg gagaagaagc 780atgagatcag catgcaggtg gcccgggcca aggggctgcc tcgcctcaag catcacctgt 840tgccacgaac caagggcttc gccatcaccg tgaggagctt gagaaatgta gtttcagctg 900tatatgactg tacactcaat ttcagaaata atgaaaatcc aacactgctg ggagtcctaa 960acggaaagaa ataccatgca gatttgtatg ttaggaggat cccactggaa gacatccctg 1020aagacgatga cgagtgctcg gcctggctgc acaagctcta ccaggagaag gatgcctttc 1080aggaggagta ctacaggacg ggcaccttcc cagagacgcc catggtgccc ccccggcggc 1140cctggaccct cgtgaactgg ctgttttggg cctcgctggt gctctaccct ttcttccagt 1200tcctggtcag catgatcagg agcgggtctt ccctgacgct ggccagcttc atcctcgtct 1260tctttgtggc ctccgtggga gttcgatgga tgattggtgt gacggaaatt gacaagggct 1320ctgcctacgg caactctgac agcaagcaga aactgaatga ctgactcagg gaggtgtcac 1380catccgaagg gaaccttggg gaactggtgg cctctgcata tcctccttag tgggacacgg 1440tgacaaaggc tgggtgagcc cctgctgggc acggcggaag tcacgacctc tccagccagg 1500gagtctggtc tcaaggccgg atggggagga agatgttttg taatcttttt ttccccatgt 1560gctttagtgg gctttggttt tctttttgtg cgagtgtgtg tgagaatggc tgtgtggtga 1620gtgtgaactt tgttctgtga tcatagaaag ggtattttag gctgcagggg agggcagggc 1680tggggaccga aggggacaag ttcccctttc atcctttggt gctgagtttt ctgtaaccct 1740tggttgccag agataaagtg aaaagtgctt taggtgagat gactaaatta tgcctccaag 1800aaaaaaaaat taaagtgctt ttctgggtca tctgtggtgt atgttgacat ggaccgctgc 1860ccctccatcc tgcccttgcc cgtggctttg gtgtttcaga tcctactcac gggaggcagc 1920tgccgcggag gtgtgggcag ctgagagggg tgggcaggcc agcacagctc ctggcaggag 1980acacaggtcc aggagcccgt gagcatttgt gagagcagag atggcaagca cgtgcgtgga 2040gaccaacgaa gcgtgtccct ggcacacagc aagggagagt ttcgctcggt ctctgcagtg 2100cagtctcctg gcgtaagtct tgaagatgga cccaactccc tgaagaaatg gatcttgaaa 2160ttgaacacaa acatcatgaa cgtacagcct gggcattctg cagtgatttg tgagatgagc 2220ttgcatcgac tgttcctctc agcagtgaca gccaaagtca cccctgataa aatgcagttt 2280cactttataa aatgcctcgc cccttcccag catgtagagc ttgtctgcag ccctaaagga 2340gccaggtcct gctctgatga gggtcaaatc agagccgaca tcccatgtac aaaaaacccc 2400caggcttctg ccttccttcc gggctcctgt ctgctcccat tttactccac ggaatagttc 2460tgccctgtag catctccagc ggcctttgca gactgctgtc agccaacagg tgccaaaaat 2520gcaaaagaag aagaaactaa aagcagtgct atttttgcag aacaaatgct agctattaaa 2580tcatcttagg ccaagacacc aatggcactt ggaccgatag gtatttggag catgagttag 2640gaaggatatg tctttctcca ggtgcgcagc tgaaagttgc tgagaaaagc tgcctgtgtt 2700gctgtggtaa catgagaagg aatgaacagc tctatacaaa aactggccac acattataag 2760gcctattcta tgcagttatg tttttggcta tttgctcatt tagtcattgt ttatcaacca 2820aactaggtaa gccaaggagt tacaagacag ctctagagaa gctccctctg cttacaggac 2880aataatgcat tgtttgtttg ttgatacaaa tgaattattt gaatccacag aagtgaaaaa 2940gggaaaaaat cctggctgac ttgtgggaag agcgtactgc agagcctagg gcctgagtta 3000actcgctggc ggccctgcag gcaggcttga tgggagcgcc cagcacatct gcccaccctg 3060cacagggcat gaagcaccgt gtgcagagat ctgtgggcaa aagcccagga cgtgacctta 3120ggcaagaggg gtccttggag aagtggaggt gtgcatggtg tgtagccttg cgtgtctgtg 3180agcacgccct agtggacctg cgcctggatt atcgggccag tctctcggag gggtccgtga 3240tgctgagtta cgccattcac ctgaactctg cagctcatcg gctgtaggat ttgggtgaga 3300cacttttcct tgctgactca tttccccatc tgcaaaatgg gggtgacgat atctacctct 3360tggggtgtgt caagggtaaa agagcacact ttaagaatcc taaagcacta agccaaggat 3420gaaagactag aaagctgcct ctatgttgct actctcaaaa atgctcagaa attttcttgt 3480cgtactaaaa atgtgttatt tttctcattt tcattcttcc attcaacaca gaagtaatct 3540aagtaagttc taaaaacata gatccggggg cccacagaca ttcaattttc ttctgaattg 3600gctctggtat cacacaacac acaagcaagc aaacagcctg cctgctaggg ccttgggttc 3660caggctggag gaatgcaggc agaaatctct taggaaataa ctaagtgagc gccaagtttt 3720gaattgcctt agagccgaaa gagaatgtgg cgtgctgggg agagatctgg acctctttct 3780catcagtcat ttgacctgtc cacgaagaac aattttgtta tgcagcctgg gaacctggtt 3840tccttacacc ctgcgccctt aatgacacag acaaccacgg gtactcctgg acggaagctc 3900atcacgcctc ctcaaatacc ttcacccatg ttcaggtcac acggaggtca ccatctcctc 3960agcacacaac aactgctttg gttcccaggg ttattttttc tacgagttga aaacccacgg 4020agcctaagcc atctttttgt cccctaagga gagccccata gactaagagc tacacttcct 4080gtctgtcttt cccacctttc catctcattc tagcttaaag cttatcacgc tactgagagc 4140ctgttctgta gttcaaggtg gcagagaaaa atacgaacct tgagtgaaat ctggagagca 4200gtgcagggtc atccccagac gtgacgggcc atatcctagg cgactcctgc agcttataga 4260agcagggaat ttaatggact tcttccagga aagccagccc acggggactc ttaaaaagac 4320accaaccatt tggaagatgc agcttgaggt ctgggggact ggactgattc tgccaccata 4380tagtgaacac gattaatcgg gaggaagaag taaggcactc tgtgagttag tctaccaccc 4440tattgacttt gacagagaga aaaccaactt ttttcatatg atcacacagt agtactggaa 4500tatctcgact gcaatatcct ctaaacaaat gcatgcaaag ctttgtaaaa gcagctgatg 4560attaaaaaaa ttttaaaaca ttagggtttt tctaatatat ccatatgtgg gacagtgatt 4620taaatgtcat taattgtcca gccacaactt gtaacagtga tgtgaaagac acaaaaaagg 4680ccccactgga gtggaggagt ggtctggctg gtccccaagc aaaacagaat gggcttcgca 4740taggctttag aacttattca taaatattga ccaaagtgtg aagcaaggta tccagtgaag 4800attctctagg gtctctactt ctgctcaaga gatttaatcc agctttctct aaagcagtgg 4860tccagacttg ccacatacta ggttaaagat aaagtgagaa aaacaaatac tttggtttgc 4920acgtctcttg aggggcccta ggctgtatgg aggaatattt agaggaatat ttgtgagctg 4980ccatttgtgt ttaaaagaac atgaaagcaa gacgggccct aacccgcctg tgtctgtagc 5040tgaccaggag gccactgctt ccttccccca gagcttctag gagagccccc caaaatgcaa 5100ctctccaagg tcctgtggag tagtcccctc ataatgcctc caccacacct gtgtctcacg 5160atgccttaac tgacgtagct cctaagtgat gttcacagag aaggaaatac ttaggcaagc 5220ccatgtgtaa catgctcaca gatgtgctgg ctttgccaat gctttcggac tccaccatgc 5280tttctgattc ttctggtcct agtcacgcct tggcacgggg cagaagcggc cgagctatgc 5340tgacaggtgc tgctgagagc caacagccat tcagccgaga aggcgtttct aggtgagggc 5400atgagagctg gcattccagg ctgctgagtg cggcatctgc aggtgcacca cattgctcca 5460cggtgtgttc agaagagacc agcatcttga atctcaggct ctgggctcat tctttgcctc 5520tgccaaggga ccattcaggg gcttcaagcc agctgctgaa aatccccctt ttctggattt 5580ttccccatct atataaggat atggtggctg tgtggacaag aaattggttt catctcagaa 5640gggtgcttcc ctacaaagat cttcagaaat ttaattgaaa acaatttttt gaactttttt 5700tgtttggcca ggatgaatga agctgaagtc acatcctgaa tgtgcatgcc agacaaaggg 5760taagcaagca gtctttacaa atgccaatcc ctctgcactc caaaaccgga gcccgtaatg 5820aaggcccagg ttccagtcat cacaggatcc cccaagccag cacagtgcct gatgcctccc 5880taggcattag cacatcccag cactctaatt cacatcctca gcatccctgc ctcctgcatc 5940cagggcttag gttgagtgtt tccagagtgt caagtacatt taaacacaaa ccaaatactc 6000cagggttttg acctgtcaca atggcttttg aaaacaacag acgtacaatt tgagagaagg 6060actcgatgga cttcttaggc tgaggactaa ggacatgttg ctgttcctct tggtccagga 6120cattcaatac cattcacagc attcatcacc aactgacata gtatcgatca cgacattcaa 6180ctgtttgaaa ttactgctat tttggtcaaa aactaagaaa tcagaaattg cacctacata 6240gtgtgtctcc tcattggagt cccatctctc tgagcacagg gatgggctcc tgagctcaca 6300gccctgccct gcccccccag cagggcctca ccctcatggc cctcagtgaa tagtgactac 6360atgaaggggg cacttactag aggcctgagt aatggaattt caattagctt ctgcttccct 6420tttctaaaaa agaaccacct ttcttaagaa taattaggcc aaaataaact tgagtaattt 6480gtacagtcaa tattttgaag tttcggagtt accagtgaaa tagcaaagct gttctccagg 6540aaaggacatc caggttccca cccaggcctt ccttcctcag ctcctgcagc ctcatcctag 6600tttaatatga aggttgtgaa tgggttaaaa agcagttctt aagcacctac ttagatcttt 6660tcagtatctg gaaatagcac ccagggctgt gttagtaaag cttttcactg ggtaagagtc 6720atacaatttt tacatttaat ttgttttttt aaaacaaggc agtcttgttt tacatattgg 6780aatgactaga tattttttga catttctggc acctctggtt ctgctgaatt ttaagggagg 6840tgagtggtat gtacacaaag ttaagattgc tgcataataa ttcctttgca tttccaaaat 6900aaattacaca aatgtcactt ttccttttct attccatagt actagtttta gccagatctt 6960tgccaaacat tctaggacat tcagaaaagt catccatgga attttggaat gccattctct 7020ctgtatcttt gcagatcatg aggaaggaaa gttgatgaac tagtacggga tggctcagac 7080ttgtaaagtg tctaagtcac aacgctgcag agccagcttc cgggtagcaa tggcatggcc 7140tcagctgtgc caaggctaca actggagctt ccttactcgc atctgaggca aacacagcaa 7200ggctggccca ggccgcccac agtcaacaga tgttcacggg agatggatca gcccctcttt 7260tgcttgttct atcaaggaaa gagatctaac catgggcaag ggtggaacac acccggttca 7320ggtcagggaa tgagttgctc taagtgaaca gtgaattctt acttctcagc ctgtatcaat 7380tgtacccagg gttcatgatt actgtgaccc actaagggat gatctttgag gaaacagacc

7440tggagggagg taatttaagg agggaaagcg agtgggtttt acagactgct ttgtggcgac 7500attcaggaac agaccattca atggatgact tttcagtaca taaaagcaag cagtaatggc 7560caggagagag caaagatgcc ctaagaatga catcagactg accaaatgtg ccttttcaaa 7620taagttatga gaacgaatga attggaatta gagcaaggta ttggacagaa ccatgctagt 7680ctttgagaga acgtgtggat tgggtggatg tttggaccga atgaatggta actttttaat 7740gtgaaacaga gaactgatat atgggctgtc atgtcaccct agggtactgt cgctctgtca 7800tgtgtagcaa tctttccaaa tttttgttgg tgggctgaac aaagataaaa ctaataaagt 7860atgtgtggat accactagaa aaaaaaaaa 7889152378PRTHomo sapiens 152Met Asp Leu Ala Gly Leu Leu Lys Ser Gln Phe Leu Cys His Leu Val1 5 10 15Phe Cys Tyr Val Phe Ile Ala Ser Gly Leu Ile Ile Asn Thr Ile Gln 20 25 30Leu Phe Thr Leu Leu Leu Trp Pro Ile Asn Lys Gln Leu Phe Arg Lys 35 40 45Ile Asn Cys Arg Leu Ser Tyr Cys Ile Ser Ser Gln Leu Val Met Leu 50 55 60Leu Glu Trp Trp Ser Gly Thr Glu Cys Thr Ile Phe Thr Asp Pro Arg65 70 75 80Ala Tyr Leu Lys Tyr Gly Lys Glu Asn Ala Ile Val Val Leu Asn His 85 90 95Lys Phe Glu Ile Asp Phe Leu Cys Gly Trp Ser Leu Ser Glu Arg Phe 100 105 110Gly Leu Leu Gly Gly Ser Lys Val Leu Ala Lys Lys Glu Leu Ala Tyr 115 120 125Val Pro Ile Ile Gly Trp Met Trp Tyr Phe Thr Glu Met Val Phe Cys 130 135 140Ser Arg Lys Trp Glu Gln Asp Arg Lys Thr Val Ala Thr Ser Leu Gln145 150 155 160His Leu Arg Asp Tyr Pro Glu Lys Tyr Phe Phe Leu Ile His Cys Glu 165 170 175Gly Thr Arg Phe Thr Glu Lys Lys His Glu Ile Ser Met Gln Val Ala 180 185 190Arg Ala Lys Gly Leu Pro Arg Leu Lys His His Leu Leu Pro Arg Thr 195 200 205Lys Gly Phe Ala Ile Thr Val Arg Ser Leu Arg Asn Val Val Ser Ala 210 215 220Val Tyr Asp Cys Thr Leu Asn Phe Arg Asn Asn Glu Asn Pro Thr Leu225 230 235 240Leu Gly Val Leu Asn Gly Lys Lys Tyr His Ala Asp Leu Tyr Val Arg 245 250 255Arg Ile Pro Leu Glu Asp Ile Pro Glu Asp Asp Asp Glu Cys Ser Ala 260 265 270Trp Leu His Lys Leu Tyr Gln Glu Lys Asp Ala Phe Gln Glu Glu Tyr 275 280 285Tyr Arg Thr Gly Thr Phe Pro Glu Thr Pro Met Val Pro Pro Arg Arg 290 295 300Pro Trp Thr Leu Val Asn Trp Leu Phe Trp Ala Ser Leu Val Leu Tyr305 310 315 320Pro Phe Phe Gln Phe Leu Val Ser Met Ile Arg Ser Gly Ser Ser Leu 325 330 335Thr Leu Ala Ser Phe Ile Leu Val Phe Phe Val Ala Ser Val Gly Val 340 345 350Arg Trp Met Ile Gly Val Thr Glu Ile Asp Lys Gly Ser Ala Tyr Gly 355 360 365Asn Ser Asp Ser Lys Gln Lys Leu Asn Asp 370 3751531863DNAHomo sapiens 153gccggcgcgc ccctgggagg gtgagccggc gccgggccca ggcccggacc tggtgggagg 60cggggggagg tggggacgag gcctggggag gcgggccccg cccatctgca ggtggctgtg 120aacgctgagc ggctccaggc gggggccggg cccgggggcg gggtctgtgg cgcgcgtccc 180cgccacgtgt ccccggtcac cggccctgcc cccgggccct gtgcttataa cctgggatgg 240gcacccctgc cagtcctgct ctgccgcctg ccaccgctgc ccgagcccga gtggttcact 300gcactgtgaa aacagattcc agacgccggg aactcacgcc tccaatccca gacgctatgt 360ccagcaaagg ctccgtggtt ctggcctaca gtggcggcct ggacacctcg tgcatcctcg 420tgtggctgaa ggaacaaggc tatgacgtca ttgcctatct ggccaacatt ggccagaagg 480aagacttcga ggaagccagg aagaaggcac tgaagcttgg ggccaaaaag gtgttcattg 540aggatgtcag cagggagttt gtggaggagt tcatctggcc ggccatccag tccagcgcac 600tgtatgagga ccgctacctc ctgggcacct ctcttgccag gccctgcatc gcccgcaaac 660aagtggaaat cgcccagcgg gagggggcca agtatgtgtc ccacggcgcc acaggaaagg 720ggaacgatca ggtccggttt gagctcagct gctactcact ggccccccag ataaaggtca 780ttgctccctg gaggatgcct gaattctaca accggttcaa gggccgcaat gacctgatgg 840agtacgcaaa gcaacacggg attcccatcc cggtcactcc caagaacccg tggagcatgg 900atgagaacct catgcacatc agctacgagg ctggaatcct ggagaacccc aagaaccaag 960cgcctccagg tctctacacg aagacccagg acccagccaa agcccccaac acccctgaca 1020ttctcgagat cgagttcaaa aaaggggtcc ctgtgaaggt gaccaacgtc aaggatggca 1080ccacccacca gacctccttg gagctcttca tgtacctgaa cgaagtcgcg ggcaagcatg 1140gcgtgggccg tattgacatc gtggagaacc gcttcattgg aatgaagtcc cgaggtatct 1200acgagacccc agcaggcacc atcctttacc atgctcattt agacatcgag gccttcacca 1260tggaccggga agtgcgcaaa atcaaacaag gcctgggctt gaaatttgct gagctggtgt 1320ataccggttt ctggcacagc cctgagtgtg aatttgtccg ccactgcatc gccaagtccc 1380aggagcgagt ggaagggaaa gtgcaggtgt ccgtcctcaa gggccaggtg tacatcctcg 1440gccgggagtc cccactgtct ctctacaatg aggagctggt gagcatgaac gtgcagggtg 1500attatgagcc aactgatgcc accgggttca tcaacatcaa ttccctcagg ctgaaggaat 1560atcatcgtct ccagagcaag gtcactgcca aatagacccg tgtacaatga ggagctgggg 1620cctcctcaat ttgcagatcc cccaagtaca ggcgctaatt gttgtgataa tttgtaattg 1680tgacttgttc tccccggctg gcagcgtagt ggggctgcca ggccccagct ttgttccctg 1740gtccccctga agcctgcaaa cgttgtcatc gaagggaagg gtggggggca gctgcggtgg 1800ggagctataa aaatgacaat taaaagagac actagtcttt tatttctaaa aaaaaaaaaa 1860aaa 18631541801DNAHomo sapiens 154gccggcgcgc ccctgggagg gtgagccggc gccgggccca ggcccggacc tggtgggagg 60cggggggagg tggggacgag gcctggggag gcgggccccg cccatctgca ggtggctgtg 120aacgctgagc ggctccaggc gggggccggg cccgggggcg gggtctgtgg cgcgcgtccc 180cgccacgtgt ccccggtcac cggccctgcc cccgggccct gtgcttataa cctgggatgg 240gcacccctgc cagtcctgct ctgccgcctg ccaccgctgc ccgagcccga cgctatgtcc 300agcaaaggct ccgtggttct ggcctacagt ggcggcctgg acacctcgtg catcctcgtg 360tggctgaagg aacaaggcta tgacgtcatt gcctatctgg ccaacattgg ccagaaggaa 420gacttcgagg aagccaggaa gaaggcactg aagcttgggg ccaaaaaggt gttcattgag 480gatgtcagca gggagtttgt ggaggagttc atctggccgg ccatccagtc cagcgcactg 540tatgaggacc gctacctcct gggcacctct cttgccaggc cctgcatcgc ccgcaaacaa 600gtggaaatcg cccagcggga gggggccaag tatgtgtccc acggcgccac aggaaagggg 660aacgatcagg tccggtttga gctcagctgc tactcactgg ccccccagat aaaggtcatt 720gctccctgga ggatgcctga attctacaac cggttcaagg gccgcaatga cctgatggag 780tacgcaaagc aacacgggat tcccatcccg gtcactccca agaacccgtg gagcatggat 840gagaacctca tgcacatcag ctacgaggct ggaatcctgg agaaccccaa gaaccaagcg 900cctccaggtc tctacacgaa gacccaggac ccagccaaag cccccaacac ccctgacatt 960ctcgagatcg agttcaaaaa aggggtccct gtgaaggtga ccaacgtcaa ggatggcacc 1020acccaccaga cctccttgga gctcttcatg tacctgaacg aagtcgcggg caagcatggc 1080gtgggccgta ttgacatcgt ggagaaccgc ttcattggaa tgaagtcccg aggtatctac 1140gagaccccag caggcaccat cctttaccat gctcatttag acatcgaggc cttcaccatg 1200gaccgggaag tgcgcaaaat caaacaaggc ctgggcttga aatttgctga gctggtgtat 1260accggtttct ggcacagccc tgagtgtgaa tttgtccgcc actgcatcgc caagtcccag 1320gagcgagtgg aagggaaagt gcaggtgtcc gtcctcaagg gccaggtgta catcctcggc 1380cgggagtccc cactgtctct ctacaatgag gagctggtga gcatgaacgt gcagggtgat 1440tatgagccaa ctgatgccac cgggttcatc aacatcaatt ccctcaggct gaaggaatat 1500catcgtctcc agagcaaggt cactgccaaa tagacccgtg tacaatgagg agctggggcc 1560tcctcaattt gcagatcccc caagtacagg cgctaattgt tgtgataatt tgtaattgtg 1620acttgttctc cccggctggc agcgtagtgg ggctgccagg ccccagcttt gttccctggt 1680ccccctgaag cctgcaaacg ttgtcatcga agggaagggt ggggggcagc tgcggtgggg 1740agctataaaa atgacaatta aaagagacac tagtctttta tttctaaaaa aaaaaaaaaa 1800a 1801155412PRTHomo sapiens 155Met Ser Ser Lys Gly Ser Val Val Leu Ala Tyr Ser Gly Gly Leu Asp1 5 10 15Thr Ser Cys Ile Leu Val Trp Leu Lys Glu Gln Gly Tyr Asp Val Ile 20 25 30Ala Tyr Leu Ala Asn Ile Gly Gln Lys Glu Asp Phe Glu Glu Ala Arg 35 40 45Lys Lys Ala Leu Lys Leu Gly Ala Lys Lys Val Phe Ile Glu Asp Val 50 55 60Ser Arg Glu Phe Val Glu Glu Phe Ile Trp Pro Ala Ile Gln Ser Ser65 70 75 80Ala Leu Tyr Glu Asp Arg Tyr Leu Leu Gly Thr Ser Leu Ala Arg Pro 85 90 95Cys Ile Ala Arg Lys Gln Val Glu Ile Ala Gln Arg Glu Gly Ala Lys 100 105 110Tyr Val Ser His Gly Ala Thr Gly Lys Gly Asn Asp Gln Val Arg Phe 115 120 125Glu Leu Ser Cys Tyr Ser Leu Ala Pro Gln Ile Lys Val Ile Ala Pro 130 135 140Trp Arg Met Pro Glu Phe Tyr Asn Arg Phe Lys Gly Arg Asn Asp Leu145 150 155 160Met Glu Tyr Ala Lys Gln His Gly Ile Pro Ile Pro Val Thr Pro Lys 165 170 175Asn Pro Trp Ser Met Asp Glu Asn Leu Met His Ile Ser Tyr Glu Ala 180 185 190Gly Ile Leu Glu Asn Pro Lys Asn Gln Ala Pro Pro Gly Leu Tyr Thr 195 200 205Lys Thr Gln Asp Pro Ala Lys Ala Pro Asn Thr Pro Asp Ile Leu Glu 210 215 220Ile Glu Phe Lys Lys Gly Val Pro Val Lys Val Thr Asn Val Lys Asp225 230 235 240Gly Thr Thr His Gln Thr Ser Leu Glu Leu Phe Met Tyr Leu Asn Glu 245 250 255Val Ala Gly Lys His Gly Val Gly Arg Ile Asp Ile Val Glu Asn Arg 260 265 270Phe Ile Gly Met Lys Ser Arg Gly Ile Tyr Glu Thr Pro Ala Gly Thr 275 280 285Ile Leu Tyr His Ala His Leu Asp Ile Glu Ala Phe Thr Met Asp Arg 290 295 300Glu Val Arg Lys Ile Lys Gln Gly Leu Gly Leu Lys Phe Ala Glu Leu305 310 315 320Val Tyr Thr Gly Phe Trp His Ser Pro Glu Cys Glu Phe Val Arg His 325 330 335Cys Ile Ala Lys Ser Gln Glu Arg Val Glu Gly Lys Val Gln Val Ser 340 345 350Val Leu Lys Gly Gln Val Tyr Ile Leu Gly Arg Glu Ser Pro Leu Ser 355 360 365Leu Tyr Asn Glu Glu Leu Val Ser Met Asn Val Gln Gly Asp Tyr Glu 370 375 380Pro Thr Asp Ala Thr Gly Phe Ile Asn Ile Asn Ser Leu Arg Leu Lys385 390 395 400Glu Tyr His Arg Leu Gln Ser Lys Val Thr Ala Lys 405 4101568305DNAHomo sapiens 156gcgcccagga gcagagccgc gctcgctcca ctcagctccc agctcccagg actccgctgg 60ctcctcgcaa gtcctgccgc ccagcccgcc gggatgcagt ccgggccgcg gcccccactt 120ccagcccccg gcctggcctt ggctttgacc ctgactatgt tggccagact tgcatccgcg 180gcttccttct tcggtgagaa ccacctggag gtgcctgtgg ccacggctct gaccgacata 240gacctgcagc tgcagttctc cacgtcccag cccgaagccc tccttctcct ggcagcaggc 300ccagctgacc acctcctgct gcagctctac tctggacgcc tgcaggtcag acttgttctg 360ggccaggagg agctgaggct gcagactcca gcagagacgc tgctgagtga ctccatcccc 420cacactgtgg tgctgactgt cgtagagggc tgggccacgt tgtcagtcga tgggtttctg 480aacgcctcct cagcagtccc aggagccccc ctagaggtcc cctatgggct ctttgttggg 540ggcactggga cccttggcct gccctacctg aggggaacca gccgacccct gaggggttgc 600ctccatgcag ccaccctcaa tggccgcagc ctcctccggc ctctgacccc cgatgtgcat 660gagggctgtg ctgaagagtt ttctgccagt gatgatgtgg ccctgggctt ctctgggccc 720cactctctgg ctgccttccc tgcctggggc actcaggacg aaggaaccct agagtttaca 780ctcaccacac agagccggca ggcacccttg gccttccagg cagggggccg gcgtggggac 840ttcatctatg tggacatatt tgagggccac ctgcgggccg tggtggagaa gggccagggt 900accgtattgc tccacaacag tgtgcctgtg gccgatgggc agccccatga ggtcagtgtc 960cacatcaatg ctcaccggct ggaaatctcc gtggaccagt accctacgca tacttcgaac 1020cgaggagtcc tcagctacct ggagccacgg ggcagtctcc ttctcggggg gctggatgca 1080gaggcctctc gtcacctcca ggaacaccgc ctgggcctga caccagaggc caccaatgcc 1140tccctgctgg gctgcatgga agacctcagt gtcaatggcc agaggcgggg gctgcgggaa 1200gctttgctga cgcgcaacat ggcagccggc tgcaggctgg aggaggagga gtatgaggac 1260gatgcctatg gacattatga agctttctcc accctggccc ctgaggcttg gccagccatg 1320gagctgcctg agccatgcgt gcctgagcca gggctgcctc ctgtctttgc caatttcacc 1380cagctgctga ctatcagccc actggtggtg gccgaggggg gcacagcctg gcttgagtgg 1440aggcatgtgc agcccacgct ggacctgatg gaggctgagc tgcgcaaatc ccaggtgctg 1500ttcagcgtga cccgaggggc acgccatggc gagctcgagc tggacatccc gggagcccag 1560gcacgaaaaa tgttcaccct cctggacgtg gtgaaccgca aggcccgctt catccacgat 1620ggctctgagg acacctccga ccagctggtg ctggaggtgt cggtgacggc tcgggtgccc 1680atgccctcat gccttcggag gggccaaaca tacctcctgc ccatccaggt caaccctgtc 1740aatgacccac cccacatcat cttcccacat ggcagcctca tggtgatcct ggaacacacg 1800cagaagccgc tggggcctga ggttttccag gcctatgacc cggactctgc ctgtgagggc 1860ctcaccttcc aggtccttgg cacctcctct ggcctccccg tggagcgccg agaccagcct 1920ggggagccgg cgaccgagtt ctcctgccgg gagttggagg ccggcagcct agtctatgtc 1980caccgcggtg gtcctgcaca ggacttgacg ttccgggtca gcgatggact gcaggccagc 2040cccccggcca cgctgaaggt ggtggccatc cggccggcca tacagatcca ccgcagcaca 2100gggttgcgac tggcccaagg ctctgccatg cccatcttgc ccgccaacct gtcggtggag 2160accaatgccg tggggcagga tgtgagcgtg ctgttccgcg tcactggggc cctgcagttt 2220ggggagctgc agaagcaggg ggcaggtggg gtggagggtg ctgagtggtg ggccacacag 2280gcgttccacc agcgggatgt ggagcagggc cgcgtgaggt acctgagcac tgacccacag 2340caccacgctt acgacaccgt ggagaacctg gccctggagg tgcaggtggg ccaggagatc 2400ctgagcaatc tgtccttccc agtgaccatc cagagagcca ctgtgtggat gctgcggctg 2460gagccactgc acactcagaa cacccagcag gagaccctca ccacagccca cctggaggcc 2520accctggagg aggcaggccc aagcccccca accttccatt atgaggtggt tcaggctccc 2580aggaaaggca accttcaact acagggcaca aggctgtcag atggccaggg cttcacccag 2640gatgacatac aggctggccg ggtgacctat ggggccacag cacgtgcctc agaggcagtc 2700gaggacacct tccgtttccg tgtcacagct ccaccatatt tctccccact ctataccttc 2760cccatccaca ttggtggtga cccagatgcg cctgtcctca ccaatgtcct cctcgtggtg 2820cctgagggtg gtgagggtgt cctctctgct gaccacctct ttgtcaagag tctcaacagt 2880gccagctacc tctatgaggt catggagcgg ccccgccatg ggaggttggc ttggcgtggg 2940acacaggaca agaccactat ggtgacatcc ttcaccaatg aagacctgtt gcgtggccgg 3000ctggtctacc agcatgatga ctccgagacc acagaagatg atatcccatt tgttgctacc 3060cgccagggcg agagcagtgg tgacatggcc tgggaggagg tacggggtgt cttccgagtg 3120gccatccagc ccgtgaatga ccacgcccct gtgcagacca tcagccggat cttccatgtg 3180gcccggggtg ggcggcggct gctgactaca gacgacgtgg ccttcagcga tgctgactcg 3240ggctttgctg acgcccagct ggtgcttacc cgcaaggacc tcctctttgg cagtatcgtg 3300gccgtagatg agcccacgcg gcccatctac cgcttcaccc aggaggacct caggaagagg 3360cgagtactgt tcgtgcactc aggggctgac cgtggctgga tccagctgca ggtgtccgac 3420gggcaacacc aggccactgc gctgctggag gtgcaggcct cggaacccta cctccgtgtg 3480gccaacggct ccagccttgt ggtccctcaa ggaggccagg gcaccatcga cacggccgtg 3540ctccacctgg acaccaacct cgacatccgc agtggggatg aggtccacta ccacgtcaca 3600gctggccctc gctggggaca gctagtccgg gctggtcagc cagccacagc cttctcccag 3660caggacctgc tggatggggc cgttctctat agccacaatg gcagcctcag cccccgcgac 3720accatggcct tctccgtgga agcagggcca gtgcacacgg atgccaccct acaagtgacc 3780attgccctag agggcccact ggccccactg aagctggtcc ggcacaagaa gatctacgtc 3840ttccagggag aggcagctga gatcagaagg gaccagctgg aggcagccca ggaggcagtg 3900ccacctgcag acatcgtatt ctcagtgaag agcccaccga gtgccggcta cctggtgatg 3960gtgtcgcgtg gcgccttggc agatgagcca cccagcctgg accctgtgca gagcttctcc 4020caggaggcag tggacacagg cagggtcctg tacctgcact cccgccctga ggcctggagc 4080gatgccttct cgctggatgt ggcctcaggc ctgggtgctc ccctcgaggg cgtccttgtg 4140gagctggagg tgctgcccgc tgccatccca ctagaggcgc aaaacttcag cgtccctgag 4200ggtggcagcc tcaccctggc ccctccactg ctccgtgtct ccgggcccta cttccccact 4260ctcctgggcc tcagcctgca ggtgctggag ccaccccagc atggagccct gcagaaggag 4320gacggacctc aagccaggac cctcagcgcc ttctcctgga gaatggtgga agagcagctg 4380atccgctacg tgcatgacgg gagcgagaca ctgacagaca gttttgtcct gatggctaat 4440gcctccgaga tggatcgcca gagccatcct gtggccttca ctgtcactgt cctgcctgtc 4500aatgaccaac cccccatcct cactacaaac acaggcctgc agatgtggga gggggccact 4560gcgcccatcc ctgcggaggc tctgaggagc acggacggcg actctgggtc tgaggatctg 4620gtctacacca tcgagcagcc cagcaacggg cgggtagtgc tgcggggggc gccgggcact 4680gaggtgcgca gcttcacgca ggcccagctg gacggcgggc tcgtgctgtt ctcacacaga 4740ggaaccctgg atggaggctt ccgcttccgc ctctctgacg gcgagcacac ttcccccgga 4800cacttcttcc gagtgacggc ccagaagcaa gtgctcctct cgctgaaggg cagccagaca 4860ctgactgtct gcccagggtc cgtccagcca ctcagcagtc agaccctcag ggccagctcc 4920agcgcaggca ctgaccccca gctcctgctc taccgtgtgg tgcggggccc ccagctaggc 4980cggctgttcc acgcccagca ggacagcaca ggggaggccc tggtgaactt cactcaggca 5040gaggtctacg ctgggaatat tctgtatgag catgagatgc cccccgagcc cttttgggag 5100gcccatgata ccctagagct ccagctgtcc tcgccgcctg cccgggacgt ggccgccacc 5160cttgctgtgg ctgtgtcttt tgaggctgcc tgtccccagc gccccagcca cctctggaag 5220aacaaaggtc tctgggtccc cgagggccag cgggccagga tcaccgtggc tgctctggat 5280gcctccaatc tcttggccag cgttccatca ccccagcgct cagagcatga tgtgctcttc 5340caggtcacac agttccccag ccggggccag ctgttggtgt ccgaggagcc cctccatgct 5400gggcagcccc acttcctgca gtcccagctg gctgcagggc agctagtgta tgcccacggc 5460ggtgggggca cccagcagga tggcttccac tttcgtgccc acctccaggg gccagcaggg 5520gcctccgtgg ctggacccca aacctcagag gcctttgcca tcacggtgag ggatgtaaat 5580gagcggcccc ctcagccaca ggcctctgtc ccactccggc tcacccgagg ctctcgtgcc 5640cccatctccc gggcccagct gagtgtggtg gacccagact cagctcctgg ggagattgag 5700tacgaggtcc agcgggcacc ccacaacggc ttcctcagcc tggtgggtgg tggcctgggg 5760cccgtgaccc gcttcacgca agccgatgtg gattcagggc ggctggcctt cgtggccaac 5820gggagcagcg tggcaggcat cttccagctg agcatgtctg atggggccag cccacccctg 5880cccatgtccc tggctgtgga

catcctacca tccgccatcg aggtgcagct gcgggcaccc 5940ctggaggtgc cccaagcttt ggggcgctcc tcactgagcc agcagcagct ccgggtggtt 6000tcagatcggg aggagccaga ggcagcatac cgcctcatcc agggacccca gtatgggcat 6060ctcctggtgg gcgggcggcc cacctcggcc ttcagccaat tccagataga ccagggcgag 6120gtggtctttg ccttcaccaa cttctcctcc tctcatgacc acttcagagt cctggcactg 6180gctaggggtg tcaatgcatc agccgtagtg aacgtcactg tgagggctct gctgcatgtg 6240tgggcaggtg ggccatggcc ccagggtgcc accctgcgcc tggaccccac cgtcctagat 6300gctggcgagc tggccaaccg cacaggcagt gtgccgcgct tccgcctcct ggagggaccc 6360cggcatggcc gcgtggtccg cgtgccccga gccaggacgg agcccggggg cagccagctg 6420gtggagcagt tcactcagca ggaccttgag gacgggaggc tggggctgga ggtgggcagg 6480ccagagggga gggcccccgg ccccgcaggt gacagtctca ctctggagct gtgggcacag 6540ggcgtcccgc ctgctgtggc ctccctggac tttgccactg agccttacaa tgctgcccgg 6600ccctacagcg tggccctgct cagtgtcccc gaggccgccc ggacggaagc agggaagcca 6660gagagcagca cccccacagg cgagccaggc cccatggcat ccagccctga gcccgctgtg 6720gccaagggag gcttcctgag cttccttgag gccaacatgt tcagcgtcat catccccatg 6780tgcctggtac ttctgctcct ggcgctcatc ctgcccctgc tcttctacct ccgaaaacgc 6840aacaagacgg gcaagcatga cgtccaggtc ctgactgcca agccccgcaa cggcctggct 6900ggtgacaccg agacctttcg caaggtggag ccaggccagg ccatcccgct cacagctgtg 6960cctggccagg ggccccctcc aggaggccag cctgacccag agctgctgca gttctgccgg 7020acacccaacc ctgcccttaa gaatggccag tactgggtgt gaggcctggc ctgggcccag 7080atgctgatcg ggccagggac aggcttgccc atgtcccggg ccccattgct tccatgcctg 7140gtgctgtctg agtatcccca gagcaagaga gacctggaga caccaggggt ggagggtcct 7200gggagatagt cccaggggtc cgggacagag tggagtcaag agctggaacc tccctcagct 7260cactccgagc ctggagaact gcaggggcca aggtggaggc aggcttaagt tcagtcctcc 7320tgccctggag ctggtttggg ctgtcaaaac cagggtaacc tcctacatgg gtcatgactc 7380tgggtcctgg gtctgtgacc ttgggtaagt cgcgcctgac ccaggctgct aagagggcaa 7440ggagaaggaa gtaccctggg gagggaaggg acagaggaag ctattcctgg cttttccact 7500ccaacccagg ccaccctttg tctctgcccc agagttgaga aaaaaacttc ctcccctggt 7560tttttaggga gatggtatcc cctggagtag agggcaagag gagagagcgc ctccagtcta 7620gaaggcataa gccaatagga taatatattc agggtgcagg gtgggtaggt tgctctgggg 7680atgggtttat ttaagggaga ttgcaaggaa gctatttaac atggtgctga gctagccagg 7740actgatggag cccctggggg tgtgggatgg aggagggtct gcagccagtt cattcccagg 7800gccccatctt gatgggccaa gggctaaaca tgcatgtgtc agtggctttg gagcaggtta 7860ggctggggct catcgagggt ctcaggccga ggccactgcg gtgccagtgc ccccctgagg 7920actagggcag gcagctgggg gcacttggtt ccatggagcc tggataaaca gtgctttgga 7980ggctctggac agctgtgtgg tgtttgtgtc ttaactatgc actgggccct tgtctgcgtc 8040ggcttgcata cagagggccc ctggggtcgg ccctccggcc tggcctcagc cagtgggatg 8100gacagggcca ggcaggcctc tgaacttcca cctcctgggg cctcccagac ctcctgtgcc 8160cccacctgtg tgggcaggtg ggccagtctt cgggtgatgg gaccaaaccc cttcagttca 8220gtagagaaag gctaggtcct ctacaaagag ctgcaagaca aaaattaaaa taaatgctcc 8280ccaccctaga aaaaaaaaaa aaaaa 83051572322PRTHomo sapiens 157Met Gln Ser Gly Pro Arg Pro Pro Leu Pro Ala Pro Gly Leu Ala Leu1 5 10 15Ala Leu Thr Leu Thr Met Leu Ala Arg Leu Ala Ser Ala Ala Ser Phe 20 25 30Phe Gly Glu Asn His Leu Glu Val Pro Val Ala Thr Ala Leu Thr Asp 35 40 45Ile Asp Leu Gln Leu Gln Phe Ser Thr Ser Gln Pro Glu Ala Leu Leu 50 55 60Leu Leu Ala Ala Gly Pro Ala Asp His Leu Leu Leu Gln Leu Tyr Ser65 70 75 80Gly Arg Leu Gln Val Arg Leu Val Leu Gly Gln Glu Glu Leu Arg Leu 85 90 95Gln Thr Pro Ala Glu Thr Leu Leu Ser Asp Ser Ile Pro His Thr Val 100 105 110Val Leu Thr Val Val Glu Gly Trp Ala Thr Leu Ser Val Asp Gly Phe 115 120 125Leu Asn Ala Ser Ser Ala Val Pro Gly Ala Pro Leu Glu Val Pro Tyr 130 135 140Gly Leu Phe Val Gly Gly Thr Gly Thr Leu Gly Leu Pro Tyr Leu Arg145 150 155 160Gly Thr Ser Arg Pro Leu Arg Gly Cys Leu His Ala Ala Thr Leu Asn 165 170 175Gly Arg Ser Leu Leu Arg Pro Leu Thr Pro Asp Val His Glu Gly Cys 180 185 190Ala Glu Glu Phe Ser Ala Ser Asp Asp Val Ala Leu Gly Phe Ser Gly 195 200 205Pro His Ser Leu Ala Ala Phe Pro Ala Trp Gly Thr Gln Asp Glu Gly 210 215 220Thr Leu Glu Phe Thr Leu Thr Thr Gln Ser Arg Gln Ala Pro Leu Ala225 230 235 240Phe Gln Ala Gly Gly Arg Arg Gly Asp Phe Ile Tyr Val Asp Ile Phe 245 250 255Glu Gly His Leu Arg Ala Val Val Glu Lys Gly Gln Gly Thr Val Leu 260 265 270Leu His Asn Ser Val Pro Val Ala Asp Gly Gln Pro His Glu Val Ser 275 280 285Val His Ile Asn Ala His Arg Leu Glu Ile Ser Val Asp Gln Tyr Pro 290 295 300Thr His Thr Ser Asn Arg Gly Val Leu Ser Tyr Leu Glu Pro Arg Gly305 310 315 320Ser Leu Leu Leu Gly Gly Leu Asp Ala Glu Ala Ser Arg His Leu Gln 325 330 335Glu His Arg Leu Gly Leu Thr Pro Glu Ala Thr Asn Ala Ser Leu Leu 340 345 350Gly Cys Met Glu Asp Leu Ser Val Asn Gly Gln Arg Arg Gly Leu Arg 355 360 365Glu Ala Leu Leu Thr Arg Asn Met Ala Ala Gly Cys Arg Leu Glu Glu 370 375 380Glu Glu Tyr Glu Asp Asp Ala Tyr Gly His Tyr Glu Ala Phe Ser Thr385 390 395 400Leu Ala Pro Glu Ala Trp Pro Ala Met Glu Leu Pro Glu Pro Cys Val 405 410 415Pro Glu Pro Gly Leu Pro Pro Val Phe Ala Asn Phe Thr Gln Leu Leu 420 425 430Thr Ile Ser Pro Leu Val Val Ala Glu Gly Gly Thr Ala Trp Leu Glu 435 440 445Trp Arg His Val Gln Pro Thr Leu Asp Leu Met Glu Ala Glu Leu Arg 450 455 460Lys Ser Gln Val Leu Phe Ser Val Thr Arg Gly Ala Arg His Gly Glu465 470 475 480Leu Glu Leu Asp Ile Pro Gly Ala Gln Ala Arg Lys Met Phe Thr Leu 485 490 495Leu Asp Val Val Asn Arg Lys Ala Arg Phe Ile His Asp Gly Ser Glu 500 505 510Asp Thr Ser Asp Gln Leu Val Leu Glu Val Ser Val Thr Ala Arg Val 515 520 525Pro Met Pro Ser Cys Leu Arg Arg Gly Gln Thr Tyr Leu Leu Pro Ile 530 535 540Gln Val Asn Pro Val Asn Asp Pro Pro His Ile Ile Phe Pro His Gly545 550 555 560Ser Leu Met Val Ile Leu Glu His Thr Gln Lys Pro Leu Gly Pro Glu 565 570 575Val Phe Gln Ala Tyr Asp Pro Asp Ser Ala Cys Glu Gly Leu Thr Phe 580 585 590Gln Val Leu Gly Thr Ser Ser Gly Leu Pro Val Glu Arg Arg Asp Gln 595 600 605Pro Gly Glu Pro Ala Thr Glu Phe Ser Cys Arg Glu Leu Glu Ala Gly 610 615 620Ser Leu Val Tyr Val His Arg Gly Gly Pro Ala Gln Asp Leu Thr Phe625 630 635 640Arg Val Ser Asp Gly Leu Gln Ala Ser Pro Pro Ala Thr Leu Lys Val 645 650 655Val Ala Ile Arg Pro Ala Ile Gln Ile His Arg Ser Thr Gly Leu Arg 660 665 670Leu Ala Gln Gly Ser Ala Met Pro Ile Leu Pro Ala Asn Leu Ser Val 675 680 685Glu Thr Asn Ala Val Gly Gln Asp Val Ser Val Leu Phe Arg Val Thr 690 695 700Gly Ala Leu Gln Phe Gly Glu Leu Gln Lys Gln Gly Ala Gly Gly Val705 710 715 720Glu Gly Ala Glu Trp Trp Ala Thr Gln Ala Phe His Gln Arg Asp Val 725 730 735Glu Gln Gly Arg Val Arg Tyr Leu Ser Thr Asp Pro Gln His His Ala 740 745 750Tyr Asp Thr Val Glu Asn Leu Ala Leu Glu Val Gln Val Gly Gln Glu 755 760 765Ile Leu Ser Asn Leu Ser Phe Pro Val Thr Ile Gln Arg Ala Thr Val 770 775 780Trp Met Leu Arg Leu Glu Pro Leu His Thr Gln Asn Thr Gln Gln Glu785 790 795 800Thr Leu Thr Thr Ala His Leu Glu Ala Thr Leu Glu Glu Ala Gly Pro 805 810 815Ser Pro Pro Thr Phe His Tyr Glu Val Val Gln Ala Pro Arg Lys Gly 820 825 830Asn Leu Gln Leu Gln Gly Thr Arg Leu Ser Asp Gly Gln Gly Phe Thr 835 840 845Gln Asp Asp Ile Gln Ala Gly Arg Val Thr Tyr Gly Ala Thr Ala Arg 850 855 860Ala Ser Glu Ala Val Glu Asp Thr Phe Arg Phe Arg Val Thr Ala Pro865 870 875 880Pro Tyr Phe Ser Pro Leu Tyr Thr Phe Pro Ile His Ile Gly Gly Asp 885 890 895Pro Asp Ala Pro Val Leu Thr Asn Val Leu Leu Val Val Pro Glu Gly 900 905 910Gly Glu Gly Val Leu Ser Ala Asp His Leu Phe Val Lys Ser Leu Asn 915 920 925Ser Ala Ser Tyr Leu Tyr Glu Val Met Glu Arg Pro Arg His Gly Arg 930 935 940Leu Ala Trp Arg Gly Thr Gln Asp Lys Thr Thr Met Val Thr Ser Phe945 950 955 960Thr Asn Glu Asp Leu Leu Arg Gly Arg Leu Val Tyr Gln His Asp Asp 965 970 975Ser Glu Thr Thr Glu Asp Asp Ile Pro Phe Val Ala Thr Arg Gln Gly 980 985 990Glu Ser Ser Gly Asp Met Ala Trp Glu Glu Val Arg Gly Val Phe Arg 995 1000 1005Val Ala Ile Gln Pro Val Asn Asp His Ala Pro Val Gln Thr Ile 1010 1015 1020Ser Arg Ile Phe His Val Ala Arg Gly Gly Arg Arg Leu Leu Thr 1025 1030 1035Thr Asp Asp Val Ala Phe Ser Asp Ala Asp Ser Gly Phe Ala Asp 1040 1045 1050Ala Gln Leu Val Leu Thr Arg Lys Asp Leu Leu Phe Gly Ser Ile 1055 1060 1065Val Ala Val Asp Glu Pro Thr Arg Pro Ile Tyr Arg Phe Thr Gln 1070 1075 1080Glu Asp Leu Arg Lys Arg Arg Val Leu Phe Val His Ser Gly Ala 1085 1090 1095Asp Arg Gly Trp Ile Gln Leu Gln Val Ser Asp Gly Gln His Gln 1100 1105 1110Ala Thr Ala Leu Leu Glu Val Gln Ala Ser Glu Pro Tyr Leu Arg 1115 1120 1125Val Ala Asn Gly Ser Ser Leu Val Val Pro Gln Gly Gly Gln Gly 1130 1135 1140Thr Ile Asp Thr Ala Val Leu His Leu Asp Thr Asn Leu Asp Ile 1145 1150 1155Arg Ser Gly Asp Glu Val His Tyr His Val Thr Ala Gly Pro Arg 1160 1165 1170Trp Gly Gln Leu Val Arg Ala Gly Gln Pro Ala Thr Ala Phe Ser 1175 1180 1185Gln Gln Asp Leu Leu Asp Gly Ala Val Leu Tyr Ser His Asn Gly 1190 1195 1200Ser Leu Ser Pro Arg Asp Thr Met Ala Phe Ser Val Glu Ala Gly 1205 1210 1215Pro Val His Thr Asp Ala Thr Leu Gln Val Thr Ile Ala Leu Glu 1220 1225 1230Gly Pro Leu Ala Pro Leu Lys Leu Val Arg His Lys Lys Ile Tyr 1235 1240 1245Val Phe Gln Gly Glu Ala Ala Glu Ile Arg Arg Asp Gln Leu Glu 1250 1255 1260Ala Ala Gln Glu Ala Val Pro Pro Ala Asp Ile Val Phe Ser Val 1265 1270 1275Lys Ser Pro Pro Ser Ala Gly Tyr Leu Val Met Val Ser Arg Gly 1280 1285 1290Ala Leu Ala Asp Glu Pro Pro Ser Leu Asp Pro Val Gln Ser Phe 1295 1300 1305Ser Gln Glu Ala Val Asp Thr Gly Arg Val Leu Tyr Leu His Ser 1310 1315 1320Arg Pro Glu Ala Trp Ser Asp Ala Phe Ser Leu Asp Val Ala Ser 1325 1330 1335Gly Leu Gly Ala Pro Leu Glu Gly Val Leu Val Glu Leu Glu Val 1340 1345 1350Leu Pro Ala Ala Ile Pro Leu Glu Ala Gln Asn Phe Ser Val Pro 1355 1360 1365Glu Gly Gly Ser Leu Thr Leu Ala Pro Pro Leu Leu Arg Val Ser 1370 1375 1380Gly Pro Tyr Phe Pro Thr Leu Leu Gly Leu Ser Leu Gln Val Leu 1385 1390 1395Glu Pro Pro Gln His Gly Ala Leu Gln Lys Glu Asp Gly Pro Gln 1400 1405 1410Ala Arg Thr Leu Ser Ala Phe Ser Trp Arg Met Val Glu Glu Gln 1415 1420 1425Leu Ile Arg Tyr Val His Asp Gly Ser Glu Thr Leu Thr Asp Ser 1430 1435 1440Phe Val Leu Met Ala Asn Ala Ser Glu Met Asp Arg Gln Ser His 1445 1450 1455Pro Val Ala Phe Thr Val Thr Val Leu Pro Val Asn Asp Gln Pro 1460 1465 1470Pro Ile Leu Thr Thr Asn Thr Gly Leu Gln Met Trp Glu Gly Ala 1475 1480 1485Thr Ala Pro Ile Pro Ala Glu Ala Leu Arg Ser Thr Asp Gly Asp 1490 1495 1500Ser Gly Ser Glu Asp Leu Val Tyr Thr Ile Glu Gln Pro Ser Asn 1505 1510 1515Gly Arg Val Val Leu Arg Gly Ala Pro Gly Thr Glu Val Arg Ser 1520 1525 1530Phe Thr Gln Ala Gln Leu Asp Gly Gly Leu Val Leu Phe Ser His 1535 1540 1545Arg Gly Thr Leu Asp Gly Gly Phe Arg Phe Arg Leu Ser Asp Gly 1550 1555 1560Glu His Thr Ser Pro Gly His Phe Phe Arg Val Thr Ala Gln Lys 1565 1570 1575Gln Val Leu Leu Ser Leu Lys Gly Ser Gln Thr Leu Thr Val Cys 1580 1585 1590Pro Gly Ser Val Gln Pro Leu Ser Ser Gln Thr Leu Arg Ala Ser 1595 1600 1605Ser Ser Ala Gly Thr Asp Pro Gln Leu Leu Leu Tyr Arg Val Val 1610 1615 1620Arg Gly Pro Gln Leu Gly Arg Leu Phe His Ala Gln Gln Asp Ser 1625 1630 1635Thr Gly Glu Ala Leu Val Asn Phe Thr Gln Ala Glu Val Tyr Ala 1640 1645 1650Gly Asn Ile Leu Tyr Glu His Glu Met Pro Pro Glu Pro Phe Trp 1655 1660 1665Glu Ala His Asp Thr Leu Glu Leu Gln Leu Ser Ser Pro Pro Ala 1670 1675 1680Arg Asp Val Ala Ala Thr Leu Ala Val Ala Val Ser Phe Glu Ala 1685 1690 1695Ala Cys Pro Gln Arg Pro Ser His Leu Trp Lys Asn Lys Gly Leu 1700 1705 1710Trp Val Pro Glu Gly Gln Arg Ala Arg Ile Thr Val Ala Ala Leu 1715 1720 1725Asp Ala Ser Asn Leu Leu Ala Ser Val Pro Ser Pro Gln Arg Ser 1730 1735 1740Glu His Asp Val Leu Phe Gln Val Thr Gln Phe Pro Ser Arg Gly 1745 1750 1755Gln Leu Leu Val Ser Glu Glu Pro Leu His Ala Gly Gln Pro His 1760 1765 1770Phe Leu Gln Ser Gln Leu Ala Ala Gly Gln Leu Val Tyr Ala His 1775 1780 1785Gly Gly Gly Gly Thr Gln Gln Asp Gly Phe His Phe Arg Ala His 1790 1795 1800Leu Gln Gly Pro Ala Gly Ala Ser Val Ala Gly Pro Gln Thr Ser 1805 1810 1815Glu Ala Phe Ala Ile Thr Val Arg Asp Val Asn Glu Arg Pro Pro 1820 1825 1830Gln Pro Gln Ala Ser Val Pro Leu Arg Leu Thr Arg Gly Ser Arg 1835 1840 1845Ala Pro Ile Ser Arg Ala Gln Leu Ser Val Val Asp Pro Asp Ser 1850 1855 1860Ala Pro Gly Glu Ile Glu Tyr Glu Val Gln Arg Ala Pro His Asn 1865 1870 1875Gly Phe Leu Ser Leu Val Gly Gly Gly Leu Gly Pro Val Thr Arg 1880 1885 1890Phe Thr Gln Ala Asp Val Asp Ser Gly Arg Leu Ala Phe Val Ala 1895 1900 1905Asn Gly Ser Ser Val Ala Gly Ile Phe Gln Leu Ser Met Ser Asp 1910 1915 1920Gly Ala Ser Pro Pro Leu Pro Met Ser Leu Ala Val Asp Ile Leu 1925 1930 1935Pro Ser Ala Ile Glu Val Gln Leu Arg Ala Pro Leu Glu Val Pro 1940 1945 1950Gln Ala Leu Gly Arg Ser Ser Leu Ser Gln Gln Gln Leu Arg Val 1955 1960 1965Val Ser Asp Arg Glu Glu Pro Glu Ala Ala Tyr Arg Leu Ile Gln 1970 1975 1980Gly Pro Gln Tyr Gly His Leu Leu Val Gly Gly Arg Pro Thr Ser 1985 1990 1995Ala Phe Ser Gln Phe Gln Ile Asp Gln Gly Glu Val Val Phe Ala 2000 2005 2010Phe Thr Asn Phe Ser Ser Ser His Asp His Phe Arg Val Leu Ala 2015 2020 2025Leu Ala Arg Gly Val Asn Ala Ser Ala Val Val Asn Val Thr Val 2030 2035 2040Arg Ala Leu Leu His Val Trp Ala Gly Gly Pro Trp Pro Gln Gly 2045

2050 2055Ala Thr Leu Arg Leu Asp Pro Thr Val Leu Asp Ala Gly Glu Leu 2060 2065 2070Ala Asn Arg Thr Gly Ser Val Pro Arg Phe Arg Leu Leu Glu Gly 2075 2080 2085Pro Arg His Gly Arg Val Val Arg Val Pro Arg Ala Arg Thr Glu 2090 2095 2100Pro Gly Gly Ser Gln Leu Val Glu Gln Phe Thr Gln Gln Asp Leu 2105 2110 2115Glu Asp Gly Arg Leu Gly Leu Glu Val Gly Arg Pro Glu Gly Arg 2120 2125 2130Ala Pro Gly Pro Ala Gly Asp Ser Leu Thr Leu Glu Leu Trp Ala 2135 2140 2145Gln Gly Val Pro Pro Ala Val Ala Ser Leu Asp Phe Ala Thr Glu 2150 2155 2160Pro Tyr Asn Ala Ala Arg Pro Tyr Ser Val Ala Leu Leu Ser Val 2165 2170 2175Pro Glu Ala Ala Arg Thr Glu Ala Gly Lys Pro Glu Ser Ser Thr 2180 2185 2190Pro Thr Gly Glu Pro Gly Pro Met Ala Ser Ser Pro Glu Pro Ala 2195 2200 2205Val Ala Lys Gly Gly Phe Leu Ser Phe Leu Glu Ala Asn Met Phe 2210 2215 2220Ser Val Ile Ile Pro Met Cys Leu Val Leu Leu Leu Leu Ala Leu 2225 2230 2235Ile Leu Pro Leu Leu Phe Tyr Leu Arg Lys Arg Asn Lys Thr Gly 2240 2245 2250Lys His Asp Val Gln Val Leu Thr Ala Lys Pro Arg Asn Gly Leu 2255 2260 2265Ala Gly Asp Thr Glu Thr Phe Arg Lys Val Glu Pro Gly Gln Ala 2270 2275 2280Ile Pro Leu Thr Ala Val Pro Gly Gln Gly Pro Pro Pro Gly Gly 2285 2290 2295Gln Pro Asp Pro Glu Leu Leu Gln Phe Cys Arg Thr Pro Asn Pro 2300 2305 2310Ala Leu Lys Asn Gly Gln Tyr Trp Val 2315 23201583654DNAHomo sapiens 158agatgccgcg ggggccgctc gcagccgccg ctgacttgtg aatgggaccg ggactggggc 60cgggactgac accgcagcgc ttgccctgcg ccagggactg gcggctcgga ggttgcgtcc 120accctcaagg gccccagaaa tcactgtgtt ttcagctcag cggccctgtg acattccttc 180gtgttgtcat ttgttgagtg accaatcaga tgggtggagt gtgttacaga aattggcagc 240aagtatccaa tgggtgaaga agaagctaac tggggacgtg ggcagccctg acgtgatgag 300ctcaaccagc agagacattc catcccaaga gaggtctgcg tgacgcgtcc gggaggccac 360cctcagcaag accaccgtac agttggtgga aggggtgaca gctgcattct cctgtgccta 420ccacgtaacc aaaaatgaag gagaactact gtttacaagc cgccctggtg tgcctgggca 480tgctgtgcca cagccatgcc tttgccccag agcggcgggg gcacctgcgg ccctccttcc 540atgggcacca tgagaagggc aaggaggggc aggtgctaca gcgctccaag cgtggctggg 600tctggaacca gttcttcgtg atagaggagt acaccgggcc tgaccccgtg cttgtgggca 660ggcttcattc agatattgac tctggtgatg ggaacattaa atacattctc tcaggggaag 720gagctggaac catttttgtg attgatgaca aatcagggaa cattcatgcc accaagacgt 780tggatcgaga agagagagcc cagtacacgt tgatggctca ggcggtggac agggacacca 840atcggccact ggagccaccg tcggaattca ttgtcaaggt ccaggacatt aatgacaacc 900ctccggagtt cctgcacgag acctatcatg ccaacgtgcc tgagaggtcc aatgtgggaa 960cgtcagtaat ccaggtgaca gcttcagatg cagatgaccc cacttatgga aatagcgcca 1020agttagtgta cagtatcctc gaaggacaac cctatttttc ggtggaagca cagacaggta 1080tcatcagaac agccctaccc aacatggaca gggaggccaa ggaggagtac cacgtggtga 1140tccaggccaa ggacatgggt ggacatatgg gcggactctc agggacaacc aaagtgacga 1200tcacactgac cgatgtcaat gacaacccac caaagtttcc gcagagcgta taccagatgt 1260ctgtgtcaga agcagccgtc cctggggagg aagtaggaag agtgaaagct aaagatccag 1320acattggaga aaatggctta gtcacataca atattgttga tggagatggt atggaatcgt 1380ttgaaatcac aacggactat gaaacacagg agggggtgat aaagctgaaa aagcctgtag 1440attttgaaac caaaagagcc tatagcttga aggtagaggc agccaacgtg cacatcgacc 1500cgaagtttat cagcaatggc cctttcaagg acactgtgac cgtcaagatc tcagtagaag 1560atgctgatga gccccctatg ttcttggccc caagttacat ccacgaagtc caagaaaatg 1620cagctgctgg caccgtggtt gggagagtgc atgccaaaga ccctgatgct gccaacagcc 1680cgataaggta ttccatcgat cgtcacactg acctcgacag atttttcact attaatccag 1740aggatggttt tattaaaact acaaaacctc tggatagaga ggaaacagcc tggctcaaca 1800tcactgtctt tgcagcagaa atccacaatc ggcatcagga agccaaagtc ccagtggcca 1860ttagggtcct tgatgtcaac gataatgctc ccaagtttgc tgccccttat gaaggtttca 1920tctgtgagag tgatcagacc aagccacttt ccaaccagcc aattgttaca attagtgcag 1980atgacaagga tgacacggcc aatggaccaa gatttatctt cagcctaccc cctgaaatca 2040ttcacaatcc aaatttcaca gtcagagaca accgagataa cacagcaggc gtgtacgccc 2100ggcgtggagg gttcagtcgg cagaagcagg acttgtacct tctgcccata gtgatcagcg 2160atggcggcat cccgcccatg agtagcacca acaccctcac catcaaagtc tgcgggtgcg 2220acgtgaacgg ggcactgctc tcctgcaacg cagaggccta cattctgaac gccggcctga 2280gcacaggcgc cctgatcgcc atcctcgcct gcatcgtcat tctcctggtc attgtagtat 2340tgtttgtgac cctgagaagg caaaagaaag aaccactcat tgtctttgag gaagaagatg 2400tccgtgagaa catcattact tatgatgatg aagggggtgg ggaagaagac acagaagcct 2460ttgatattgc caccctccag aatcctgatg gtatcaatgg atttatcccc cgcaaagaca 2520tcaaacctga gtatcagtac atgcctagac ctgggctccg gccagcgccc aacagcgtgg 2580atgtcgatga cttcatcaac acgagaatac aggaggcaga caatgacccc acggctcctc 2640cttatgactc cattcaaatc tacggttatg aaggcagggg ctcagtggcc gggtccctga 2700gctccctaga gtcggccacc acagattcag acttggacta tgattatcta cagaactggg 2760gacctcgttt taagaaacta gcagatttgt atggttccaa agacactttt gatgacgatt 2820cttaacaata acgatacaaa tttggcctta agaactgtgt ctggcgttct caagaatcta 2880gaagatgtgt aaacaggtat ttttttaaat caaggaaagg ctcatttaaa acaggcaaag 2940ttttacagag aggatacatt taataaaact gcgaggacat caaagtggta aatactgtga 3000aatacctttt ctcacaaaaa ggcaaatatt gaagttgttt atcaacttcg ctagaaaaaa 3060aaaacacttg gcatacaaaa tatttaagtg aaggagaagt ctaacgctga actgacaatg 3120aagggaaatt gtttatgtgt tatgaacatc caagtctttc ttctttttta agttgtcaaa 3180gaagcttcca caaaattaga aaggacaaca gttctgagct gtaatttcgc cttaaactct 3240ggacactcta tatgtagtgc atttttaaac ttgaaatata taatattcag ccagcttaaa 3300cccatacaat gtatgtacaa tacaatgtac aattatgtct cttgagcatc aatcttgtta 3360ctgctgattc ttgtaaatct ttttgcttct actttcatct taaactaata cgtgccagat 3420ataactgtct tgtttcagtg agagacgccc tatttctatg tcatttttaa tgtatctatt 3480tgtacaattt taaagttctt attttagtat acgtataaat atcagtattc tgacatgtaa 3540gaaaatgtta cggcatcaca cttatatttt atgaacattg tactgttgct ttaatatgag 3600cttcaatata agaagcaatc tttgaaataa aaaaagattt ttttttaaaa aaaa 3654159796PRTHomo sapiens 159Met Lys Glu Asn Tyr Cys Leu Gln Ala Ala Leu Val Cys Leu Gly Met1 5 10 15Leu Cys His Ser His Ala Phe Ala Pro Glu Arg Arg Gly His Leu Arg 20 25 30Pro Ser Phe His Gly His His Glu Lys Gly Lys Glu Gly Gln Val Leu 35 40 45Gln Arg Ser Lys Arg Gly Trp Val Trp Asn Gln Phe Phe Val Ile Glu 50 55 60Glu Tyr Thr Gly Pro Asp Pro Val Leu Val Gly Arg Leu His Ser Asp65 70 75 80Ile Asp Ser Gly Asp Gly Asn Ile Lys Tyr Ile Leu Ser Gly Glu Gly 85 90 95Ala Gly Thr Ile Phe Val Ile Asp Asp Lys Ser Gly Asn Ile His Ala 100 105 110Thr Lys Thr Leu Asp Arg Glu Glu Arg Ala Gln Tyr Thr Leu Met Ala 115 120 125Gln Ala Val Asp Arg Asp Thr Asn Arg Pro Leu Glu Pro Pro Ser Glu 130 135 140Phe Ile Val Lys Val Gln Asp Ile Asn Asp Asn Pro Pro Glu Phe Leu145 150 155 160His Glu Thr Tyr His Ala Asn Val Pro Glu Arg Ser Asn Val Gly Thr 165 170 175Ser Val Ile Gln Val Thr Ala Ser Asp Ala Asp Asp Pro Thr Tyr Gly 180 185 190Asn Ser Ala Lys Leu Val Tyr Ser Ile Leu Glu Gly Gln Pro Tyr Phe 195 200 205Ser Val Glu Ala Gln Thr Gly Ile Ile Arg Thr Ala Leu Pro Asn Met 210 215 220Asp Arg Glu Ala Lys Glu Glu Tyr His Val Val Ile Gln Ala Lys Asp225 230 235 240Met Gly Gly His Met Gly Gly Leu Ser Gly Thr Thr Lys Val Thr Ile 245 250 255Thr Leu Thr Asp Val Asn Asp Asn Pro Pro Lys Phe Pro Gln Ser Val 260 265 270Tyr Gln Met Ser Val Ser Glu Ala Ala Val Pro Gly Glu Glu Val Gly 275 280 285Arg Val Lys Ala Lys Asp Pro Asp Ile Gly Glu Asn Gly Leu Val Thr 290 295 300Tyr Asn Ile Val Asp Gly Asp Gly Met Glu Ser Phe Glu Ile Thr Thr305 310 315 320Asp Tyr Glu Thr Gln Glu Gly Val Ile Lys Leu Lys Lys Pro Val Asp 325 330 335Phe Glu Thr Lys Arg Ala Tyr Ser Leu Lys Val Glu Ala Ala Asn Val 340 345 350His Ile Asp Pro Lys Phe Ile Ser Asn Gly Pro Phe Lys Asp Thr Val 355 360 365Thr Val Lys Ile Ser Val Glu Asp Ala Asp Glu Pro Pro Met Phe Leu 370 375 380Ala Pro Ser Tyr Ile His Glu Val Gln Glu Asn Ala Ala Ala Gly Thr385 390 395 400Val Val Gly Arg Val His Ala Lys Asp Pro Asp Ala Ala Asn Ser Pro 405 410 415Ile Arg Tyr Ser Ile Asp Arg His Thr Asp Leu Asp Arg Phe Phe Thr 420 425 430Ile Asn Pro Glu Asp Gly Phe Ile Lys Thr Thr Lys Pro Leu Asp Arg 435 440 445Glu Glu Thr Ala Trp Leu Asn Ile Thr Val Phe Ala Ala Glu Ile His 450 455 460Asn Arg His Gln Glu Ala Lys Val Pro Val Ala Ile Arg Val Leu Asp465 470 475 480Val Asn Asp Asn Ala Pro Lys Phe Ala Ala Pro Tyr Glu Gly Phe Ile 485 490 495Cys Glu Ser Asp Gln Thr Lys Pro Leu Ser Asn Gln Pro Ile Val Thr 500 505 510Ile Ser Ala Asp Asp Lys Asp Asp Thr Ala Asn Gly Pro Arg Phe Ile 515 520 525Phe Ser Leu Pro Pro Glu Ile Ile His Asn Pro Asn Phe Thr Val Arg 530 535 540Asp Asn Arg Asp Asn Thr Ala Gly Val Tyr Ala Arg Arg Gly Gly Phe545 550 555 560Ser Arg Gln Lys Gln Asp Leu Tyr Leu Leu Pro Ile Val Ile Ser Asp 565 570 575Gly Gly Ile Pro Pro Met Ser Ser Thr Asn Thr Leu Thr Ile Lys Val 580 585 590Cys Gly Cys Asp Val Asn Gly Ala Leu Leu Ser Cys Asn Ala Glu Ala 595 600 605Tyr Ile Leu Asn Ala Gly Leu Ser Thr Gly Ala Leu Ile Ala Ile Leu 610 615 620Ala Cys Ile Val Ile Leu Leu Val Ile Val Val Leu Phe Val Thr Leu625 630 635 640Arg Arg Gln Lys Lys Glu Pro Leu Ile Val Phe Glu Glu Glu Asp Val 645 650 655Arg Glu Asn Ile Ile Thr Tyr Asp Asp Glu Gly Gly Gly Glu Glu Asp 660 665 670Thr Glu Ala Phe Asp Ile Ala Thr Leu Gln Asn Pro Asp Gly Ile Asn 675 680 685Gly Phe Ile Pro Arg Lys Asp Ile Lys Pro Glu Tyr Gln Tyr Met Pro 690 695 700Arg Pro Gly Leu Arg Pro Ala Pro Asn Ser Val Asp Val Asp Asp Phe705 710 715 720Ile Asn Thr Arg Ile Gln Glu Ala Asp Asn Asp Pro Thr Ala Pro Pro 725 730 735Tyr Asp Ser Ile Gln Ile Tyr Gly Tyr Glu Gly Arg Gly Ser Val Ala 740 745 750Gly Ser Leu Ser Ser Leu Glu Ser Ala Thr Thr Asp Ser Asp Leu Asp 755 760 765Tyr Asp Tyr Leu Gln Asn Trp Gly Pro Arg Phe Lys Lys Leu Ala Asp 770 775 780Leu Tyr Gly Ser Lys Asp Thr Phe Asp Asp Asp Ser785 790 795160468DNAMus musculus 160ttcacctccg cacccagcag cttgtagaga gcagttccga cccacagccg gcacccttcg 60gctagcgctg tttgtttagg gctcggtgag tccaatcaga gcgcaggctg cagttttccg 120gcagagcagt aagaggcgcc ctctctcctt tttattcacc agcagcgact agcagacccc 180ggactctcgc tctccgccgg cgccctccgc ctctctccgc gccccggagc accctcggtc 240gcggccgtct tctcgccatc gctcgaggaa tcaaaagtca ggttggagta ggccggacag 300tggatggcct tgactgacgg cggctggtgc ctgccaaagc gtttcggggc gctgctgcgg 360acgccggcga ctccgggccc tttccagcgc gggagccctc ctcgccgctt cccccatctc 420gtcttcgtcc tcctcctgct cccggggcgg ggatcgcggt ccctgcgg 468161319DNAArtificial sequenceSynthetic consensus sequence 161ttatttaggg gttccgatga gcaacaagcc cgggaggcct ctctctcctt attctcgctc 60tccgccggcg ccctcccctc tctcgcgccg caccctcgtc ggcctcctcg ccgctgagga 120atcaaaagtc aggttggagt aggccggaca gtggatggcc ttgactgacg gcggctggtg 180cctgccaaag cgtttcgggg cgctgctgcg gacgccggcg actccgggcc ctttccagcg 240cgggagccct cctcgccgct tcccccatct cgtcttcgtc ctcctcctgc tcccggggcg 300gggatcgcgg tccctgcgg 319162527DNAMus musculus 162tgggcattaa ttttagtgtg gttatctccg atgagcctaa gcgatttgga aaacagcccg 60gtggaggcct gcctggttcc ccacccctcc aagtctccct gtcattcttc ctgctctccc 120tttggggtgg cctcggctct ggggcggtct cacccccctc ccctcctgcg ttttccctcc 180ttttctctgc gctctgctcc accctactat gaccaattcc agaacgatct ggccttcccc 240tgctggggtt gaccatgggg tgggccaggg gtggcccggc ccgcctgagt acgccgctgg 300tggttgtaag gcggtttgtg tttaaggaat caaaagtcag gttggagtag gccggacagt 360ggatggcctt gactgacggc ggctggtgcc tgccaaagcg tttcggggcg ctgctgcgga 420cgccggcgac tccgggccct ttccagcgcg ggagccctcc tcgccgcttc ccccatctcg 480tcttcgtcct cctcctgctc ccggggcggg gatcgcggtc cctgcgg 527163900DNAHomo sapiens 163gacccacagc ctggcaccct tcggcgagcg ctgtttgttt agggctcggt gagtccaatc 60aggagcccag gctgcagttt tccggcagag cagtaagagg cgcctcctct ctccttttta 120ttcaccagca gcgcggcgca gaccccggac tcgcgctcgc ccgctggcgc cctcggcttc 180tctccgcgcc tgggagcacc ctccgccgcg gccgttctcc atgcgcagcg cccgcccgag 240gagctagacg tcagcttgga gcggcgccgg accgtggatg gccttgactg acggcggctg 300gtgcttgccg aagcgcttcg gggccgcggg tgcggacgcc agcgactcca gagcctttcc 360agcgcgggag ccctccacgc cgccttcccc catctcttcc tcgtcctcct cctgctcccg 420gggcggagag cggggccccg gcggcgccag caactgcggg acgcctcagc tcgacacgga 480ggcggcggcc ggacccccgg cccgctcgct gctgctcagt tcctacgctt cgcatccctt 540cggggctccc cacggacctt cggcgcctgg ggtcgcgggc cccgggggca acctgtcgag 600ctgggaggac ttgctgctgt tcactgacct cgaccaagcc gcgaccgcca gcaagctgct 660gtggtccagc cgcggcgcca agctgagccc cttcgcaccc gagcagccgg aggagatgta 720ccagaccctc gccgctctct ccagccaggg tccggccgcc tacgacggcg cgcccggcgg 780cttcgtgcac tctgcggccg cggcggcagc agccgcggcg gcggccagct ccccggtcta 840cgtgcccacc acccgcgtgg gttccatgct gcccggccta ccgtaccacc tgcaggggtc 900164737DNAHomo sapiens 164gaccacccgg gcgttttgag ggtctgagtc caaaggagag gctgcagcct cctctttacc 60cgtcgctccc cgttcccccc cccccagggc tagacgtcag cttggagcgg cgccggaccg 120tggatggcct tgactgacgg cggctgggct tgccgaagcg cttcggggcc gcgggtgcgg 180acgccagcga ctccagagcc tttccacgcg ggagccctcc acgccgcctt cccccatctc 240ttcctcgtcc tcctcctgct cccgggcgga gagcggggcc ccggcggcgc cagcaactgc 300gggacgcctc agctcgacac ggagcggcgg ccggaccccc ggcccgctcg ctgctgctca 360gttcctacgc ttcgcatccc ttcgggctcc ccacggacct tcggcgcctg gggtcgcggg 420ccccgggggc aacctgtcga gcgggaggac ttgctgctgt tcactgacct cgaccaagcc 480gcgaccgcca gcaagctgct gggtccagcc gcggcgccaa gctgagcccc ttcgcacccg 540agcagccgga ggagatgtac agaccctcgc cgctctctcc agccagggtc cggccgccta 600cgacggcgcg cccggcggct cgtgcactct gcggccgcgg cggcagcagc cgcggcggcg 660gccagctccc cggtctactg cccaccaccc gcgtgggttc catgctgccc ggcctaccgt 720accacctgca ggggtcg 737165831DNAHomo sapiens 165attgatctcc acgcccgggg cagaaatagg atctttgaga agtctcaatg ggatctttga 60gaagtcagat cccatttgaa ctagaaaaag gagtggaggc gaggtgcgtg cagcctacgc 120tcttgttaac ccgtcgatct cctaccatac ccgttccccc accccacctc agggctagac 180gtcagcttgg agcggcgccg gaccgtggat ggccttgact gacggcggct ggtgcttgcc 240gaagcgcttc ggggccgcgg gtgcggacgc cagcgactcc agagcctttc cagcgcggga 300gccctccacg ccgccttccc ccatctcttc ctcgtcctcc tcctgctccc ggggcggaga 360gcggggcccc ggcggcgcca gcaactgcgg gacgcctcag ctcgacacgg aggcggcggc 420cggacccccg gcccgctcgc tgctgctcag ttcctacgct tcgcatccct tcggggctcc 480ccacggacct tcggcgcctg gggtcgcggg ccccgggggc aacctgtcga gctgggagga 540cttgctgctg ttcactgacc tcgaccaagc cgcgaccgcc agcaagctgc tgtggtccag 600ccgcggcgcc aagctgagcc ccttcgcacc cgagcagccg gaggagatgt accagaccct 660cgccgctctc tccagccagg gtccggccgc ctacgacggc gcgcccggcg gcttcgtgca 720ctctgcggcc gcggcggcag cagccgcggc ggcggccagc tccccggtct acgtgcccac 780cacccgcgtg ggttccatgc tgcccggcct accgtaccac ctgcaggggt c 831166958DNAMus musculus 166ctggtaacag caatgaggct gacgcccccg ggcccgctag ggagcacagc ccacagctcc 60cccttgccag gcgcccaagg accctcaagg cgcggggctc acacttgaag cctgggaacg 120ctcagacagg aaacccactt cctcctaagc agtttcttcc tagccggatg agaggcgccc 180aattgaagca gaatgatcct catctactaa tatccagcgt ggccacaaag cgaccggcca 240tttacgccgc cactttagac aaagatattt ggttattccc ggggaagcaa gtgcactttt 300gcatggctga gctccgggag gaggcgagcc tcagcccagc ctcccgcccg ctgggctgcg 360ggcgtcgaga tattcgcctc ctcccggaca acgagttcca cccgggttca gactcagttc 420cactctgcaa cggatctgcg ggcgctcacg cggctccccg cccgggcttt cactgaagca 480tcggaaggga aaactgcggg gatctgagct ggggtgctgg gactgggatg tcctcggaaa 540gacagcatca gcttctgaag ccgaagtatc caggccatgg gcaagggtca ggggcaccag 600ccgacgccga atcatgtcga tgagtccaaa gcacacgact ccgttctcag tgtctgacat 660cttgagtccc ctggaggaaa gctacaagaa agtgggcatg gagggcggcg gcctcggggc 720tccgctcgca gcgtacagac agggccaggc ggccccaccg gccgcggcca tgcagcagca

780cgccgtgggg caccacggcg ccgtcaccgc cgcctaccac atgacggcgg cgggggtgcc 840ccagctctcg cactccgccg tggggggcta ctgcaacggc aacctgggca acatgagcga 900gctgccgcct taccaggaca ccatgcggaa cagcgcttcg ggccccggat ggtacggc 958167390DNAMus musculus 167tttttttttc ctcctcttcc ttcctcctcc agccgacgcc gaatcatgtc gatgagtcca 60aagcacacga ctccgttctc agtgtctgac atcttgagtc ccctggagga aagctacaag 120aaagtgggca tggagggcgg cggcctcggg gctccgctcg cagcgtacag acagggccag 180gcggccccac cggccgcggc catgcagcag cacgccgtgg ggcaccacgg cgccgtcacc 240gccgcctacc acatgacggc ggcgggggtg ccccagctct cgcactccgc cgtggggggc 300tactgcaacg gcaacctggg caacatgagc gagctgccgc cttaccagga caccatgcgg 360aacagcgctt cgggccccgg atggtacggc 390168391DNAMus musculus 168tttttttttt cctcctcttc cttcctcctc cagccgacgc cgaatcatgt cgatgagtcc 60aaagcacacg actccgttct cagtgtctga catcttgagt cccctggagg aaagctacaa 120gaaagtgggc atggagggcg gcggcctcgg ggctccgctc gcagcgtaca gacagggcca 180ggcggcccca ccggccgcgg ccatgcagca gcacgccgtg gggcaccacg gcgccgtcac 240cgccgcctac cacatgacgg cggcgggggt gccccagctc tcgcactccg ccgtgggggg 300ctactgcaac ggcaacctgg gcaacatgag cgagctgccg ccttaccagg acaccatgcg 360gaacagcgct tcgggccccg gatggtacgg c 391169517DNAHomo sapiens 169ctgacagaca cgtagaccaa cagtgcggcc ccagggttcg tccccagact cgctcgctca 60tttgttggcg actggggctc agcgcagcga agcccgatgt ggtccggagg cagtgggaag 120gcgcggggct gggaggccgc ggcgggaggg aggagcagcc ccggcaggct cagccgccgc 180cgaatcatgt cgatgagtcc aaagcacacg actccgttct cagtgtctga catcttgagt 240cccctggagg aaagctacaa gaaagtgggc atggagggcg gcggcctcgg ggctccgctg 300gcggcgtaca ggcagggcca ggcggcaccg ccaacagcgg ccatgcagca gcacgccgtg 360gggcaccacg gcgccgtcac cgccgcctac cacatgacgg cggcgggggt gccccagctc 420tcgcactccg ccgtgggggg ctactgcaac ggcaacctgg gcaacatgag cgagctgccg 480ccgtaccagg acaccatgag gaacagcgcc tctggcc 517170430DNAHomo sapiens 170gaactaaggt tgtccagatc tcgcattgtt gcttagcgcg cctcggggcg aaggcgcggg 60ctggcgggag ggagcagcag gctcagccgc cgccgaatca tgtcgatgag tccaaagcac 120acgactccgt tctcagtgtc tgacatcttg agtcccctgg aggaaagcta caagaaagtg 180ggcatggagg gcggcggcct cggggctccg ctggcggcgt acaggcaggg ccaggcggca 240ccgccaacag cggccatgca gcagcacgcc gtggggcacc acggcgccgt caccgccgcc 300taccacatga cggcggcggg ggtgccccag ctctcgcact ccgccgtggg gggctactgc 360aacggcaacc tgggcaacat gagcgagctg ccgccgtacc aggacaccat gaggaacagc 420gcctctggcc 430171672DNAHomo sapiens 171gaaacttaaa ggtgtttacc ttgtcatcag catgtaagct aattatctcg ggcaagatgt 60aggcttctat tgtcttgttg ctttagcgct tacgccccgc ctctggtggc tgcctaaaac 120ctggcgccgg gctaaaacaa acgcgaggca gcccccgagc ctccactcaa gccaattaag 180gaggactcgg tccactccgt tacgtgtaca tccaacaaga tcggcgttaa ggtaacacca 240gaatatttgg caaagggaga aaaaaaaagc agcgaggctt cgccttcccc ctctcccttt 300tttttcctcc tcttccttcc tcctccagcc gccgccgaat catgtcgatg agtccaaagc 360acacgactcc gttctcagtg tctgacatct tgagtcccct ggaggaaagc tacaagaaag 420tgggcatgga gggcggcggc ctcggggctc cgctggcggc gtacaggcag ggccaggcgg 480caccgccaac agcggccatg cagcagcacg ccgtggggca ccacggcgcc gtcaccgccg 540cctaccacat gacggcggcg ggggtgcccc agctctcgca ctccgccgtg gggggctact 600gcaacggcaa cctgggcaac atgagcgagc tgccgccgta ccaggacacc atgaggaaca 660gcgcctctgg cc 672172820DNAMus musculus 172ggtcgtttgt tgtggctgtt aaattttaaa ccgccatgca ctcggcttcc agtatgctgg 60gagccgtgaa gatggaaggg cacgagccat ccgactggag cagctactac gcggagcccg 120agggctactc ttccgtgagc aacatgaacg ccggcctggg gatgaatggc atgaacacat 180acatgagcat gtccgcggct gccatgggcg gcggttccgg caacatgagc gcgggctcca 240tgaacatgtc atcctatgtg ggcgctggaa tgagcccgtc gctagctggc atgtccccgg 300gcgccggcgc catggcgggc atgagcggct cagccggggc ggccggcgtg gcgggcatgg 360gacctcacct gagtccgagt ctgagcccgc tcgggggaca ggcggccggg gccatgggtg 420gccttgcccc ctacgccaac atgaactcga tgagccccat gtacgggcag gccggcctga 480gccgcgctcg ggaccccaag acataccgac gcagctacac acacgccaaa cctccctact 540cgtacatctc gctcatcacc atggccatcc agcagagccc caacaagatg ctgacgctga 600gcgagatcta tcagtggatc atggacctct tccctttcta ccggcagaac cagcagcgct 660ggcagaactc catccgccac tctctctcct tcaacgactg ctttctcaag gtgccccgct 720cgccagacaa gcctggcaag ggctccttct ggaccctgca cccagactcg ggcaacatgt 780tcgagaacgg ctgctacctg cgccgccaga agcgcttcaa 820173751DNAMus musculus 173ctgttaatta acgagggctc cagtatgctg ggagccgtga agatggaagg gcacgagcca 60tccgactgga gcagctacta cgcggagccc gagggctact cttccgtgag caacatgaac 120gccggcctgg ggatgaatgg catgaacaca tacatgagca tgtccgcggc tgccatgggc 180ggcggttccg gcaacatgag cgcgggctcc atgaacatgt catcctatgt gggcgctgga 240atgagcccgt cgctagctgg catgtccccg ggcgccggcg ccatggcggg catgagcggc 300tcagccgggg cggccggcgt ggcgggcatg ggacctcacc tgagtccgag tctgagcccg 360ctcgggggac aggcggccgg ggccatgggt ggccttgccc cctacgccaa catgaactcg 420atgagcccca tgtacgggca ggccggcctg agccgcgctc gggaccccaa gacataccga 480cgcagctaca cacacgccaa acctccctac tcgtacatct cgctcatcac catggccatc 540cagcagagcc ccaacaagat gctgacgctg agcgagatct atcagtggat catggacctc 600ttccctttct accggcagaa ccagcagcgc tggcagaact ccatccgcca ctctctctcc 660ttcaacgact gctttctcaa ggtgccccgc tcgccagaca agcctggcaa gggctccttc 720tggaccctgc acccagactc gggcaacatg t 751174878DNAMus musculus 174ctgacgacca gggcggccag accacgcgag tcctacgcgc ctcctgaggc cgccccggga 60cttaactgta acggggaggg gcctccggag cagcggccag cgagttaaag tatgctggga 120gccgtgaaga tggaagggca cgagccatcc gactggagca gctactacgc ggagcccgag 180ggctactctt ccgtgagcaa catgaacgcc ggcctgggga tgaatggcat gaacacatac 240atgagcatgt ccgcggctgc catgggcggc ggttccggca acatgagcgc gggctccatg 300aacatgtcat cctatgtggg cgctggaatg agcccgtcgc tagctggcat gtccccgggc 360gccggcgcca tggcgggcat gagcggctca gccggggcgg ccggcgtggc gggcatggga 420cctcacctga gtccgagtct gagcccgctc gggggacagg cggccggggc catgggtggc 480cttgccccct acgccaacat gaactcgatg agccccatgt acgggcaggc cggcctgagc 540cgcgctcggg accccaagac ataccgacgc agctacacac acgccaaacc tccctactcg 600tacatctcgc tcatcaccat ggccatccag cagagcccca acaagatgct gacgctgagc 660gagatctatc agtggatcat ggacctcttc cctttctacc ggcagaacca gcagcgctgg 720cagaactcca tccgccactc tctctccttc aacgactgct ttctcaaggt gccccgctcg 780ccagacaagc ctggcaaggg ctccttctgg accctgcacc cagactcggg caacatgttc 840gagaacggct gctacctgcg ccgccagaag cgcttcaa 878175811DNAHomo sapiens 175cccgcccact tccaactacc gcctccggcc tgcccaggga gagagaggga gtggagccca 60gggagaggga gcgcgagaga gggagggagg aggggacggt gctttggctg actttttttt 120aaaagagggt gggggtgggg ggtgattgct ggtcgtttgt tgtggctgtt aaattttaaa 180ctgccatgca ctcggcttcc agtatgctgg gagcggtgaa gatggaaggg cacgagccgt 240ccgactggag cagctactat gcagagcccg agggctactc ctccgtgagc aacatgaacg 300ccggcctggg gatgaacggc atgaacacgt acatgagcat gtcggcggcc gccatgggca 360gcggctcggg caacatgagc gcgggctcca tgaacatgtc gtcgtacgtg ggcgctggca 420tgagcccgtc cctggcgggg atgtcccccg gcgcgggcgc catggcgggc atgggcggct 480cggccggggc ggccggcgtg gcgggcatgg ggccgcactt gagtcccagc ctgagcccgc 540tcggggggca ggcggccggg gccatgggcg gcctggcccc ctacgccaac atgaactcca 600tgagccccat gtacgggcag gcgggcctga gccgcgcccg cgaccccaag acctacaggc 660gcagctacac gcacgcaaag ccgccctact cgtacatctc gctcatcacc atggccatcc 720agcagagccc caacaagatg ctgacgctga gcgagatcta ccagtggatc atggacctct 780tccccttcta ccggcagaac cagcagcgct g 811176687DNAHomo sapiens 176cgccctccct cgccccggcc cccagggagg agggagagcc aggagaggcg cgagaaggga 60gggagagggc ggttaaagta tgctgggagc ggtgaagatg gaagggcacg agccgtccga 120ctggagcagc tactatgcag agcccgaggg ctactcctcc gtgagcaaca tgaacgccgg 180cctggggatg aacggcatga acacgtacat gagcatgtcg gcggccgcca tgggcagcgg 240ctcgggcaac atgagcgcgg gctccatgaa catgtcgtcg tacgtgggcg ctggcatgag 300cccgtccctg gcggggatgt cccccggcgc gggcgccatg gcgggcatgg gcggctcggc 360cggggcggcc ggcgtggcgg gcatggggcc gcacttgagt cccagcctga gcccgctcgg 420ggggcaggcg gccggggcca tgggcggcct ggccccctac gccaacatga actccatgag 480ccccatgtac gggcaggcgg gcctgagccg cgcccgcgac cccaagacct acaggcgcag 540ctacacgcac gcaaagccgc cctactcgta catctcgctc atcaccatgg ccatccagca 600gagccccaac aagatgctga cgctgagcga gatctaccag tggatcatgg acctcttccc 660cttctaccgg cagaaccagc agcgctg 687177798DNAHomo sapiens 177cggccgctgc tagaggggct gcttgcgcca ggcgccggcc gccccactgc gggtccctgg 60cggccggtgt ctgaggagtc ggagagccga ggcggccaga ccgtgcgccc cgcgcttctc 120ccgaggccgt tccgggtctg aactgtaaca gggaggggcc tcgcaggagc agcagcgggc 180gagttaaagt atgctgggag cggtgaagat ggaagggcac gagccgtccg actggagcag 240ctactatgca gagcccgagg gctactcctc cgtgagcaac atgaacgccg gcctggggat 300gaacggcatg aacacgtaca tgagcatgtc ggcggccgcc atgggcagcg gctcgggcaa 360catgagcgcg ggctccatga acatgtcgtc gtacgtgggc gctggcatga gcccgtccct 420ggcggggatg tcccccggcg cgggcgccat ggcgggcatg ggcggctcgg ccggggcggc 480cggcgtggcg ggcatggggc cgcacttgag tcccagcctg agcccgctcg gggggcaggc 540ggccggggcc atgggcggcc tggcccccta cgccaacatg aactccatga gccccatgta 600cgggcaggcg ggcctgagcc gcgcccgcga ccccaagacc tacaggcgca gctacacgca 660cgcaaagccg ccctactcgt acatctcgct catcaccatg gccatccagc agagccccaa 720caagatgctg acgctgagcg agatctacca gtggatcatg gacctcttcc ccttctaccg 780gcagaaccag cagcgctg 7981781079DNAMus musculus 178agcaaaacaa gaattcagaa ttaaagcatt ggagtcaaga gctctaaact ttttcaaaat 60gtggctgcat ctaggaaggg tgctgaaaga ttccaaacct cgtacgtaac agaattttct 120tttaaaaaca gcgataagct gtcagtcaat agctaggacc acctacctga caaagagctt 180cccaagagct ctaagtgttg gaatgtgaca ccagaaatca cgatttgtgc ataattaatc 240gcatcacttt gccacctaca ctgaagggca cagaccaagg gcagtgtatg taaatgtagt 300tccagtgtgc aaaccccact aatgaccttc gattaatgga gtcattatag taaccctgcc 360tcattcttgg gggtgggggg agttccgaat gcaccgggtc cctcggggct cctctgcggt 420ctgagggaga ccgcacagtg ttcctacaat tcgtgtcact gagtttccga gaaggcctcc 480cgcgttgctc caagttgcaa agcttcacgc taaacctgtc gtggacgtgt atgtgggcat 540tggctgcgaa cgcggaagaa ccgagagctc atactcacca atgggagaat tcgcctggta 600tgatggacgg gagcccttcc accaatggca attcagggat gcccgattga gcggccaggg 660cgagtgcaca taaaagacgc cccgcccggc tcgcgcttca ttctgaaccg agcctggtgc 720cgcgcagtca gctcagcccc ctgtggcggc tccctcccgg tcttcctcct acgagcagca 780tgaaagcctt cagtccggtg aggtccgtta ggaaaaacag cctgtcggac cacagcttgg 840gcatctcccg gagcaaaacc ccggtggacg acccgatgag tctgctctac aacatgaacg 900actgctactc caagctcaag gaactggtgc ccagcatccc ccagaacaag aaggtgacca 960agatggaaat cctgcagcac gtcatcgatt acatcttgga cctgcagatc gccctggact 1020cgcatcccac tatcgtcagc ctgcatcacc agagacctgg acagaaccag gcgtccagg 1079179385DNAMus musculus 179gcttcattct gaaccgagcc tggtgccgcg cagtcagctc agccccctgt ggcggctccc 60tcccggtctt cctcctacga gcagcatgaa agccttcagt ccggtgaggt ccgttaggaa 120aaacagcctg tcggaccaca gcttgggcat ctcccggagc aaaaccccgg tggacgaccc 180gatgagtctg ctctacaaca tgaacgactg ctactccaag ctcaaggaac tggtgcccag 240catcccccag aacaagaagg tgaccaagat ggaaatcctg cagcacgtca tcgattacat 300cttggacctg cagatcgccc tggactcgca tcccactatc gtcagcctgc atcaccagag 360acctggacag aaccaggcgt ccagg 385180117PRTMus musculus 180Met Lys Ala Phe Ser Pro Val Arg Ser Val Arg Lys Asn Ser Leu Ser1 5 10 15Asp His Ser Leu Gly Ile Ser Arg Ser Lys Thr Pro Val Asp Asp Pro 20 25 30Met Ser Leu Leu Tyr Asn Met Asn Asp Cys Tyr Ser Lys Leu Lys Glu 35 40 45Leu Val Pro Ser Ile Pro Gln Asn Lys Lys Val Thr Lys Met Glu Ile 50 55 60Leu Gln His Val Ile Asp Tyr Ile Leu Asp Leu Gln Ile Ala Leu Asp65 70 75 80Ser His Pro Thr Ile Val Ser Leu His His Gln Arg Pro Gly Gln Asn 85 90 95Gln Ala Ser Arg Thr Pro Leu Thr Thr Leu Asn Thr Asp Ile Ser Ile 100 105 110Leu Ser Leu Gln Val 115181479DNAHomo sapiens 181ggggacgaag ggaagctcca gcgtgtggcc ccggcgagtg cggataaaag ccgccccgcc 60gggctcgggc ttcattctga gccgagcccg gtgccaagcg cagctagctc agcaggcggc 120agcggcggcc tgagcttcag ggcagccagc tccctcccgg tctcgccttc cctcgcggtc 180agcatgaaag ccttcagtcc cgtgaggtcc gttaggaaaa acagcctgtc ggaccacagc 240ctgggcatct cccggagcaa aacccctgtg gacgacccga tgagcctgct atacaacatg 300aacgactgct actccaagct caaggagctg gtgcccagca tcccccagaa caagaaggtg 360agcaagatgg aaatcctgca gcacgtcatc gactacatct tggacctgca gatcgccctg 420gactcgcatc ccactattgt cagcctgcat caccagagac ccgggcagaa ccaggcgtc 479182409DNAHomo sapiens 182ttcattctga gccgagcccg gtgccaagcg cagctagctc agcaggcggc agcggcggcc 60tgagcttcag ggcagccagc tccctcccgg tctcgccttc cctcgcggtc agcatgaaag 120ccttcagtcc cgtgaggtcc gttaggaaaa acagcctgtc ggaccacagc ctgggcatct 180cccggagcaa aacccctgtg gacgacccga tgagcctgct atacaacatg aacgactgct 240actccaagct caaggagctg gtgcccagca tcccccagaa caagaaggtg agcaagatgg 300aaatcctgca gcacgtcatc gactacatct tggacctgca gatcgccctg gactcgcatc 360ccactattgt cagcctgcat caccagagac ccgggcagaa ccaggcgtc 409183117PRTHomo sapiens 183Met Lys Ala Phe Ser Pro Val Arg Ser Val Arg Lys Asn Ser Leu Ser1 5 10 15Asp His Ser Leu Gly Ile Ser Arg Ser Lys Thr Pro Val Asp Asp Pro 20 25 30Met Ser Leu Leu Tyr Asn Met Asn Asp Cys Tyr Ser Lys Leu Lys Glu 35 40 45Leu Val Pro Ser Ile Pro Gln Asn Lys Lys Val Ser Lys Met Glu Ile 50 55 60Leu Gln His Val Ile Asp Tyr Ile Leu Asp Leu Gln Ile Ala Leu Asp65 70 75 80Ser His Pro Thr Ile Val Ser Leu His His Gln Arg Pro Gly Gln Asn 85 90 95Gln Ala Ser Arg Thr Pro Leu Thr Thr Leu Asn Thr Asp Ile Ser Ile 100 105 110Leu Ser Leu Gln Pro 11518490DNAArtificial sequenceSynthetic oligonucleotide 184gtggatggcc ttgactgacg gcggctggtg cttgccgaag cgcttcgggg ccgcgggtgc 60ggacgccagc gactccagag cctttccagc 9018589DNAArtificial sequenceSynthetic oligonucleotide 185aggacccaga ctgctgcccc cgccctggcg tcccactttc cctgggccga gttgcatttc 60tctctggggc tcgcgttcgg gctggtcag 8918679DNAArtificial sequenceSynthetic oligonucleotide 186cagcgaggct tcgccttccc cctctccctt ttttttcctc ctcttccttc ctcctccagc 60cgccgccgaa tcatgtcga 7918789DNAArtificial sequenceSynthetic oligonucleotide 187tccggaggca gtgggaaggc gcggggctgg gaggccgcgg cgggagggag gagcagcccc 60ggcaggctca gccgccgccg aatcatgtc 89

Claims

1. A method of assessing whether a subject suffers from cancer or is prone to suffering from cancer, said method comprising the steps of a) measuring in a sample of said subject the amount of specific transcription factor isoforms wherein said specific transcription isoforms are i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2; b) comparing the amount of said specific transcription factor Em isoforms with the amount of said specific transcription factor Em isoforms in a control sample; and c) assessing that said subject suffers from cancer or is prone to suffering from cancer if the amount of said two specific transcription factor Em isoforms in said sample from said subject is increased in comparison to the amount of said specific transcription factor Em isoforms in the control sample.

2. The method according to claim 1, wherein the amount of said specific transcription factor isoform(s) is measured via a polymerase chain reaction-based method, an in situ hybridization-based method, or a microarray.

3. The method according to claim 2, wherein the amount of said specific transcription factor isoform(s) is measured via a polymerase chain reaction-based method and wherein said polymerase chain reaction-based method is a quantitative reverse transcriptase polymerase chain reaction.

4. The method according to claim 3, wherein the step of measuring in a sample of said subject the amount of a specific transcription factor comprises the contacting of the sample with primers, wherein said primers can be used for amplifying at least one of the specific transcription factor isoforms.

5. The method according to claim 4, wherein said primers are selected from the group of primers having a nucleic acid sequence as set forth in SEQ ID NOs 9 to 40.

6. The method according to any one of claims 1 to 5, wherein said step a) further comprises measuring in a sample of said subject the amount of one or two further specific transcription factor isoform(s) selected from the group of specific transcription factor isoforms consisting of i) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and ii) the ID2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4; and wherein for assessing that said subject suffers from cancer or is prone to suffering from cancer the amount of all analyzed specific transcription factor Em isoforms has to be increased in comparison to the amount of the analyzed specific transcription factor Em isoforms in the control sample.

7. The method according to any one of claims 1 to 6, wherein for assessing that said subject suffers from cancer or is prone to suffering from cancer the amount of said analyzed specific transcription factor Em isoform(s) has to be increased by at least 1.3-fold in comparison to the amount of the analyzed specific transcription factor Em isoform(s) in the control sample.

8. The method according to any of claims 1 to 7, wherein the amount of said specific transcription factor isoform(s) is measured on the polypeptide level.

9. The method according to claim 8, wherein the amount of said specific transcription factor isoform(s) is measured by an ELISA, a gel- or blot-based method, mass spectrometry, flow cytometry or FACS.

10. The method according to any one of claims 1 to 9, wherein said cancer is a lung cancer.

11. The method according to claim 10, wherein said lung cancer is an adenocarcinoma or a bronchoalveolar carcinoma.

12. The method according to any one of claims 1 to 11, wherein said sample comprises tumor cells.

13. The method according to any one of claims 1 to 12, wherein said sample is a breath condensate sample, a blood sample, a bronchoalveolar lavage fluid sample, a mucus sample or a phlegm sample.

14. The method according to any one of claims 1 to 12, wherein said sample is a breath condensate sample.

15. The method according to any one of claims 1 to 14, wherein said subject is a human subject.

16. The method of claim 15, wherein said human subject is a subject having an increased risk for developing cancer.

17. A method of treating a patient, said method comprising a) selecting a cancer patient according to the method of any of claims 1 to 16 b) administering to said cancer patient an effective amount of an anti-cancer agent and/or radiation therapy.

18. The method of treating a patient according to claim 17, wherein said anti-cancer agent is an inhibitor of i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; or ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

19. The method of treating a patient according to claim 17 or 18, wherein said cancer patient is a patient suffering from lung cancer.

20. The method of treating a patient according to claim 19, wherein said lung cancer is a lung adenocarcinoma or a bronchoalveolar carcinoma.

21. A kit for use in any of the methods according to claims 1 to 20 comprising reagents for measuring in a sample specifically the amount of two transcription factor isoforms selected from the group of specific transcription factor isoforms consisting of i) the GATA6 Em isoform comprising the nucleic acid sequence of SEQ ID No: 1 or the GATA6 Em isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 1; and ii) the NKX2-1 Em isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Em isoform comprising a nucleic acid sequence with up to 39 additions, deletions or substitutions of SEQ ID NO: 2.

22. The kit according to claim 21 further comprising reagents for measuring in a sample specifically the amount of one or two transcription factor isoforms selected from the group of specific transcription factor isoforms consisting of iii) the FOXA2 Em isoform comprising the nucleic acid sequence of SEQ ID No: 3 or the FOXA2 Em isoform comprising nucleic acid sequence with up to 68 additions, deletions or substitutions of SEQ ID NO: 3; and iv) the ID2 Ern isoform comprising the nucleic acid sequence of SEQ ID No: 4 or the ID2 Em isoform comprising nucleic acid sequence with up to 34 additions, deletions or substitutions of SEQ ID NO: 4.

23. The kit according to claim 21 or 22, further comprising reagents for measuring in a sample specifically the amount of one or several further transcription factor isoform(s) selected from the group of specific transcription factor isoforms consisting of i) the GATA6 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 5 or the GATA6 Ad isoform comprising a nucleic acid sequence with up to 55 additions, deletions or substitutions of SEQ ID NO: 5; ii) the NKX2-1 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 2 or the NKX2-1 Ad isoform comprising the nucleic acid sequence with up to 38 additions, deletions or substitutions of SEQ ID NO: 6; iii) the FOXA2 Ad isoform comprising the nucleic acid sequence of SEQ ID No: 7 or FOXA2 Ad isoform comprising the nucleic acid sequence with up to 74 additions, deletions or substitutions of SEQ ID NO: 3; and iv) the ID2 Ad isoform consisting of the nucleic acid sequence of SEQ ID No: 8 or ID2 Ad isoform consisting of nucleic acid sequence with up to 30 additions, deletions or substitutions of SEQ ID NO: 8;

24. The kit of any one of claims 21 to 23, wherein said sample is breath condensate sample or a blood sample.

25. The kit of any one of claims 21 to 23, wherein said sample is a breath condensate sample.

26. The kit of any one of claims 21 to 25, wherein said sample is a sample from a human subject.

27. The kit of claim 26, wherein the kit comprises one or several primers selected from the group of primers comprising the nucleic acid sequence of SEQ IDs 9 to 40.