REGULATOR GENES OF ANGIOGENESIS, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND THEIR APPLICATIONS

Abstract

the corresponding polypeptide sequences implicated in the regulation of angiogenesis are identified. The nucleotide and polypeptide sequences, or pharmaceutical composition made from such sequences can be used in the clinical study of the angiogenesis process, the prognosis, diagnosis and treatment of pathologies linked to angiogenesis, and in the implementation of pharmaceutical, pharmacogenomic and drug identification trials.

Description

[0001] This application is a new divisional application of co-pending U.S. application Ser. No. 10/947,476 filed on Sep. 9, 2004, which is the 35 U.S.C. §371 national stage of International PCT/FR03/00912 filed on Mar. 21, 2003, which claimed priority to French Application No. FR 02/03655 filed on Mar. 22, 2002. The entire contents of each of the above-identified applications are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention pertains to the treatment of angiogenic disorders, in particular to pharmaceutical compositions that are useful for the treatment of pathologies resulting from a deregulation of the angiogenesis mechanism.

BACKGROUND OF THE INVENTION

[0003] Angiogenesis is a fundamental process by means of which new blood vessels are formed. This process is essential in many normal physiological phenomena such as reproduction, development and cicatrization. Angiogenesis is under strict control in these normal biological phenomena; i.e., it is triggered during a brief period of several days and then completely inhibited. However, many pathologies are linked to invasive, uncontrolled angiogenesis. Arthritis, for example, is a pathology caused by damage caused to cartilage by invasive neovessels. In diabetic retinopathy, the invasion of the retina by neovessels results in the patients going blind; neovascularization of the ocular apparatus is the major cause of blindness and this neovascularization dominates at least twenty diseases of the eye. Lastly, the growth and metastasis of many tumors are directly dependent on angiogenesis. The tumor stimulates the growth of the neovessels for its own use. Furthermore, these neovessels present escape routes by means of which the tumors can reach the blood circulatory system and cause metastases in remote sites such as the liver, lungs or bones.

[0004] Angiogenesis can present an important therapeutic basis in other pathologies such as cardiovascular diseases, diseases of the peripheral arteries and vascular or cerebral lesions. In fact, the promotion of angiogenesis in damaged areas can lead to the formation of lateral blood neovessels as alternatives to the damaged vessels, thereby providing the damaged area with oxygen and other nutritive and biological factors necessary for the survival of the tissues in question.

[0005] The formation of neovessels by endothelial cells involves the migration, growth and differentiation of endothelial cells. Regulation of these biological phenomena is directly linked to genetic expression. An increasing number of studies have shown that the regulation of angiogenesis is implemented via an equilibrium among the factors acting directly on the endothelial cells. These factors can be stimulatory on the one hand, such as (among others) VEGF, FGFs, IL-8, HGF/SF and PDGF. The factors can also be inhibitory, such as (among others) IL-10, IL-12, gro-[alpha] and gro-[gamma], platelet factor 4, angiostatin, the human chondrocyte derivative inhibitor, thrombospondin and the leukemia inhibitor. (Jensen, 1998 Surg. Neural., 49, 189-195; Tamatani et al., 1999, Carcinogenesis, 20, 957-962; Tanaka et al., 1998, Cancer Res., 58, 3362-3369; Ghe et al., 1997, Cancer Res., 57, 3733-3740; Kawahara et al., 1998, Hepatology, 28, 1512-1517; Chandhuni et al., 1997, Cancer Res., 57, 1814-1819; Jendraschak and Sage, 1996, Semin. Cancer Biol., 7, 139-146; Majewski et al., 1996, J. Invest. Dermatol., 106, 1114-1119.)

[0006] The regulation of angiogenesis as described at present is implemented via an equilibrium of two types of factors:

the angiogenic factors (extracellular polypeptides, primarily mitogenic) acting directly on endothelial cells inducing angiogenesis; and the angiostatic factors (extracellular polypeptides, also mostly mitogenic and acting on mitogenesis), also acting directly on endothelial cells so as to inhibit angiogenesis.

[0007] The equilibrium between these two types of extracellular factors regulates angiogenesis. It should be noted at this stage that the control of angiogenesis is implemented via the production of angiogenic and angiostatic factors. For example, it has already been shown that the stimulation of the endothelial cell by an angiogenic factor induces the expression of 1) urokinase plasminogen activator (uPA) and its inhibitor PAI-I (Pepper et al., 1990, J. Cell Biol. 111(2), 743-44; Pepper et al., 1996, Enzyme Protein, 49 (1-3), 138-62); 2) matrix metalloproteinases (MMPs) and physiological inhibitors of the activity of these MMPs (TIMPs) (Cornelius et al., 1995, J. Invest. Dermatol., 105(2), 170-6; Jackson and Nguyen, 1997, Int. J. Biochem. Cell Biol., 29(10), 1167-77); 3) inhibitors such as angiopoietin-2 (Ang-2) or thrombospondin-1 (TSP-1) (Mandriota and Pepper, 1998, Circ. Res. 83, 852-859; Oh et al., 1999, J. Biol. Chem. 274(22), 15732-9; Suzuma et al., 1999, American Journal of Pathology, 154, 343-354.) It thus appears that an endothelial cell in the angiogenic state normally produces not only angiogenic factors but also produces angiostatic factors as well. The production of these angiostatic factors enables control of angiogenesis.

[0008] Parallel to this operation, endothelial cells stimulated by an angiostatic factor produce not only angiostatic factors, but also produce angiogenic factors for controlling the angiostatic state. This phenomenon has already been described for other types of cells that produce factors implicated in angiogenesis when they are stimulated by an angiostatic factor such as interferon-gamma (Kobayashi et al., 1995, Immunopharmacology, 31(1), 93-101; Arkins et al., 1995, Mol. Endocrinol., 9(3), 350-60; Kodelja et al., 1997, Immunobiology, 197(5), 478-93).

[0009] Angiopartnerine is homologous with the negative regulator of the prostaglandin F2 receptor (PTGFRN), (access no. XM_--040709, nucleic sequence: 5975 bp, protein sequence: 560 aa), with the protein 6 associated with the human smooth muscle cell (SMAP6) (accession no. AB014734, nucleic sequence: 2197 bp, partial protein sequence: 186 aa), identified by the numbers SEQ ID No. 27 and SEQ ID No. 28 respectively in the attached sequence listing, itself being similar to the regulatory protein of the prostaglandin F2 alpha (FPRP) also designated CD9P-1 and renamed EWI-F by Stipp et al. (2001, J. Biol. Chem., 276, 44, 40545-40554). The sequence GS-N1 comprises the sequences SEQ ID No. 27 and SEQ ID No. 28, presenting 99% of homology with them.

[0010] FPRP is a type 1 transmembrane glycoprotein containing 6 extracellular immunoglobulin domains. It was originally identified and characterized by its capacity to combine with prostaglandin F2 alpha and inhibit the binding of this prostaglandin with its receptor. It can also combine with other receptors that are coupled to G protein and contain 7 transmembrane domains, and reduce the ligand-receptor interaction (Orlicky and Nordeen, 1996, Prostaglandins Leukot. Essent. Fatty Acids, 55: 261-268; Orlicky et al., 1998, J. Lip. Res., Vol. 39, 1152-1161). The augmentation of the expression of FPLP has already been associated with cell differentiation, notably that of adipocytes (Orlicky et al., 1998, J. Lip. Res., Vol. 39, 1152-1161). Different studies have shown that CD9P-1 or FPLP is a major partner of two member of the tetraspanin family (also called TM4SF), CD9 and CD81 in protein complexes, combining specifically either with CD81 or with CD9 and CD81 (Charrin S. et al., 2001, J. Biol. Chem.; Stipp et al. (2001, J. Biol. Chem., 276, 7, 4854-4862). The tetraspanins have been implicated in many cellular functions such as adhesion, migration, co-stimulation, transduction of the signal and differentiation, the various functions attributed to the tetraspanins can be linked to their specific combination with the specific partner molecules (Le Naour et al., 2000, Science, 287, 319-321).

[0011] The protein CD9 has a broad tissue distribution; it has notably been found in various types of tumors (Si and Hersey, 1993, Int. J. Cancer, 54: 37-43; Miyake et al., 1996, Cancer Res., 56: 1244-1249) as well as in the vessels formed by endothelial cells (Zola et al., 1989, Immunol. Cell Biol.; 67: 63-70). This protein has been implicated in functions such as transduction of the signal, cell adhesion, motility, tumor progression (Ozaki et al., 1995, J. Biol. Chem., 270: 15119-15124; Forsyth, 1991, Immunology, 72: 292-296; Anton et al., 1995, J. Neurosci., 15: 584-595; Shaw et al., 1995, J. Biol. Chem., 270: 24092-24099; Ikeyama et al., 1993, J. Exp. Med., 177: 1231-1237) and notably the adhesion and migration of endothelial cells during angiogenesis (Klein-Soyer et al., 2000, Arterioscler. Thromb. Vasc. Biol., 20: 360-9). The overexpression of CD9 in adenocarcinoma cells suppresses their motility and metastatic potential (Ikeyama et al., 1993, J. Exp. Med., 177: 1231-1237); its expression is inversely correlated with the primary tumors and the appearance of metastases in melanomas, lung cancer, colon cancer and breast cancer (Si and Hersey, 1993, Int. J. Cancer, 54, 37-43; Miyake et al., 1995, Cancer Res., 55: 4127-4131; Adachi et al., 1998, J. Clin. Oncol., 15, 1397-1406; Mori et al., 1998, Clin. Cancer Res., 4, 1507-1510).

[0012] The protein CD9P-1 (or FPLP) was identified as being the major partner molecule of CD9 in cancer lines (Serru et al., 1999, Biochem. J., 340, 103-111).

[0013] It has also been reported that the protein CD81 is implicated in various functions such as cell signalization and activation of the B lymphocytes (Fearon and Carter, 1995), regulation of the proliferation of the T lymphocytes (Miyazaki et al., 1997, EMBO J., 16, 4217-4225); it could also play a role in cancer because CD81 is a possible receptor for hepatitis C virus, a major cause of hepatic carcinoma (Pileri et al., 1998, Science, 282, 938-941).

[0014] Although the exact role of CD9P-1 or FPRP has yet to be defined, its association with CD9 or CD81 can suggest a role in the regulation functions of the CD9 or CD81 receptors. However, no role in the regulation of angiogenesis has been reported to date for the protein called angiopartnerine, identified by the number SEQ ID No. 6 in attached sequence listing, nor for the proteins PTGFRN, CD9P-1/FPRP.

[0015] The protein NKX3.1 is a member of the NK class of Homeobox proteins, closely linked to the protein NK-3 of Drosophila (Kim, Y. and Nirenberg, 1989, Proc. Natl. Acad. Sci. USA, 86, 7716-7720; He et al., 1997, Genomics, 43, 69-77). Studies on the mouse showed the expression of the gene NKX3.1 in the fetus and embryo in development in a variety of tissue types such as the mesoderm, vascular smooth muscle, epithelium and regions of the central nervous system (Kos et al., 1998, Mech. Dev., 70, 25-34; Tanaka et al., 1999, Mech. Dev., 85, 179-182; Bhatia-Gaur et al., 1999, Genes Dev., 13, 966-977). In the adult, the protein NKX3.1 is localized predominantly in the prostate, more particularly in the epithelial cells, and its expression is regulated by the androgens (He et al., 1997, Genomics, 43, 69-77; Prescott et al., 1998, Prostate, 35, 71-80; Sciavolino et al., 1997, Dev. Dyn., 209, 127-138; Omstein et al., 2001, J. Urol., 165(4): 1329-34). It appears to play an essential role in the function of the prostate and regulates the proliferation of the epithelial cells of the prostate; the gene NKX3.1 was proposed to be a suppressor gene of the specific tumors of the prostate (Bhatia-Gaur et al., 1999, Genes Dev., 13(8): 966-966). The loss of expression of NKX3.1 in the human cancers of the prostate was recently correlated with the progression of tumors (Bowen et al., 2000, Cancer Res., 60(21): 6111-5). Moreover, it has already been reported that the homeobox proteins are implicated in the regulation of angiogenesis (review: Gorski and Walsh, 2000, Circulation Research, 87: 865-872).

[0016] However, no role for the homeobox protein NKX3.1 has been reported to date in the regulation of angiogenesis.

[0017] The protein hZFH (human zinc-finger helicase) belongs to the family of Snf2 type helicases known to act as transcriptional regulators for multiple genes (Aubry et al., 1998, Eur. J. Biochem., 243(3): 558-64). It also contains a chromodomain and is homologous with the protein CHD3 ("chromodomain helicase DNA binding protein 3") identified by the sequence SEQ ID No. 29 and SEQ ID No. 30 in the attached sequence listing. It has been reported that the CHD3 proteins could regulate the expression of genes by repressing transcription via an alteration of the structure of chromatin (Zhang et al., 1998, Cell, 95, 279-289; Kehle et al., 1998, Science, 282, 1898-1900). No role has been reported to date in the regulation of the expression of the genes implicated in angiogenesis either for the protein hZFH or for the protein CHD3.

[0018] Factor 3 of initiation of eukaryote translation (EIF3), the largest initiation factor of protein synthesis, with a size of 650 kDa, is composed of at least nine peptide subunits (Hershey et al., 1996, Biochimie, 78, 903-907), including subunit 8 (p110) (Asano et al., 1997, J. Biol. Chem., 272, 1101-1109). EIF3 plays a central role in the initiation process of protein biosynthesis notably in the binding of the initiator methionyl-tRNA and mRNA to the ribosome subunit 40S so as to form the initiation complex 40S (Merrick and Hershey, 1996, The pathway and mechanisms of eukaryotic protein synthesis. In: Hershey J W B, Mathews M B, Sonenberg N, eds. Translational Control. Cold Spring Harbor, N.Y.: Cold Spring Harbor Press; 1996; 31-67). EIF3 appears to play a central role in the initiation by interaction with numerous other translational components (Vornlocher et al., 1999, J. Biol. Chem., Vol. 274, Issue 24, 16802-16812). The functions of each subunit are still poorly understood. High levels of expression of certain subunits are detected in tumors such as p150, p170; it has been proposed that p170 plays another role in addition to its functions in the initiation of translation (Lin et al., 2001, J. Cell Biochem., 80(4): 483-90; Pincheira et al., 2000, Eur. J. Cell Biol., 80(6): 410-8). Overexpression of subunit 8 (p 110) has also been demonstrated in a tumor of the germinal cells by Roche et al. (2000, American Journal of Pathology, 157: 1597-1604) which suggests a role of this subunit in the development of the tumor by augmenting translation in general, leading to augmented growth and cell division. No implication in the regulation of angiogenesis of subunit 8 of EIF3 nor of its similar protein have been reported to date.

[0019] The control of angiogenesis thus represents a strategic axis both for fundamental research (in order to improve the comprehension of numerous pathological phenomena linked to angiogenesis) and for the development of new therapies intended to treat pathologies linked to angiogenesis.

[0020] In order to control angiogenesis, multiple pharmaceutical groups have therefore developed therapeutic strategies based directly on the use of paracrine stimulatory and inhibitory factors as agents for promoting or inhibiting angiogenesis. These strategies are based essentially on the use of such factors in their polypeptide form as stimulatory or inhibitory agents of angiogenesis, or more recently in the form of expression vectors coding for the selected factors.

SUMMARY OF THE INVENTION

[0021] The invention pertains to compositions comprising sequences of new genes, the function of which had not been identified to date. The implication of these genes in the angiogenesis mechanism has been demonstrated for the first time by the Applicant. Other gene sequences, at least one function of which had been previously identified, but for which the implication in the angiogenesis mechanism was demonstrated for the first time by the Applicant are also described. These genes are identified by their nucleotide sequences in the attached sequence listing. The present invention also pertains to the polypeptide sequences of the factors coded by said genes, which find their application in the clinical study of the angiogenesis process, the prognosis, diagnosis and treatment of pathologies linked to this process, as well as in the implementation of pharmacological, pharmacogenomic and drug identification trials.

[0022] The invention thus provides to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an active agent, comprising at least one substance selected from the group consisting of (i) a nucleic acid molecule, the expression of which is induced in an endothelial cell by an angiostatic agent, or a complementary sequence or a fragment of the nucleic acid molecule; (ii) a polypeptide sequence coded by the nucleic acid molecule or a fragment thereof; (iii) an antisense nucleic acid molecule that inhibits the expression of a nucleic acid molecule according to (i); and (iv) an antibody capable of binding to a polypeptide sequence according to (ii).

[0023] This invention also provides an antibody that has an affinity for one or more of the polypeptide sequences identified by SEQ ID No. 6 to SEQ ID No. 10 or by SEQ ID No. 31 to SEQ ID No. 34, or fragments thereof.

[0024] This invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an active compound comprising one or more antibodies.

[0025] This invention still further provides an antisense nucleotide sequence comprising at least 10 contiguous nucleotides of a nucleotide sequence selected from among the sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5, SEQ ID No. 12 to SEQ ID No. 14, and SEQ ID No. 27 to SEQ ID No. 30.

[0026] This invention also further provides a mammalian expression vector comprising at least one antisense sequence.

[0027] This invention also provides a method for the preparation of a genetically modified cell underexpressing a gene implicated in an angiogenic disorder, comprising inserting the vector into a mammalian cell.

[0028] This invention also provides a genetically modified cell, wherein the cell overexpresses at least one gene implicated in angiogenesis, and wherein the gene is identified by a nucleotide sequence selected from among the group of sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30, or fragments thereof.

[0029] This invention further still relates to a pharmaceutical composition comprising a genetically modified cell and a pharmaceutically acceptable carrier.

[0030] This invention also provides a method for the preparation of a recombinant protein, comprising the steps of a) constructing an expression vector comprising at least one sequence selected from those identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30, or fragments thereof; b) introducing the vector into a cellular host; c) culturing the cells in a suitable medium; and d) purifying the expressed protein so that the recombinant protein or a fragment thereof is expressed.

[0031] This invention also provides a method for the diagnosis and/or prognosis of an angiogenic pathology in a mammal, comprising detecting in cells isolated from the mammal the overexpression or the underexpression of one or more polypeptide sequences identified by the numbers SEQ ID No. 6 to SEQ ID No. 10 or SEQ ID No. 31 to SEQ ID No. 34, or fragments thereof.

[0032] This invention also provides a method for the verification of the therapeutic efficacy of an angiogenic treatment in a mammal, including identifying in vitro in a cell population from the mammal, the overexpression or the underexpression of at least one gene implicated in an angiogenic disorder, wherein the gene is identified by one of the nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30.

[0033] This invention also provides a method for screening for compounds useful for the treatment of an angiogenic disorder of a mammal, comprising a) detecting the expression of at least one nucleotide sequence identified by SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in a mammalian cell population contacted with a test compound; b) detecting the expression of the at least one nucleotide sequence in a reference cell population, the angiogenic state of which is known; and c) identifying the differences in the level of expression of the nucleotide sequences in the mammalian and reference cell populations, wherein a difference in expression of the nucleotide sequences in the mammalian and reference cell population indicates that the test compound has a therapeutic effect on an angiogenic disorder.

[0034] This invention also provides a device comprising a support comprising one or more specific probes of one or more nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30.

[0035] The invention also provides a kit for measuring the differential display of genes implicated in angiogenic disorders, comprising a device comprising a support comprising one or more specific probes of one or more nucleotide sequences; and specific primers and accessories required for the amplification of nucleotide sequences extracted from a sample, hybridization of such nucleotide sequences with the probes, and the performance of differential display measurements.

BRIEF DESCRIPTION OF THE DRAWING

[0036] FIGS. 1A-F are a photomicrographs of a human endothelial cell cultures showing capillary tube formation upon transfection of cells with the following expression vectors: 1A) GS-V1 coding for the specific antisense transcript of GS-N1; 1B) GS-V2 coding for the specific antisense transcript of GS-N2; 1C) GS-V3 coding for the specific antisense transcript of GS-N3; 1D) GS-V4 coding for the specific antisense transcript of GS-N4 and its homologue GS-N5; and 1F) empty vector (control).

DETAILED DESCRIPTION OF THE INVENTION

[0037] A method for the identification of new genes implicated in the regulation of angiogenesis has been developed. This method was the object of a French patent application published as FR no. 2798674 and of an International patent application published as WO 01/218312, the entire disclosures of which are herein incorporated by reference. This method has the distinctive characteristic of faithfully translating the innermost mechanisms regulating angiogenesis, taking into account all of the extracellular factors described as regulatory agents of angiogenesis; i.e., the angiogenic factors and angiostatic factors as well as the different components of the extracellular matrix. This method consists of bringing to bear these different extracellular factors via four clearly defined experimental conditions, in which endothelial cells are cultured on a component and/or on a clearly defined mixture of multiple components of the extracellular matrix and placed under the four experimental conditions, i.e.:

[0038] A control condition in which the endothelial cells are not stimulated.

[0039] An angiogenic condition in which the endothelial cells are stimulated by one or more angiogenic factors.

[0040] An angiogenesis inhibition condition in which the endothelial cells are stimulated by one or more angiogenic factors and brought into the presence of one or more angiostatic conditions.

[0041] Another control condition in which the endothelial cells are stimulated by one or more angiostatic factors.

[0042] By means of these four conditions, it is possible to obtain mRNA preparations specific of angiogenesis, i.e., of the angiogenic state and/or the inhibition of angiogenesis, and to make it possible to detect genes coding for the cellular constituents implicated in the regulation of angiogenesis, including positive regulators and negative regulators. Thus, the method described above enables the systematic screening of all of the angiogenic and angiostatic factors, as well as the different components of the extracellular matrix, for the purpose of revealing and identifying the genes coding for the cellular constituents implicated in the regulation of angiogenesis. Moreover, given that the gene expression can be analyzed all along the pathway of the formation of neovessels by endothelial cells, this approach constitutes an in vitro methodology making it possible to link the gene expression with the biological functional parameters of angiogenesis.

[0043] The identification of the five genes reported below was performed according to the above-described method, using the angiogenic and angiostatic factors as well as type I collagen as component of the extracellular matrix, in order to reproduce the four experimental conditions.

[0044] The five genes identified by the sequences SEQ ID No. 1 to SEQ ID No. 5 in the attached sequence listing are implicated in the regulation mechanism of angiogenesis.

[0045] In the present invention, the applicant demonstrated that the stimulation of endothelial cells by an angiostatic factor leads to the expression of genes coding for the cellular constituents implicated in the promotion of angiogenesis.

[0046] Thus, the stimulation of endothelial cells by an angiogenic factor or an angiostatic factor can induce expression of both positive and negative regulators of angiogenesis in those cells.

[0047] The invention more particularly pertains to a pharmaceutical composition active on angiogenesis phenomena, comprising a pharmaceutically acceptable carrier and an active agent comprising at least one substance selected from among: (i) a nucleic acid molecule from a gene of an endothelial cell, the expression of which is induced by an angiostatic factor, or a complementary sequence or a fragment or derivative thereof; (ii) a polypeptide sequence coded by (i); and (iii) a molecule capable of inhibiting the expression of a nucleic acid molecule according to (i) or of binding to a polypeptide sequence according to (ii).

[0048] Pharmaceutical compositions of the invention can be for human or veterinary use, and are preferably sterile and pyrogen free. Pharmaceutical compositions of the invention comprise, in addition to at least one active ingredient, at least one pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include water (e.g., sterile water for injection); saline solutions such as physiological saline or phosphate buffered saline (PBS); polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose; stabilizing or preservative agents, such as sodium bisulfite, sodium sulfite and ascorbic acid, citric acid and its salts, ethylenediaminetetraacetic acid, benzalkonium chloride, methyl- or propylparaben chlorobutanol; and combinations thereof.

[0049] According to one particular embodiment, the pharmaceutical composition of the invention comprises as an active compound at least one nucleotide sequence selected from among the group of nucleotide sequences identified by numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, their complementary sequences and their corresponding antisense sequences, or one of their fragments or derivatives.

[0050] In the context of the present invention, the term "equivalent sequences" (also called "derivative sequences" or "derivatives") with respect to the present nucleic acid sequences includes nucleotide sequences presenting minor structural modifications not modifying their function, such as deletions, mutations or additions of bases, the identity of which is at least about 90%, for example at least about 95%, at least about 98%, or at least about 99%, with the nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5, and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing. One skilled in the art can readily identify derivatives of the present nucleic acids by testing them for the ability to regulate angiogenesis in the human endothelial cell culture assays described in the "Examples" section below. As used herein, "fragments" of the present nucleic acids comprise a smaller, contiguous sequence of nucleotides found within a larger nucleic acid sequence.

[0051] According to another embodiment, the pharmaceutical composition of the invention comprises at least one angiogenesis inhibitory sequence.

[0052] According to one embodiment, the pharmaceutical composition of the invention comprises one or more angiogenesis inhibitory sequences comprising an antisense sequence of at least one sequence selected from among SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, or fragments or derivatives thereof.

[0053] The pharmaceutical composition of the invention preferably comprises one or more antisense sequences selected from among SEQ ID No. 11 to SEQ ID No. 14 in the attached sequence listing.

[0054] The invention also provides a pharmaceutical composition intended for the diagnosis, prognosis and/or treatment of pathologies linked to angiogenesis, characterized in that it comprises at least one polypeptide sequence selected from among the polypeptide sequences identified by the numbers SEQ ID No. 6 to SEQ ID No. 10 or among the polypeptide sequences identified by the numbers SEQ ID No. 31 to SEQ ID No. 34 in the attached sequence listing, or their fragments or derivatives.

[0055] In the context of the present invention, the term "equivalent sequences" with respect to the present polypeptide sequences (also called "derivative sequences" or "derivatives") should be understood to encompass polypeptide sequences presenting minor structural modifications not modifying their function, such as deletions, mutations or additions of amino acid residues, the identity of which is at least about 85%, preferably at least about 90%, for example at least about 95%, at least about 98% or at least about 99%, with the polypeptide sequences identified by the numbers SEQ ID No. 6 to SEQ ID No. 10 or with the polypeptide sequences identified by the numbers SEQ ID No. 31 to SEQ ID No. 34 in the attached sequence listing. One skilled in the art can readily identify derivatives of the present polypeptides by testing them for the ability to regulate angiogenesis in the human endothelial cell culture assays described in the "Examples" section below. As used herein, "fragments" of the present polypeptides comprise a smaller, contiguous sequence of amino acids found within a larger polypeptide sequence.

[0056] The invention also provides a pharmaceutical composition intended for the diagnosis, prognosis and/or treatment of pathologies linked to angiogenesis comprising at least one antagonist of one or more of the above-mentioned polypeptide sequences.

[0057] As used herein, the term "antagonist" is understood to mean any compound inhibitory of the biological activity of said polypeptide sequences in the angiogenesis mechanism, for example as measured by the endothelial cell culture assays described in the "Examples" section below.

[0058] Suitable antagonists comprise antibodies having an affinity for the present polypeptide sequences.

[0059] The invention also pertains to antibodies having an affinity for each of the polypeptide sequences identified by the numbers SEQ ID No. 6 to SEQ ID No. 10 or with the polypeptide sequences identified by the numbers SEQ ID No. 31 to SEQ ID No. 34 in the attached sequence listing, or for one of their fragments or derivatives, as well as pharmaceutical compositions containing them.

[0060] The antibodies of the invention can be obtained from an immunocompetent cell of an animal by any in vivo or in vitro immunization method, notably an immunocompetent cell from a vertebrate and preferably a mammal, with any one of the polypeptide sequences identified by the numbers SEQ ID No. 6 to SEQ ID No. 10 or with the polypeptide sequences identified by the numbers SEQ ID No. 31 to SEQ ID No. 34 in the attached sequence listing, or one of their fragments or derivatives conserving the immunogenicity of the total protein. Suitable immunization methods that can be used to produce antibodies of the invention are within the skill in the art; see, e.g., Kohler G. and Milstein C., Nature 1975 Aug. 7; 256(5517): 495-497, the entire disclosure of which is herein incorporated by reference.

[0061] The antibodies of the invention can be polyclonal or monoclonal antibodies.

[0062] The invention also pertains to a pharmaceutical or diagnostic composition comprising one or more antibodies having an affinity for one or more of the polypeptide sequences identified by the numbers SEQ ID No. 6 to SEQ ID No. 10 or with the polypeptide sequences identified by the numbers SEQ ID No. 31 to SEQ ID No. 34, or by one of their fragments or derivatives conserving this affinity or prepared as indicated above.

[0063] The invention also provides antisense nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing.

[0064] In the context of the present invention, the term "antisense sequence" is understood to mean any DNA sequence of at least 10 contiguous nucleotides complementary to at least a portion of an mRNA, which inhibits its expression of that mRNA; i.e., inhibits its translation into a protein.

[0065] The antisense sequences of the invention can have an identity of at least about 80%, at least about 85% or at least about 90%, preferably at least about 95%, and more preferably at least about 99%, with a sequence selected from among the sequences identified by the numbers SEQ ID No. 11 to SEQ ID No. 14 in the attached sequence listing.

[0066] The invention also provides a mammalian expression vector comprising at least one antisense sequence as defined above for expression of the antisense sequence

[0067] According to a preferred embodiment, said mammalian expression vector comprises at least one antisense sequence of at least one of the sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30, or fragments or derivatives thereof, in the attached sequence listing, as well as a promoter which enables expression of said antisense DNA.

[0068] Said vector is more particularly selected from among the group of vectors GS-V1 to GS-V4 identified by their sequence bearing the numbers SEQ ID No. 15 to SEQ ID No. 18 in the attached sequence listing.

[0069] Moreover, introduction of said antisense sequences identified by the numbers SEQ ID No. 11 to SEQ ID No. 14 in the attached sequence listing, or one of their derivatives, into the mammalian expression vectors and subsequent insertion of said vectors in mammalian cells enables production of cell lines underexpressing genes intervening in the angiogenesis mechanism.

[0070] The invention thus also provides a genetically modified cell comprising at least one of the vectors comprising antisense sequences for underexpressing at least one nucleotide sequence selected from among the sequences SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing.

[0071] The invention also provides a method for the preparation of such a genetically modified cell underexpressing a gene implicated in an angiogenic disorder, characterized in that it comprises the insertion into a mammalian cell of one of the previously described expression vectors.

[0072] Thus, for the construction of these vectors, specific primers are designated for each of the identified sequences. These primers comprise restriction sites at their ends that are not contained in the cloned fragment or present in the multiple cloning region of the expression vector.

[0073] Preferred primers are indicated in Table I and are identified by the sequence numbers SEQ ID No. 19 to SEQ ID No. 26 in the attached sequence listing.

[0074] The invention also provides a mammalian expression vector comprising at least one nucleotide sequence selected from among the group of sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, or one of their fragments or derivatives.

[0075] The expression vectors described above are useful for preparing therapeutic compositions intended for treatment by cell therapy of angiogenic disorders and, for verifying the efficacy of a treatment of an angiogenic disorder in a mammal, notably in a human being, or for verifying the functionality of genes possibly implicated in the angiogenesis mechanism in said mammal.

[0076] The invention also pertains to a method for the preparation of a genetically modified cell line stably expressing an expression vector, said vector comprising at least one antisense sequence of at least one of the sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing or fragments or derivatives thereof, as well as a promoter which enables expression of said antisense DNA, comprising the following steps:

a) introducing at least one antibiotic resistance gene into said genetically modified cell; b) culturing the cells obtained in step a) in the presence of said antibiotic; and c) selecting the viable cells.

[0077] The invention also pertains to a genetically modified cell comprising at least one vector comprising a nucleotide sequence selected from among the group of sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, or one of their fragments or derivatives overexpressing said sequence.

[0078] The invention also pertains to a pharmaceutical composition intended for the diagnosis, prognosis and/or treatment of pathologies linked to angiogenesis, comprising as an active agent said genetically modified cell, and a pharmaceutically acceptable carrier.

[0079] The invention thus pertains to a method for the preparation of a genetically modified cell line stably expressing an expression vector, said vector comprising at least one of the sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, or one of their fragments or derivatives, as well as a promoter which enable expression of said sequence, comprising the following steps:

a) introducing at least one antibiotic resistance gene into said genetically modified cell; b) culturing the cells obtained in step a) in the presence of said antibiotic; and c) selecting the viable cells.

[0080] It is thus possible to isolate human cells and transfect them in vitro with at least one of the vectors defined above, which vectors comprise at least one of the sequences defined by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30, or one of their fragments or derivatives. These genetically modified cells can then be administered to a mammal, preferably to a human being.

[0081] The therapeutic compositions containing such cells can be administered in the form of simple cell suspensions, but they can also be encapsulated in a suitable device using, e.g., semipermeable membranes.

[0082] The invention also provides a method for preparing a protein encoded by at least one of the genes the sequences of which are identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, or one of their fragments or derivatives.

[0083] The proteins identified by the sequences SEQ ID No. 6 to SEQ ID No. 10 and SEQ ID No. 31 to SEQ ID No. 34 in the attached sequence listing, or their fragments or derivatives can be produced in the form of recombinant proteins in vitro by introducing into a suitable host a suitable expression vector. The proteins (or fragments or derivatives thereof) can then be purified and subsequently used as a therapeutic agent.

[0084] Such a method for the preparation of a recombinant protein according to the invention comprises the following steps:

a) constructing an expression vector comprising at least one sequence from among those identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing or one of their fragments or derivatives; b) introducing said vector into a cellular host; c) culturing said cells in a suitable medium; and d) purifying the expressed proteins or one of their fragments or derivatives.

[0085] The invention also provides to a recombinant protein obtained by the above method.

[0086] The invention also provides a pharmaceutical composition comprising such a recombinant protein and a pharmaceutically acceptable carrier.

[0087] As an example, expression systems of recombinant proteins in bacteria such as E. coli can be used for expressing non-glycosylated proteins or polypeptides

[0088] The coding sequence or a partial sequence of the gene of interest can be amplified by PCR using specific primers of this gene preferably with different restriction enzyme sites at their ends so as to enable the orientation of the amplified gene sequence in the expression vector. The amplified DNA is purified, then digested by the restriction enzymes and inserted by ligation into the expression vector previously digested by these same restriction enzymes. A large number of different vectors can be used, such as the vector pBR322 (Bolivar et al., Gene 2 (1977) 95-113, the entire disclosure of which is herein incorporated by reference) or its derivatives, containing, e.g., the promoter of the RNA polymerase of the bacteriophage T7 for a high level of expression, or the plasmid pET3a (Studier and Moffatt, 1986, J. Mol. Biol., 189(1): 113-30, the entire disclosure of which is herein incorporated by reference), preferably containing sequences coding for the selection markers (e.g., resistance to antibiotics), a multiple cloning site containing restriction enzyme sites suitable for the insertion of DNA. The cell/host system is preferably an inducible system such as that used for the in vivo radiotagging of the growth factor FGF2 (Colin et al., 1997, Eur. J. Biochem., 249, 473-480, the entire disclosure of which is herein incorporated by reference) and previously described by Patry et al. (1994, FEBS Lett., 349(1): 23-8, the entire disclosure of which is herein incorporated by reference); it can also contain a region coding for a polyhistidine tail at the end of the polypeptide of interest in order to facilitate purification.

[0089] The amplified DNA can be ligated in the plasmid, which is then transformed into the bacterium according to the method described by Sambrook et al. (1989, Molecular Cloning: A Laboratory Manual, 2^nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.). The transformed cells were spread on LB agar medium containing the antibiotics, the colonies resistant to the antibiotics were then controlled by PCR and then analyzed on gel. The plasmid DNA can then be isolated then sequenced to confirm the construction of the vector. Other suitable methods for producing recombinant protein are known in the art. For example, the production and purification of the recombinant protein can be performed as described (Patry et al., 1994, FEBS Lett., 349(1): 23-8, 473-480, the entire disclosure of which is herein incorporated by reference).

[0090] In brief, an isolated colony is inoculated in the liquid culture medium such as LB broth medium with the addition of the antibiotics. After incubation overnight, the preculture can be used to seed a culture of a larger volume. The expression of the polypeptide was then induced, the cells developed over several hours and were then collected by centrifugation. The cellular deposit can by lysed by chemical agents known in the art or mechanically, e.g., by sonication. The protein can be purified by means of its physicochemical properties as described for the purification of recombinant FGF2 (Colin et al., 1997, Eur. J. Biochem., 249, 473-480, the entire disclosure of which is herein incorporated by reference) or, if the protein is tagged with a polyhistidine tail, it can be purified via this tail by immobilization on a metallic ion chelator support as described (Tang et al., Protein Expr. Purif. 1997 Dec. 11(3): 279-83, the entire disclosure of which is herein incorporated by reference).

[0091] As an example, eukaryotic recombinant protein expression systems (e.g., from yeasts, plants, insects) for expressing polypeptides having post-translational modifications such as glycosylation can be used.

[0092] Thus, the recombinant protein can be produced, e.g., in the yeast Pichia pastoris as described by Sreekrishna et al. (1988, J. Basic Microbiol., 28(4): 265-78, the entire disclosure of which is herein incorporated by reference). The amplified DNA can be introduced in the same manner described above after digestion and ligation in an expression vector of Pichia pastoris, preferably containing a sequence coding for a selection marker (Scorer et al., Biotechnology (NY), 1994 February; 12(2): 181-184, the entire disclosure of which is herein incorporated by reference). The protein can be either intracellular or secreted if the vector contains sequences for introducing into the expressed sequence a sequence coding for a secretion signal sequence such as, e.g., the prepropeptide factor of Saccharomyces cerevisiae (Cregg et al., 1993; Scorer et al., 1993, the entire disclosure of which is herein incorporated by reference). A histidine tail can also be added to one of the ends of the recombinant protein in order to facilitate purification (Mozley et al., 1997, Photochem. Photobiol., 66(5): 710-5, the entire disclosure of which is herein incorporated by reference).

[0093] Said host is preferably selected from among: a bacterium, a yeast, an insect cell, a mammal cell, and a plant cell.

[0094] The administration of pharmaceutical compositions comprising recombinant proteins as described above can be implemented, e.g., via the topical, oral, intradermal, transdermal intra-ocular or intravenous route, or any other suitable enteral or parenteral route.

[0095] In the practice of the present invention, the fragments of said proteins can be used as antagonists of the protein from which they originate. Thus, the suitable administration to an animal of a pharmaceutical composition comprising such fragments is recommended for inducing a diminution in the activity of said protein in the angiogenesis mechanism of a given pathology.

[0096] The present invention also pertains to a method for the diagnosis and/or prognosis of an angiogenic pathology in a mammal, notably in a human being, consisting of detecting in the cells of said mammal the overexpression or the underexpression of one or more nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing.

[0097] Such a diagnostic and/or prognostic method comprises the following steps:

detecting the expression of one or more of said nucleotide sequences SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in a mammalian cell population; detecting the expression of the nucleotide sequences in a reference cell population, the angiogenic state of which is known; and identifying the differences in the level of expression of the nucleotide sequences in the two cell populations, wherein a difference in the expression of more nucleotide sequences in the mammalian and reference cell populations indicates the presence of, or susceptibility to, an angiogenic pathology in the mammal.

[0098] As used herein, a "cell population of a mammal" or "mammalian cell population" is a collection of mammalian cells of a certain type or lineage, or which are obtained from the same tissue or organ. It is understood that a cell population of a mammal can comprise different cell types; for example, when the population is obtained from the same tissue (e.g., blood) or organ (e.g., the liver). A cell population of a mammal can be obtained from both in vivo and in vitro (i.e., cultured cell) sources.

[0099] As used herein, a "reference cell population" is a collection of cells of a certain type or lineage, or which are obtained from the same tissue or organ, for which the angiogenic state is known. It is understood that a "reference cell population" can comprise different cell types, and can also be obtained from both in vivo and in vitro sources.

[0100] As used herein, a gene is "overexpressed" when that gene produces an amount of RNA and/or corresponding protein in a cell population of a mammal which is greater than the amount of RNA and/or corresponding protein produced from the same gene in a reference cell population.

[0101] As used herein, a gene is "underexpressed" when that gene produces an amount of RNA and/or corresponding protein in a cell population of a mammal which is less than the amount of RNA and/or corresponding protein produced from the same gene in a reference cell population.

[0102] The present invention also pertains to a method for the diagnosis and prognosis of an angiogenic pathology in a mammal, notably in a human being, consisting of detecting in the cells of said mammal the overexpression or underexpression of one or more polypeptides identified by the numbers SEQ ID No. 6 to SEQ ID No. 10 or by the numbers SEQ ID No. 31 to SEQ ID No. 34 in the attached sequence listing.

[0103] According to a preferred embodiment, said method comprises the following steps:

a) detecting the expression of one or more polypeptide sequences SEQ ID No. 6 to SEQ ID No. 10 or SEQ ID No. 31 to SEQ ID No. 34 in a mammalian cell population; b) detecting the expression of the polypeptide sequences in a reference cell population, the angiogenic state of which is known; and c) identifying the differences in the level of expression of the polypeptide sequences in the two cell populations, wherein a difference in expression of the polypeptide sequences in the mammalian and reference cell populations indicates the presence of, or susceptibility to, an angiogenic pathology in the mammal.

[0104] According to one particular embodiment, in the diagnostic and prognostic method of the invention, the detection of expression of the sequences is performed after having contacted the endothelial cells with a biological fluid obtained from a patient.

[0105] The present invention also pertains to a method for the verification of the therapeutic efficacy of an angiogenic treatment in a mammal, notably in a human being, by the identification of a cell population in said mammal that overexpresses or underexpresses one or more nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing.

[0106] Such a method for the verification of therapeutic efficacy can comprise the following steps: detecting the expression of one or more of said nucleotide sequences SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 by a cell population from a mammal contacted with a test compound intended to treat an angiogenic disorder. As used herein, such a test compound is a compound which is suspected or is capable of having, or which has, a therapeutic effect on an angiogenic pathology;

detecting the expression of the nucleotide sequences in a reference cell population, the angiogenic state of which is known; and identifying the differences in the level of expression of the nucleotide sequences in the two cell populations, wherein a difference in expression of the nucleotide sequences in the mammalian and reference cell populations indicates that the test compound has therapeutic efficacy.

[0107] According to a preferred embodiment, the verification method is performed on a cell population from a mammal in vivo, ex-vivo or on a cell population isolated from said mammal in vitro.

[0108] According to one particular embodiment, in the verification method of the invention the detection of the expression of the sequences is performed after having contacted the endothelial cells with a biological fluid from a patient.

[0109] The present invention also pertains to a method for screening for compounds useful for the angiogenic treatment of a mammal, notably a human being.

[0110] According to one preferred embodiment, such a screening method comprises the following steps:

detecting the expression of one or more of said nucleotide sequences SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in a mammalian cell population contacted with a test compound suspected of or capable of having, or which has, a therapeutic effect on an angiogenic pathology; detecting the expression of the nucleotide sequences in a reference cell population, the angiogenic state of which is known; and identifying the differences in the level of expression of the nucleotide sequences in the two cell populations, wherein a difference in expression of nucleotide sequences in the mammalian and reference cell populations indicates that the test compound has a therapeutic effect on an angiogenic pathology.

[0111] According to another preferred embodiment, such a screening method also comprises the following steps:

detecting the expression of one or more of said polypeptide sequences identified by the numbers SEQ ID No. 5 to SEQ ID No. 10 or with the polypeptide sequences identified by the numbers SEQ ID No. 31 to SEQ ID No. 34 in the attached sequence listing in a cell population contacted with a test compound suspected of or capable of having, or which has, a therapeutic effect on an angiogenic pathology; detecting the expression of the polypeptide sequences in a reference cell population, the angiogenic state of which is known, and identifying the differences in the level of expression of the polypeptide sequences in the two cell populations, wherein a difference in expression of polypeptide sequences in the mammalian and reference cell populations indicates that the test compound has a therapeutic effect on an angiogenic disorder.

[0112] According to one particular embodiment of the screening method of the invention, the detection of the expression of the sequences is performed after having contacted the endothelial cells with a biological fluid from a patient.

[0113] As used herein, a compound has a "therapeutic effect" or "therapeutic efficacy" on an angiogenic pathology when, upon administration of that compound to an individual suffering from an angiogenic pathology, the symptoms of the angiogenic pathology are lessened, prevented or otherwise alleviated, or the growth of new blood vessels in the region of the angiogenic pathology is slowed or halted. In the practice of the present method, it is understood that a test compound which causes a difference in the expression of nucleotide sequences between a cell population of a mammal and a reference population indicates that the test compound has a therapeutic effect on an angiogenic pathology.

[0114] The following can be cited among the angiogenic disorders (also called "angiogenic pathologies") that could be diagnosed or treated with the pharmaceutical compositions of the invention: tumor vascularization, retinopathies (e.g., diabetic retinopathy), rheumatoid arthritis, Crohn's disease, atherosclerosis, hyperstimulation of the ovary, psoriasis, endometriosis associated with neovascularization, restenosis due to balloon angioplasty, tissue overproduction due to cicatrization, peripheral vascular disease, hypertension, vascular inflammation, Raynaud's disease and phenomena, aneurism, arterial restenosis, thrombophlebitis, lymphangitis, lymphedema, tissue cicatrization and repair, ischemia, angina, myocardial infarction, chronic heart disease, cardiac insufficiencies such as congestive heart failure, age-related macular degeneration and osteoporosis.

[0115] The invention also provides a device comprising a support comprising one or more specific probes of one or more nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, or fragments or derivatives thereof, for the implementation of the screening method of the invention.

[0116] In the framework of the present invention, the term "probe" is understood to mean any single-stranded DNA fragment, the sequence of which is complementary to a targeted sequence: this sequence can be detected by hybridization with the tagged sequence (tagged by radioactive atoms or fluorescent groups) which play the role of a molecular "fish hook."

[0117] According to a preferred embodiment, the support of said device is selected from among a glass membrane, a metal membrane, a polymer membrane and a silica membrane.

[0118] Such devices can comprise, e.g., DNA chips comprising one or more nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, or fragments or derivatives thereof.

[0119] The invention also provides a kit for measuring the differential display of genes implicated in angiogenic disorders, comprising a device as previous described, specific primers and the accessories required for the amplification of sequences extracted from a sample, their hybridization with the probes of the device, and the performance of the measurements of the differential display.

[0120] The invention also provides a kit intended for the measurement of the differential display of genes implicated in angiogenic disorders, comprising a line of genetically modified cells stably expressing a vector expressing at least one of the nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, or one of their fragments or derivatives, as a reference cell population and the means necessary for the measurement of said differential display.

[0121] The invention also provides a kit intended for the measurement of the differential display of genes implicated in angiogenic disorders, comprising a line of genetically modified cells stably expressing a vector expressing at least one antisense sequence of one of the nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in the attached sequence listing, or one of their fragments or derivatives, as a reference cell population, and the means necessary for the measurement of said differential display.

[0122] Verification of the implication of the five identified genes and their homologues in the angiogenesis mechanism was performed according to the methodology described in the Materials and Methods section.

[0123] This verification is further illustrated by means of the attached FIG. 1, which shows the results obtained on the formation of capillary tubes on human endothelial cells under the effect of the expression of the vectors GS-V1, GS-V2, GS-V3 and GS-V4:

[0124] FIG. 1A shows that the formation of capillary tubes is inhibited in endothelial cells transfected with the vector GS-V1 coding for the specific antisense transcript of GS-N1.

[0125] FIG. 1B shows that the formation of capillary tubes is inhibited in endothelial cells transfected with the vector GS-V2 coding for the specific antisense transcript of GS-N2.

[0126] FIG. 1C shows that the formation of capillary tubes is inhibited in endothelial cells transfected with the vector GS-V3 coding for the specific antisense transcript of GS-N3.

[0127] FIG. 1D shows that the formation of capillary tubes is inhibited in endothelial cells transfected with the vector GS-V4 coding for the specific antisense transcript of GS-N4 and its homologue GS-N5.

[0128] FIG. 1E shows that the formation of capillary tubes is not modified by endothelial cells transfected with the empty vector (control).

[0129] The invention will now be illustrated by the following non-limiting examples. Throughout the Examples, certain suitable or preferred embodiments or elements of the invention beyond those which were employed in the Examples are indicated.

EXAMPLES

Material and Methods

1. Culture of the Cells and Angiogenesis Test

[0130] Human endothelial cells from umbilical veins (HUVEC) grown under the following four culture conditions (see WO 01/218312, supra) were used for identifying the genes coding for the cellular constituents implicated in the regulation of angiogenesis:

[0131] A control condition in which the endothelial cells are not stimulated.

[0132] An angiogenic condition in which the endothelial cells are stimulated by one or more angiogenic factors.

[0133] An angiogenesis inhibition condition in which the endothelial cells are stimulated by one or more angiogenic factors and brought into the presence of one or more angiostatic conditions.

[0134] Another control condition in which the endothelial cells are stimulated by one or more angiostatic factors.

[0135] The endothelial cells were maintained in complete medium (EGM-2-MV from Clonetics).

[0136] For the identification of the genes implicated in angiogenesis in the in vitro angiogenesis test according to the model of Montesano et al. (1986, Proc. Natl. Acad. Sci. USA, 83(19), 7297-301, the entire disclosure of which is herein incorporated by reference), the cells were first cultured on a collagen type I gel in complete medium until confluence. The reference HUVEC cells were then cultured in serum-poor medium without growth factors: EBM-2-MV+2% serum and different factors were added in the test conditions as follows.

[0137] FGF2: at concentrations comprised between 5 ng/ml and 60 ng/ml, preferably between 10 and 40 ng/ml; VEGF: at concentrations comprised between 10 ng/ml and 60 ng/ml, preferably comprised between 30 ng/ml and 50 ng/ml; PF4: at concentrations between 0.1 and 5μg/ml, preferably between 0.5μg/ml and 1μg/ml; TNF-alpha: at concentrations comprised between 20 ng/ml and 100 ng/ml, preferably comprised between 30 ng/ml and 60 ng/ml; IFN-gamma: at concentrations comprised between 50 ng/ml and 200 ng/ml, preferably between 80 ng/ml and 120 ng/ml.

[0138] The human endothelial cells placed under the previously mentioned four culture conditions were then used to identify the genes coding for the cellular constituents implicated in the regulation of angiogenesis.

2. Angiogenic and Angiostatic Factors

[0139] The angiogenic and angiostatic factors which were found to have an effect on the expression of the genes identified in correlation with the formation of neovessels or the inhibition of neovessels respectively, are described below.

VEGF=vascular endothelial growth factor. PF4=platelet factor 4. TNF-α=tumor necrosis factor alpha

[0140] TNF-α, which is a regulator of angiogenesis, can induce angiogenesis in vivo but also inhibit the formation of vessels in vitro (Frater-Schroder et al., 1987, Proc. Natl. Acad. Sci. USA, 84(15), 5277-81; Sato et al., 1987, J. Natl. Cancer Inst. 79(6), 1383-91; Fajardo et al., 1992, Am. J. Pathol. Mar, 140(3), 539-44; Niida et al., 1995, Neurol. Med. Chir. (Tokyo), 35(4), 209-14). In the in vitro model of angiogenesis used herein, TNF-α was used under angiogenesis inhibition conditions.

3. Comparison of the Gene Expression

[0141] Gene expression can then be compared using DNA chips, SAGE, quantitative PCR amplification reaction, viral vectors to construct subtractive banks or differential display analysis. In the framework of the experimental studies supporting the present invention, the Applicant preferentially used the differential display technique for the identification of said genes.

Differential Display

[0142] RNA was prepared from HUVEC cells cultured on a collagen gel in the presence of the different factors employed by means of the RNeasy Mini kit (Qiagen) method integrating a step of DNase I digestion as recommended by the manufacturer.

[0143] Differential display from the total RNAs was performed according to the method described by Liang and Pardee (1992, Science, 14; 257(5072), 967-7, the entire disclosure of which is herein incorporated by reference) using alpha_P33-ATP in isotopic dilution during the PCR amplification, for the visualization by autoradiography of the electrophoresis gels.

[0144] Thus, the DNA fragments differentially present on the gel as a function of the culture conditions analyzed were cut out, reamplified, cloned in a PGEM easy vector plasmid (Promega), sequenced and identified by querying the BLAST bank.

4. Verification of the Implication of the Identified Genes in the Angiogenesis Mechanism Functionality Test of the Genes

[0145] In a second step, the functionality of each identified sequence was tested in the in vitro angiogenesis model, with endothelial cells transfected with an expression vector comprising an antisense oligonucleotide of said sequence.

[0146] For the construction of these vectors, specific primers for each of the identified sequences were designated. These primers are indicated in Table I below and identified with the numbers of SEQ ID No. 19 to SEQ ID No. 26 in the attached sequence listing.

TABLE-US-00001 TABLE I ID SEQ of the identified gene Name of primer SEQ ID No. 1 (GS-N1) GV1-1 GV1-2 SEQ ID No. 2 (GS-N2) GV2-1 GV2-2 SEQ ID No. 3 (GS-N3) GV3-1 GV3-2 SEQ ID No. 4 (GS-N4) GV4-1 GV4-2 SEQ ID No. 5 (GS-N5) GV5-1 GV5-2 Each of these primers contain at their ends a different restriction enzyme site (SalI GTCGAC or MluI: ACGCGT).

[0147] Amplified fragments of each gene were obtained by PCR from bacterial plasmids containing the fragment of the identified gene using said primers.

[0148] These fragments were purified, digested by the restriction enzymes SalI and MluI and inserted in an expression vector of the type pCI-neo vector (Promega), which itself had been digested by these two restriction enzymes.

[0149] Each fragment was introduced into the vector in the antisense orientation.

[0150] Generally speaking, the vectors that could be used for the demonstration of the functionality of the identified genes in the present invention in the angiogenesis mechanism comprise any expression vector systems in mammals comprising a promoter enabling expression of a cloned gene; for example, the strong promoter of the human cytomegalovirus (CMV).

[0151] Constitutive or inducible vectors capable of being used in the practice of the present invention are indicated in the nonexhaustive list below:

[0152] The vectors pCI Mammalian Expression vector, Expression Vector System cloning vector pALTER®*-MAX (Promega), vectors pcDNA3.1, -/hygro, -/Zeo, pcDNA4/H isMAx, -E, pBudCE4, pRcRSV, pRcCMV2, pSecTag2, -/hygro secretion vectors, the vectors pEBVHis A, B and C) (Invitrogen), the expression vectors in mammals pIES, pIRES-EYFP pIRES2-EGFP, pCMV-Myc and pCMV-HA, Epitope-Tagged pTRE, the vectors VP16 Minimal Domain (ptTA 2, ptTA 3 and ptTA 4), the expression vectors Tet bidirectional (pBI, pBI-EGFP, pBI-G, pBI-L), pRevTRE, pTRE2, pLEGFP-N1 Vector Retroviral pLEGFP-C1, the adenoviral expression systems Adeno-X, pCMS-EGFP, pd1EGFP-N1, pd2ECFP-N1, pd2EYFP-N1, pEGFP(-C1, -C2, -C3, -N1, -N2, -N3), pEYFP-C1, -N1 (Clontech).

[0153] Each vector comprising said antisense fragment was then produced in E. coli, extracted, purified and quantified. Oneμg of each vector was incubated in the presence of a transfectant agent (Effectene, Qiagen) according to the protocol recommended by the manufacturer with the endothelial cells. Twenty-four hours after transfection, the endothelial cells were trypsinized and spread on the extracellular matrix containing the angiogenesis factors in Matrigel according to the model described by Grant et al. (1989, Cell, 58(5), 933-43, the entire disclosure of which is herein incorporated by reference). After 24 h of incubation, the formation of vessels was observed and compared to the control cells transfected with the empty mammalian expression vector.

5. Establishment of the Bank of Stable Lines Expressing the Expression Vectors Containing the Gene Sequences or their Fragments or their Antisense Sequences

[0154] The expression systems can comprise an antibiotic selection marker (an antibiotic resistance gene) in order to select the transfected cells expressing in a stable manner the vector comprising the nucleic acid cloned in said vector either in this same vector or in a second co-transfected vector.

[0155] This expression vector can be a constitutive or inducible expression system.

[0156] In the particular example described below, the stable lines for the expression of the antisense oligonucleotide corresponding to each identified gene were obtained with a constitutive expression vector after selection in the presence of antibiotic.

[0157] In order to do this, 24 h after the transfection performed under the conditions described above, the BAEC endothelial cells were trypsinized and sown at the rate of 80,000 cells/well in six-well plates in the presence of 700μg/ml of the antibiotic G418 (Promega). A control well was sown with non-transfected cells. The medium was changed every three days with a recharge of the antibiotic. The control cells were eliminated after 8 to 10 days. The cells resistant to the antibiotic were collected at confluence (after 2 to 3 weeks) then transferred to culture flasks still in the presence of the antibiotic. The stable lines were then tested for their capacity to form or not form vessels in the in vitro angiogenesis test.

6. Results

6.1 Identification of the Genes

[0158] The nucleic acid sequence designated GS-N1 and the protein coded by said nucleic acid sequence GS-N1 identified by the number SEQ ID No. 6, designated angiopartnerine, had not previously been identified as having any biological role, least of all a role in the angiogenesis process or the differentiation of endothelial cells into capillary tubes. The nucleic acid sequences designated GS-N2 to GS-N5 identified by the numbers SEQ ID No. 2 to SEQ ID No. 5 in the attached sequence listing and, respectively, the proteins coded by said nucleic acids identified by the numbers SEQ ID No. 7 to SEQ ID No. 10 in the attached sequence listing, had not previously been identified as having a biological role in the angiogenesis process or in the differentiation of endothelial cells into capillary tubes. These sequences are described below.

[0159] The previously described differential display method allowed identification of the following mRNAs:

GS-N1: a 6160-bp mRNA identified by the sequence SEQ ID No. 1 in the attached sequence listing. A BLAST search on the GENBANK sequence database identified it by the accession number AB037857.

[0160] The coding sequence of this mRNA has a partial coding sequence from nucleotide 1 to nucleotide 2777. There was thus identified a protein GS-P1 resulting from the translation of this RNA. This protein was composed of 924 aa, identified by the number SEQ ID No. 6 in the attached sequence listing, called angiopartnerine.

[0161] GS-N2: a 3266-bp mRNA identified by the sequence SEQ ID No. 2 in the attached sequence listing. A BLAST search of the GENBANK sequence database identified it as accession number AF247704.

[0162] The sequence of this mRNA has a coding sequence from nucleotide 49 to nucleotide 753. There was thus identified a protein GS-P2 resulting from the translation of this mRNA. This protein is composed of 234 aa, identified by the number SEQ ID No. 7 in the attached sequence listing; it is called protein homeobox NKX3.1.

[0163] G3-N3: a 6711-bp mRNA identified by the sequence SEQ ID No. 3 in the attached sequence listing. A BLAST search of the GENBANK sequence database identified it as accession number U91543.

[0164] The sequence of this mRNA has a coding sequence from nucleotide 151 to nucleotide 6153. There was thus identified a protein GS-P3 resulting from the translation of this mRNA. This protein is composed of 2000 aa, identified by the number SEQ ID No. 8 in the attached sequence listing, called zinc finger helicase.

[0165] GS-N4: a 3041-bp mRNA identified by the sequence SEQ ID No. 4 in the attached sequence listing. A BLAST search of the GENBANK sequence database identified it as accession number BC001571.

[0166] The sequence of this mRNA has a coding sequence from nucleotide 67 to nucleotide 2808. There was thus identified a protein GS-P4 resulting from the translation of this mRNA. This protein is composed of 913 aa, identified by the number SEQ ID No. 9 in the attached sequence listing, designated initiation factor of eukaryote translation, subunit 8 (110 kDa) (E1F3S8).

[0167] This sequence GS-N4 presents an homology with the following sequence:

GS-N5: a 1507-pb mRNA identified by the sequence SEQ ID No. 5 in the attached sequence listing. A BLAST search on the GENBANK sequence database identified it as accession number BC000533.

[0168] The sequence of this mRNA has a coding sequence from nucleotide 407 to nucleotide 1384. There was thus identified a protein GS-P5 resulting from the translation of this mRNA. This protein is composed of 325 aa, identified by the number SEQ ID No. 10 in the attached sequence listing, designated protein similar to the initiation factor of eukaryote translation, subunit 8 (110 kDa).

[0169] The expression of the above identified mRNAs is observed in human endothelial cells when the formation of capillary tubes, synonymous with angiogenesis, is inhibited following the action of an angiostatic factor.

[0170] The Applicant has demonstrated that the augmentation of the expression of the gene corresponding to each of these mRNAs accompanies the inhibition of the formation of neovessels by endothelial cells.

[0171] In fact, the human endothelial cells forming neovessels following stimulation by an angiogenic factor exhibit a very weak expression of these mRNAs, whereas the same human endothelial cells stimulated by the same angiogenic factor and contacted with an angiostatic factor (where angiogenesis is inhibited) and/or the same endothelial cells stimulated solely by the angiostatic factor, exhibit an elevated expression of this gene (as shown in Table II). These results indicate the existence of a direct correlation between the expression of each of these genes and the angiostatic state (i.e., the inhibition of angiogenesis) of human endothelial cells.

TABLE-US-00002 TABLE II ID SEQ Inducers of expression SEQ ID No. 1 (GS-N1) TNF-alpha SEQ ID No. 2 (GS-N2) TNF-alpha SEQ ID No. 3 (GS-N3) TNF-alpha SEQ ID No. 4 (GS-N4) PF4 SEQ ID No. 5 (GS-N5) PF4

6.2 Verification of the Role of the Identified Genes in the Regulation of Angiogenesis

[0172] The functional role of the above-described genes in the formation of neovessels by human endothelial cells was also demonstrated.

[0173] In fact, a specific nucleotide sequence of each of the identified genes, selected from among the nucleotide sequences identified by the sequences SEQ ID No. 11 to SEQ ID No. 14, was introduced into the expression vector pCI-neo Vector in the antisense orientation.

[0174] The resultant vectors, designated GS-V1 to GS-V4 and identified by their sequences SEQ ID No. 15 to SEQ ID No. 18, were used to repress the expression of the gene coding for this mRNA in human endothelial cells following the transfection of these cells by these vectors.

[0175] The human endothelial cells were then stimulated by angiogenic factors. The results obtained for each of the sequences GS-N1 to GS-N5 using the antisense sequences and the corresponding vectors show that repression of the expression of the genes identified by the sequence numbers SEQ ID No. 1 to SEQ ID No. 5 inhibits the formation of neovessels by human endothelial cells.

[0176] The results obtained for each of the sequences using the antisense sequences and the corresponding vectors, indicated in Table III below, are further illustrated in FIGS. 1A to 1E.

TABLE-US-00003 TABLE III Vector with Genes Proteins Antisens Inserted Control Name SEQ ID SEQ ID SEQ ID antisens FIG. FIG. 1 SEQ ID SEQ ID No. 6 SEQ ID SEQ ID 1A 1F No. 1 (GS-P1) No 11 No 15 (GS-N1) angiopartnerine (392 bp) (GS-V1) 2 SEQ ID SEQ ID No. 7 SEQ ID SEQ ID 1B 1F No. 2 (GS-P2) No 12 No 16 (GS-N2) homeobox (250 bp) (GS-V2) NFX3.1 3 SEQ ID SEQ ID No. 8 SEQ ID SEQ ID 1C 1F No. 3 (GS-P3) No 13 No 17 (GS-N3) zinc finger (bp) (GS-V3) helicase 4 SEQ ID SEQ ID No. 9 SEQ ID SEQ ID 1D 1F No. 4 (GS-P4) No 14 No 18 (GS-N4) initiation factor (167 bp) (GS-V4) of eukaryote translation, subunit 8 e 5 SEQ ID SEQ ID No. 10 SEQ ID SEQ ID 1F No. 5 (GS-P5) No 14 No 18 (GS-N5) initiation factor (167 bp) (GS-V4) of eukaryote translation, subunit 8

[0177] A variety of modifications to the embodiments described will be apparent to those skilled in the art from the disclosure provided herein. Thus, the invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.

Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 34 <210> SEQ ID NO 1 <211> LENGTH: 6160 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AB037857 <309> DATABASE ENTRY DATE: 2000-03-14 <313> RELEVANT RESIDUES IN SEQ ID NO: RELEVANT RESIDUES: (1)..(6160) <400> SEQUENCE: 1 ctcgcgagga gagcggagca ggcgcgcggc ccaggcggag gagcgccgac tctggagcag 60 ccggagctgg aagaggagga ggaggagagg cggcggggaa ggaggaggag ggggagagtc 120 gctcccgccg ggcgagcatg gggcgcctgg cctcgaggcc gctgctgctg gcgctcctgt 180 cgttggctct ttgccgaggg cgtgtggtga gagtccccac agcgaccctg gttcgagtgg 240 tgggcactga gctggtcatc ccctgcaacg tcagtgacta tgatggcccc agcgagcaaa 300 actttgactg gagcttctca tctttgggga gcagctttgt ggagcttgca agcacctggg 360 aggtggggtt cccagcccag ctgtaccagg agcggctgca gaggggcgag atcctgttaa 420 ggcggactgc caacgacgcc gtggagctcc acataaagaa cgtccagcct tcagaccaag 480 gccactacaa atgttcaacc cccagcacag atgccactgt ccagggaaac tatgaggaca 540 cagtgcaggt taaagtgctg gccgactccc tgcacgtggg ccccagcgcg cggcccccgc 600 cgagcctgag cctgcgggag ggggagccct tcgagctgcg ctgcactgcc gcctccgcct 660 cgccgctgca cacgcacctg gcgctgctgt gggaggtgca ccgcggcccg gccaggcgga 720 gcgtcctcgc cctgacccac gagggcaggt tccacccggg cctggggtac gagcagcgct 780 accacagtgg ggacgtgcgc ctcgacaccg tgggcagcga cgcctaccgc ctctcagtgt 840 cccgggctct gtctgccgac cagggctcct acaggtgtat cgtcagcgag tggatcgccg 900 agcagggcaa ctggcaggaa atccaagaaa aggccgtgga agttgccacc gtggtgatcc 960 agccatcagt tctgcgagca gctgtgccca agaatgtgtc tgtggctgaa ggaaaggaac 1020 tggacctgac ctgtaacatc acaacagacc gagccgatga cgtccggccc gaggtgacgt 1080 ggtccttcag caggatgcct gacagcaccc tacctggctc ccgcgtgttg gcgcggcttg 1140 accgtgattc cctggtgcac agctcgcctc atgttgcttt gagtcatgtg gatgcacgct 1200 cctaccattt actggttcgg gatgttagca aagaaaactc tggctactat tactgccacg 1260 tgtccctgtg ggcacccgga cacaacagga gctggcacaa agtggcagag gccgtgtctt 1320 ccccagctgg tgtgggtgtg acctggctag aaccagacta ccaggtgtac ctgaatgctt 1380 ccaaggtccc cgggtttgcg gatgacccca cagagctggc atgccgggtg gtggacacga 1440 agagtgggga ggcgaatgtc cgattcacgg tttcgtggta ctacaggatg aaccggcgca 1500 gcgacaatgt ggtgaccagc gagctgcttg cagtcatgga cggggactgg acgctaaaat 1560 atggagagag gagcaagcag cgggcccagg atggagactt tattttttct aaggaacata 1620 cagacacgtt caatttccgg atccaaagga ctacagagga agacagaggc aattattact 1680 gtgttgtgtc tgcctggacc aaacagcgga acaacagctg ggtgaaaagc aaggatgtct 1740 tctccaagcc tgttaacata ttttgggcat tagaagattc cgtgcttgtg gtgaaggcga 1800 ggcagccaaa gcctttcttt gctgccggaa atacatttga gatgacttgc aaagtatctt 1860 ccaagaatat taagtcgcca cgctactctg ttctcatcat ggctgagaag cctgtcggcg 1920 acctctccag tcccaatgaa acgaagtaca tcatctctct ggaccaggat tctgtggtga 1980 agctggagaa ttggacagat gcatcacggg tggatggcgt tgttttagaa aaagtgcagg 2040 aggatgagtt ccgctatcga atgtaccaga ctcaggtctc agacgcaggg ctgtaccgct 2100 gcatggtgac agcctggtct cctgtcaggg gcagcctttg gcgagaagca gcaaccagtc 2160 tctccaatcc tattgagata gacttccaaa cctcaggtcc tatatttaat gcttctgtgc 2220 attcagacac accatcagta attcggggag atctgatcaa attgttctgt atcatcactg 2280 tcgagggagc agcactggat ccagatgaca tggcctttga tgtgtcctgg tttgcggtgc 2340 actcttttgg cctggacaag gctcctgtgc tcctgtcttc cctggatcgg aagggcatcg 2400 tgaccacctc ccggagggac tggaagagcg acctcagcct ggagcgcgtg agtgtgctgg 2460 aattcttgct gcaagtgcat ggctccgagg accaggactt tggcaactac tactgttccg 2520 tgactccatg ggtgaagtca ccaacaggtt cctggcagaa ggaggcagag atccactcca 2580 agcccgtttt tataactgtg aagatggatg tgctgaacgc cttcaagtat cccttgctga 2640 tcggcgtcgg tctgtccacg gtcatcgggc tcctgtcctg tctcatcggg tactgcagct 2700 cccactggtg ttgtaagaag gaggttcagg agacacggcg cgagcgccgc aggctcatgt 2760 cgatggagat ggactaggct ggcccgggag gggagtgaca gagggacgtt ctaggagcaa 2820 ttggggcaag aagaggacag tgatatttta aaacaaagtg tgttacacta aaaaccagtc 2880 ctctctaatc tcaggtggga cttggcgctc tctcttttct gcatgtcaag ttctgagcgc 2940 ggacatgttt accagcacac ggctcttctt cccacggcac tttctgatgt aacaatcgag 3000 tgtgtgtttt cccaactgca gctttttaat ggttaacctt catctaattt tttttctccc 3060 actggtttat agatcctctg acttgtgtgt gtttatagct tttgtttcgc ggggttgtgg 3120 tgaggaaggg gtgatggcat gcggagttct ttatcttcag tgagaatgtg cctgcccgcc 3180 tgagagccag cttccgcgtt ggaggcacgt gttcagagag ctgctgagcg ccaccctcta 3240 cccggctgac agacaacaca gacctgtgcc gaaggctaat ttgtggcttt tacgacccta 3300 ccccaccccc tgttttcagg ggtttagact acatttgaaa tccaaacttg gagtatataa 3360 cttcttattg agcccaactg cttttttttt tttttttttt gcttctctgc cccttttcca 3420 tttcttttgt atttgttttc tgtgagagca ctgaaatggc agccctggaa tctacaattt 3480 ggctctccac tgagcacctt atcttgccac cttagcctta agaatgaata tgaagaaaaa 3540 tacacagcca cctctgtcca gggcagtaag aagggctgca aggaagggga ggatggggac 3600 aaggaaagga tcagatacct gctccagtag ttgtgaggcc actgtgtctc aggggactcc 3660 aggaggagca gaagagggat cccacgaagt tattcttacg cagctggggc caggagggtc 3720 agagtggtgc caggtgcaag ttaggctaaa gaagccacca ctattcctct ctcttgccca 3780 ttgtgggggg caaaggcatt ggtcaccaag agtcttgcag ggggacccac agatatgcca 3840 tgtccttcac acgtgcttgg gctccttaac ctgaaggcaa attgctactt gcaagactga 3900 ctgacttcaa ggaatcagaa attacctaga agcaccatgt tttttctatg accttttcag 3960 tccttcaggt cattttaagg tccactgcag ggggttagtg agaaagggta tactttgtgg 4020 tatgttttgc tttcctaata gggacatgaa ggaaacccag caatttgctg ttatgtgaat 4080 ggcctgtaga gcagagtcaa gagcggtgtg ctttgcccga ctgctcccat caggaatagg 4140 agagtagaca gagatcttcc acatcccagg cttctgctgc tgctttaaaa gctctgtcct 4200 tggagcctcc cgctccctga agtgtctcgc cccctgcaca gcactggcct ttcggaagca 4260 tcccagtagg gttttctgag gctcgctggt gactcatgcc ctaattgcaa tcctctgctt 4320 ttatcttgac tttgaaggat ctaacactgc tctctcttcc aaaggggaaa aaaagattca 4380 tttgttttga gcaataaact aatacaaaat gatggccatt catgtgcagc tctttgtcac 4440 catgggccgg atgagttgtg ctcctcctgg ctcaccattt ccccctgctc ccccacagcc 4500 ggttctgcac ttatcaccga gtcgcccctg gaagcagatt cccattgagt tttccccacc 4560 aaggggacca tgcacatggt agaaacatta gattctgcat tgacagtagc ctttccttgg 4620 cccgggcctg tggtgggaag acgggcaaca agtatacccc accagggcct gagtgactag 4680 aggaagagga cgaggccttg ttggcactag atttgggtat tttctgcatg tcataacata 4740 tcctaactgc tatttcagaa gaggcagctt gtaggtgatt gtacaagtga gaattaaaga 4800 gagaacagat atttaaacag gtgctgtatt agtaacagcc agtgcccttt cagcccttgc 4860 atctattaaa aggagattca ggattttatt ggcacaggcc cttcttagta ggaagaaagg 4920 gtgcttagct ttggacctga ccgggtgtgt gtaaaaccat ggactgagtc acagcagaca 4980 ctcgatggtg gtaaatgtga tgggtgctta cacactgtac cttttccttt catactgatg 5040 ctgcagttca gggctggagt tgttaaggca ttgacctcca cccacctgcc ccatgtccac 5100 tgggctgccc aagctgcatg tcacctgagg gctggcagga aggggcgaga aatcccaggg 5160 cattgtacca aggacctagt tccttctagg gatataaatt tccaggaatg tgtattttta 5220 atgtggtgag atgcactctt ttgttgtacc aaatagggct ccccacccca cccctgcgac 5280 aagtgctctt ctagaacagg ttcctaccag cagcactggt gtgaatgaaa gagagaccca 5340 gccgcgtctc acacaggtgg aattgcactt cttaacaaaa aggaacttta taaaagtttg 5400 ggattttttt tcctaatcat aaaaatagcc ccagaaagag cctaagctat gttcagatag 5460 aagcctcgaa attcctgtaa attgtttact ttatgatgtt tacatacacg tttcactttg 5520 aaaaaaaatg caaatcgact ttttaacaac tgttgagatg tttcatggga cagtagaact 5580 ctgactcacc aactgggcta aattttaatt taaaaatgta tttatttgag tgtctttccc 5640 cccctcaccc tcaccatctg aggggctccc tgagatcttg gtagaggagg cccctcctgc 5700 ccagaccttc gtttgtttcc ccggtggccc ttgcttcttg ctttgcagac tgcctgcagc 5760 catgattttg tcactgacat ctgtgagcca aagactgagc ctttttggca ggaataataa 5820 gcaatactac acaacttgct actttcagaa aacttttttt tagcttcacc gatgacaaca 5880 gaggaagaag ggaactggga tttgggtaag ttctcctcca ctgtttgacc aaattctcag 5940 tgataaatat gtgtgcagat ccctagaaga gaaaacgctg actttctttt taagtgtggc 6000 acataaggat ctgcagaatt ttccgtagac aaagaaagga tcttgtgtat ttttgtccat 6060 atccaatgtt atatgaacta attgtattgt tttatactgt gaccacaaat attatgcaat 6120 gcaccatttg ttttttattt cattaaagga agtttaattt 6160 <210> SEQ ID NO 2 <211> LENGTH: 3266 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AF247704 <309> DATABASE ENTRY DATE: 2000-09-02 <313> RELEVANT RESIDUES IN SEQ ID NO: RELEVANT RESIDUES: (1)..(3266) <400> SEQUENCE: 2 gcggtgcggg ccgggcgggt gcattcaggc caaggcgggg ccgccgggat gctcagggtt 60 ccggagccgc ggcccgggga ggcgaaagcg gagggggccg cgccgccgac cccgtccaag 120 ccgctcacgt ccttcctcat ccaggacatc ctgcgggacg gcgcgcagcg gcaaggcggc 180 cgcacgagca gccagagaca gcgcgacccg gagccggagc cagagccaga gccagaggga 240 ggacgcagcc gcgccggggc gcagaacgac cagctgagca ccgggccccg cgccgcgccg 300 gaggaggccg agacgctggc agagaccgag ccagaaaggc acttggggtc ttatctgttg 360 gactctgaaa acacttcagg cgcccttcca aggcttcccc aaacccctaa gcagccgcag 420 aagcgctccc gagctgcctt ctcccacact caggtgatcg agttggagag gaagttcagc 480 catcagaagt acctgtcagc ccctgaacgg gcccacctgg ccaagaacct caagctcacg 540 gagacccaag tgaagatatg gttccagaac agacgctata agactaagcg aaagcagctc 600 tcctcggagc tgggagactt ggagaagcac tcctctttgc cggccctgaa agaggaggcc 660 ttctcccggg cctccctggt ctccgtgtat aacagctatc cttactaccc atacctgtac 720 tgcgtgggca gctggagccc agctttttgg taatgccagc tcaggtgaca accattatga 780 tcaaaaactg ccttccccag ggtgtctcat atgaaaagca caaggggcca aggtcaggga 840 gcaagaggtg tgcacaccaa aactattgga gaattgcgtg gaaatcttca gattcttcac 900 tggtgagaca atgaaacaac agagacagtg aaagttttaa tacctaagtc attcccccag 960 tgcatactgt agcgtcaagt ttttgcttct ggctacctgt ttgaagggga gagagggaaa 1020 atcaagtggt attttccagc actttgtatg attttggatg agctgtacac ccaaggattc 1080 tgttctgcaa ctccatcctc ctgtgtcact gaatatcaac tctgaaagag caaacctaac 1140 aggagaaagg acaaccagga tgaggatgtc accaactgaa ttaaacttaa gtccagaagc 1200 ctcctgttgg ccttggaata tggccaaggc tctctctgtc cctgtaaaag agaggggcaa 1260 atagtctcca aagagaacgc cctcatgctc agcacatatt tgcatggaag ggggagatgg 1320 gtgggaggag atgaaaatat cagcttttct tattcctttt tattcctttt aaaatggtat 1380 gccaacttaa gtatttacag ggtggcccaa atagaacaag atgcactcgc tgtgatttta 1440 agacaagctg tataaacaga actccactgc aagagggagg gccgggccag gagaatctcc 1500 gcttgtccaa gacaggggcc taaggagggt ctccacactg ctgctagggg ctgttgcatt 1560 tttttattag tagaaagtgg aaaggcctct tctcaacttt tttcccttgg gctggagaat 1620 ttagaatcag aagtttcctg gagttttcag gctatcatat atactgtatc ctgaaaggca 1680 acataattct tccttccctc cttttaaaat tttgtgttcc tttttgcagc aattactcac 1740 taaagggctt cattttagtc cagattttta gtctggctgc acctaactta tgcctcgctt 1800 atttagcccg agatccggtc tttttttttt tttttttttc cgtctcccca aagctttatc 1860 tgtcttgact ttttaaaaaa gtttgggggc agattctgaa ttggctaaaa gacatgcatt 1920 tttaaaacta gcaactctta tttctttcct ttaaaaatac atagcattaa atcccaaatc 1980 ctatttaaag acctgacagc ttgagaaggg tcactactgc atttatagga ccttctggtg 2040 gttctgctgt tacgtttgaa gtctgacaat ccttgagaat ctttgcatgc agaggaggta 2100 agaggtattg gattttcaca gagggaagaa cacagcgcag aatgaaggcg caggcttact 2160 gagctgtcca gtggagggct catgggtggg acatggaaaa gaaggcagcc taggccctgg 2220 ggagcccagt ccactgagca agcaagggac tgagtgagcc ttttgcagga aaaggctaag 2280 aaaaaggaaa accattctaa aacacaacaa gaaactgtcc aaatgctttg ggaactgtgt 2340 ttattgccta taatggggtc cccaaaatgg gtaacctaga cttcagagag aatgagcaga 2400 gagcaaagga gaaatctggg ctgtccttcc attttcattc tgttatctca ggtgagctgg 2460 tagaggggag acattagaaa aaaatgaaac aacaaaacaa ttactaatga ggtacgctga 2520 ggcctgggag tctcttgagc tccacgactt caaaattaaa atgagccatg agtcaaacca 2580 ctgcaatcca gcctgggcaa cgagcaagac ccagtctcta ctgttggtgg caaaattgcc 2640 aacataagtt aatagaaagt tggccaattt caccccattt tctgtggttt gggctccaca 2700 ttgcaatgtt caatgccacg tgctgctgac accgaccgga gtactagcca gcacaaaagg 2760 cagggtagcc tgaattgctt tctgctcttt acatttcttt taaaataagc atttagtgct 2820 cagtccctac tgagtactct ttctctcccc tcctctgaat ttaattcttt caacttgcaa 2880 tttgcaaggg ttacacattt cactgtgatg tatattgtgt tgcaaaaaaa aaaaagtgtc 2940 tttgtttaaa attacttggt ttgtgaatcc atcttgcttt ccccattgga actagtcatt 3000 aacccatctc tgaactggta gaaaaacatc tgaagagcta gtctatcagc atctgacagg 3060 tgaattggat ggttctcaga accatttcac ccagacagcc tgtttctatc ctgtttaata 3120 aattagtttg ggttctctac atgcataaca aaccctgctc caatctgtca cataaaagtc 3180 tgtgacttga agtttagtca gcacccccac caaactttat ttttctatgt gttttttgca 3240 acatatgagt gttttgaaaa taaagt 3266 <210> SEQ ID NO 3 <211> LENGTH: 6771 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/U91543 <309> DATABASE ENTRY DATE: 1998-08-04 <313> RELEVANT RESIDUES IN SEQ ID NO: RELEVANT RESIDUES: (1)..(6771) <400> SEQUENCE: 3 atatggaggt gaagggtgag atcgggaaac aaagggtatg gccccctagt tcccaaaggg 60 agcagggaga tgggaataga attgaaggta ggttttaggc tacttgggag gaggaatatt 120 taggtaattg tggagacttt ctcctgtgtg atgaaggcgg cagacactgt gatcctgtgg 180 gcaagaagta aaaatgacca gctgaggatt tcttttcctc caggactgtg ttggggtgac 240 aggatgcctg ataaggatga cattcggctg ctgccgtcag cattgggtgt gaagaagaga 300 aaacgaggac ccaagaagca gaaggagaac aagccaggaa aaccccgaaa acgcaagaag 360 cgtgacagtg aggaggaatt tggttctgag cgagatgagt accgggagaa gtcagagagt 420 gggggcagtg aatatggaac cggaccgggt cggaaacgaa gaaggaagca ccgagaaaaa 480 aaggagaaga agacaaagcg gcggaaaaag ggggagggag atggggggca aaagcaagtg 540 gaacagaagt catcagcaac tctgcttctg acctggggcc tggaggatgt ggagcatgtg 600 ttctctgagg aggattacca cacgctcacc aactacaaag ccttcagcca gttcatgagg 660 cccctaattg ctaagaagaa tcctaagatc ccaatgtcta agatgatgac catccttggg 720 gccaaatgga gagagttcag tgccaacaac cccttcaagg ggtcagcagc tgctgtggcg 780 gcggcagcgg cagcagcagc agcagctgta gctgagcagg tgtcagctgc tgtctcgtcg 840 gccaccccca tagcaccctc cggacccccc gcccttccac caccccctgc tgctgatatc 900 cagcccccac ccatccgaag agccaaaacc aaagagggca aaggtccagg ccataagagg 960 cggagtaaga gcccccgagt gcctgatgga cgcaagaagc ttcggggaaa gaaaatggca 1020 ccactcaaaa taaaactagg gcttctgggt ggcaagagga agaaaggagg ctcgtatgtt 1080 tttcagagcg acgaaggtcc tgaaccagag gctgaggaat cagacctgga cagtggcagt 1140 gtccacagtg cctcaggccg gcctgatggc cctgtccgca ccaagaaact aaagagaggc 1200 cggccaggaa ggaagaagaa gaaggtcctg ggctgtcctg cagtggccgg ggaggaggag 1260 gttgatggct acgagacgga tcaccaggat tactgtgagg tgtgccagca gggtggggaa 1320 attattctgt gtgacacctg ccctcgtgcc taccacctcg tctgccttga tcctgagctt 1380 gaccgggctc cagagggcaa atggagctgc cctcactgtg agaaggaggg ggtccagtgg 1440 gaggccaagg aggaagaaga agaatacgaa gaggagggag aggaagaagg ggagaaggag 1500 gaggaggatg atcacatgga gtactgccgc gtatgcaagg acggcgggga gctcctgtgc 1560 tgtgacgcgt gcatctcctc ctaccacatt cattgtctaa accctcccct gcctgacatt 1620 cccaatggtg aatggctgtg tccccgatgc acatgccccg tgctgaaggg tcgagtgcag 1680 aagatcctac attggcggtg gggggagcca cctgtagcag tgccagcccc tcaacaggca 1740 gatggaaatc cagatgtccc acccccccgt cctcttcaag gcagatcaga gcgagagttc 1800 tttgtcaagt gggtaggact atcctactgg cactgctcct gggccaagga gcttcagctg 1860 gaaatcttcc atttggttat gtatcgaaac taccagcgga agaatgacat ggatgagccc 1920 ccacccctgg actatggctc cggcgaggat gatgggaaga gcgacaagcg taaagtgaaa 1980 gacccgcact atgctgagat ggaggagaag tactatcgtt ttggcatcaa gccagagtgg 2040 atgaccgtcc accgcatcat caaccacagt gtggataaaa aggggaatta ccactatcta 2100 gtaaaatgga gggacttacc atatgaccag tccacgtggg aggaagatga aatgaatatc 2160 cctgaatacg aagaacataa gcaaagctac tggagacacc gagaactaat tatgggggaa 2220 gaccctgccc agccccgcaa gtataagaag aagaagaagg agctacaggg tgatgggcct 2280 cccagttctc ccactaatga tcctaccgtg aaatatgaga ctcagccacg gtttatcaca 2340 gccactggag gcaccctgca catgtatcag ttggaagggc tgaactggct acgcttctcc 2400 tgggcccagg gcactgacac cattctagct gatgagatgg ggctaggcaa gaccatacaa 2460 accatcgtct tcctctactc actctacaag gagggccaca caaaaggtcc cttcctggtg 2520 agtgccccac tctctaccat cattaactgg gagcgggagt tccagatgtg ggcacccaaa 2580 ttctatgtgg tgacatacac gggtgacaag gacagccggg ccatcattcg tgagaatgaa 2640 ttctcctttg aggacaatgc catcaaaggg ggcaagaaag cttttaagat gaagagggag 2700 gcacaggtga agttccatgt tctcctgaca tcgtatgagc tgatcaccat tgatcaggca 2760 gcacttggtt ccatccgctg ggcctgtctt gtggtagatg aggcccatcg actcaagaac 2820 aaccagtcca agtttttcag ggttctcaat ggttacaaga tagatcataa gttgctgctg 2880 acaggaaccc cattgcagaa taatctggag gagctcttcc atctcctgaa cttcctcacc 2940 ccagagagat ttaacaactt ggagggcttc ctggaggagt ttgctgacat atccaaagag 3000 gaccagatca agaaactgca tgatttgctg gggccacaca tgctgcggag actcaaggca 3060 gatgtcttta agaacatgcc agccaagaca gagctcatcg ttcgggtgga gctaagcccc 3120 atgcagaaga aatactacaa atacatcctg actcgaaatt ttgaggcctt gaattcacga 3180 ggtggtggga accaggtgtc gctgcttaat atcatgatgg atcttaagaa gtgctgcaac 3240 catccatacc tttttcccgt ggctgctatg gagtccccca aactccccag tggggcttat 3300 gagggtgggg cacttattaa gtcgtctggg aagctcatgc tgctccagaa gatgctgcga 3360 aagctgaagg agcaaggaca ccgagtgctc atcttctcgc agatgaccaa aatgttagac 3420 ttgcttgagg acttcttaga ctatgaaggc tacaagtatg agcgcatcga tggtggtatc 3480 acgggtgccc tgaggcagga ggccatcgat cggtttaatg ctcctggggc ccaacaattc 3540 tgcttcctcc tgtccacccg agctgggggc ctgggcatca atctggccac tgctgacact 3600 gtcatcatct ttgattctga ctggaacccc cataatgaca tccaggcctt tagccgggct 3660 catcggattg gccaggccaa caaagtgatg atttaccggt ttgtgactcg cgcgtcagtg 3720 gaagagcgaa tcacacaagt ggccaagaga aagatgatgc tgacacacct ggttgtgcgg 3780 cctgggctgg gctccaaggc aggctccatg tccaagcagg agcttgacga cattctcaaa 3840 tttggcactg aagagctatt caaggatgaa aacgaggggg agaacaagga ggaggacagc 3900 agtgtgattc attatgacaa tgaggccatc gctcggctgt tggaccggaa ccaggatgca 3960 actgaggaca ctgacgtgca gaacatgaat gagtatctca gctccttcaa ggtggcacag 4020 tacgtcgtgc gggaagaaga caagattgag gaaattgagc gagagatcat caagcaggag 4080 gagaatgtgg accctgacta ctgggagaag ctgctgaggc atcactatga gcaacagcag 4140 gaagacctag cccggaatct aggcaagggc aagcgggttc gcaagcaagt taactacaat 4200 gatgctgctc aggaagacca agacaaccag tcagagtact cggtgggttc agaggaggag 4260 gatgaagact tcgatgaacg tcctgaaggg cgtagacagt caaagaggca gctccggaat 4320 gagaaagata agccactgcc tccactgctg gcccgagtcg ggggcaacat tgaggtgctg 4380 ggcttcaaca cccgtcagcg gaaggctttc ctcaatgctg tgatgcgctg ggggatgcca 4440 ccacaggatg ccttcaccac acagtggctg gtgcgggacc tgaggggcaa gactgagaag 4500 gagtttaagg cctatgtgtc tttgttcatg cgccatctgt gtgagcctgg ggcagacggc 4560 tctgaaacct ttgccgatgg ggtccctcgg gagggactga gtcgccagca ggtgttgacc 4620 cgcattggag tcatgtctct cgtcaaaaag aaggtgcagg agtttgagca catcaatggg 4680 cgttggtcaa tgccggaact gatgcctgac cccagcgccg attctaagcg ctcctccaga 4740 gcctcctctc ctaccaaaac gtctcccacc actcctgagg cttctgctac caacagtccc 4800 tgcacctcta aacctgctac tccagctcca agtgagaaag gagaaggcat aaggacacct 4860 cttgagaagg aggaagctga aaaccaggag gaaaagccag agaagaacag cagaattggg 4920 gagaagatgg agacagaggc tgatgccccc agcccagccc catcacttgg ggagcggctg 4980 gagccaagga agattcctct agaggatgag gtgccagggg tgcctggaga gatggagcct 5040 gaacctgggt accgtgggga cagagagaag tcagccacag agtcgacgcc aggagaaagg 5100 ggggaggaga agccgttgga tggacaggaa cacagggaga ggccggaggg ggaaacaggg 5160 gatttgggca agagagaaga tgtaaaaggt gaccgggagc ttcgaccagg gcctcgagat 5220 gagccacggt ccaatgggcg acgagaggaa aagacagaga acccccggtt catgttcaat 5280 atcgccgatg gtggcttcac agagcttcac acactgtggc agaatgagga acgggcagct 5340 atttcctcgg ggaaactcaa tgagatctgg cacagaagac atgactattg gcttctggct 5400 gggattgtcc tccatggcta tgcacggtgg caggacatcc agaatgatgc tcaatttgcc 5460 attatcaacg agccatttaa aactgaagcc aataagggga actttctgga gatgaaaaat 5520 aagttcctgg cccggaggtt caagctcctg gagcaggcgc tggtgattga ggagcagctg 5580 cggcgggcgg cctacctgaa cctgtcgcag gagccggcgc accccgccat ggccctccac 5640 gcccgcttcg ccgaggccga gtgcctggcc gagagccacc agcacctctc caaggagtcg 5700 ctggcgggga acaagccggc caacgccgtc ctgcacaagg ttctgaacca gctggaggag 5760 ttgctgagcg acatgaaggc ggacgtgacc cgcctgccag ccacgctgtc ccgaataccc 5820 cccatcgcag cccgccttca gatgtccgag cgcagcatcc tcagccggct ggccagcaag 5880 ggcacggagc ctcaccccac accggcctac ccgccgggtc cctacgctac acctccgggg 5940 tacggggcgg ccttcagcgc cgcacccgta ggggccctgg ccgccgcagg cgccaattac 6000 agccagatgc ctgcagggtc cttcatcaca gccgccacca acggccctcc agtgcttgtg 6060 aagaaggaga aggaaatggt gggggcattg gtgtcagacg ggctggatcg gaaggagccc 6120 cgagccgggg aggtgatctg tatagacgac tgactggatc ccaggcctgc ccttcaccca 6180 ggccccgtcc ccgaggccga cccccagctc aagcgctggg gcctgctgcc agccctccac 6240 cttccccacc ccttgggcca tcactgggct aggaacccct ttgcccctct ctgcagctcc 6300 tctcttcaag aagggccctt tgtctttctc cactcccaca cacctttccc accaagcctt 6360 gaagactgtg ctggtgagaa gaagtctggg tgggagatgg ctggcagggt cttccaagta 6420 ccttcctccc acactgccaa gtatacacaa cttcccagta aatggttgtg gggaggaaag 6480 aggtggagcc tccccagccg tttccctgca gaatcagctc tgtctcatgt ggaagtggag 6540 aatcagcctt gcctggcctt taggaacttt tgtggggaag agagctttga agagaggagg 6600 gggactttag agagggatga aaatgagccc tgggagggag gaagggacga ggaggggtgg 6660 ctgcatgtta ccgtccccta cctctcccca cgtggagggt ggagcagtta tgagggagga 6720 agtcaactgc tgttcagcct cagaataaag gtgccgttca ctggctcagt t 6771 <210> SEQ ID NO 4 <211> LENGTH: 3041 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/BC001571 <309> DATABASE ENTRY DATE: 2001-10-29 <313> RELEVANT RESIDUES IN SEQ ID NO: RELEVANT RESIDUES: (1)..(3041) <400> SEQUENCE: 4 gtcagggccc tgcggtgtga ctcgcgggct cagctggtcc ggccgtagca cctccgcgcc 60 gtcgccatgt cgcggttttt caccaccggt tcggacagcg agtccgagtc gtccttgtcc 120 ggggaggagc tcgtcaccaa acctgtcgga ggcaactatg gcaaacagcc attgttgctg 180 agcgaggatg aagaagatac caagagagtt gtccgcagtg ccaaggacaa gaggtttgag 240 gagctgacca accttatccg gaccatccgt aatgccatga agattcgtga tgtcaccaag 300 tgcctggaag agtttgagct cctgggaaaa gcatatggga aggccaaaag cattgtggac 360 aaagaaggtg tcccccggtt ctatatccgc atcctggctg acctagagga ctatcttaat 420 gagctttggg aagataagga agggaagaag aagatgaaca agaacaatgc caaggctctg 480 agcaccttgc gtcagaagat ccgaaaatac aaccgtgatt tcgagtccca tatcacaagc 540 tacaagcaga accccgagca gtctgcggat gaagatgctg agaaaaatga ggaggattca 600 gaaggctctt cagatgagga tgaggatgag gacggagtca gtgctgcaac tttcttgaag 660 aagaaatcag aagctccttc tggggagagt cgcaagttcc tcaaaaagat ggatgatgaa 720 gatgaggact cagaagattc cgaagatgat gaagactggg acacaggttc cacatcttcc 780 gattccgact cagaggagga agaagggaaa caaaccgcgc tggcctcaag atttcttaaa 840 aaggcaccca ccacagatga ggacaagaag gcagccgaga agaaacggga ggacaaagct 900 aagaagaagc acgacaggaa atccaagcgc ctggatgagg aggaggagga caatgaaggc 960 ggggagtggg aaagggtccg gggcggagtg ccgttggtta aggagaagcc aaaaatgttt 1020 gccaagggaa ctgagatcac ccatgctgtt gttatcaaga aactgaatga gatcctacag 1080 gcacgaggca agaagggaac tgatcgtgct gcccagattg agctgctgca actgctggtt 1140 cagattgcag cggaaaacaa cctgggagag ggcgtcattg tcaagatcaa gttcaatatc 1200 atcgcctctc tctatgacta caaccccaac ctggcaacct acatgaagcc agagatgtgg 1260 gggaagtgcc tggactgcat caatgagctg atggatatcc tgtttgcaaa tcccaacatt 1320 tttgttggag agaatattct ggaagagagt gagaacctgc acaacgctga ccagccactg 1380 cgtgtccgtg gctgcatcct aactctggtg gaacgaatgg atgaagaatt taccaaaata 1440 atgcaaaata ctgaccctca ctcccaagag tacgtggagc acttgaagga tgaggcccag 1500 gtgtgtgcca tcatcgagcg tgtgcagcgc tacctggagg agaagggcac taccgaggag 1560 gtctgccgca tctacctgct gcgcatcctg cacacctact acaagtttga ttacaaggcc 1620 catcagcgac agctgacccc gcctgagggc tcctcaaagt ctgagcaaga ccaggcagaa 1680 aatgagggcg aggactcggc tgtgttgatg gagagactgt gcaagtacat ctacgccaag 1740 gaccgcacag accggatccg cacatgtgcc atcctctgcc acatctacca ccatgctctg 1800 cactcgcgct ggtaccaggc ccgcgacctc atgctcatga gccacttgca ggacaacatt 1860 cagcatgcag acccgccagt gcagatcctt tacaaccgca ccatggtgca gctgggcatc 1920 tgtgccttcc gccaaggcct gaccaaggac gcacacaacg ccctgctgga catccagtcg 1980 agtggccgag ccaaggagct tctgggccag ggcctgctgc tgcgcagcct gcaggagcgc 2040 aaccaggagc aggagaaggt ggagcggcgc cgtcaggtcc ccttccacct gcacatcaac 2100 ctggagctgc tggagtgtgt ctacctggtg tctgccatgc tcctggagat cccctacatg 2160 gccgcccatg agagcgatgc ccgccgacgc atgatcagca agcagttcca ccaccagctg 2220 cgcgtgggcg agcgacagcc cctgctgggt ccccctgagt ccatgcggga acatgtggtc 2280 gctgcctcca aggccatgaa gatgggtgac tggaagacct gtcacagttt tatcatcaat 2340 gagaagatga atgggaaagt gtgggacctt ttccccgagg ctgacaaagt ccgcaccatg 2400 ctggttagga agatccagga agagtcactg aggacctacc tcttcaccta cagcagtgtc 2460 tatgactcca tcagcatgga gacgctgtca gacatgtttg agctggatct gcccactgtg 2520 cactccatca tcagcaaaat gatcattaat gaggagctga tggcctccct ggaccagcca 2580 acacagacag tggtgatgca ccgcactgag cccactgccc agcagaacct ggctctgcag 2640 ctggccgaga agctgggcag cctggtggag aacaacgaac gggtgtttga ccacaagcag 2700 ggcacctacg ggggctactt ccgagaccag aaggacggct accgcaaaaa cgagggctac 2760 atgcgccgcg gtggctaccg ccagcagcag tctcagacgg cctactgagc tctccactct 2820 gtttcccgcc tgggccatcc aaccttgaag tcctaaacca cacctcagtc actaaaggtc 2880 tgtttaaagt tgttctggtt gattgcttgt tgccacaaag gtgtgttgag cccattcatt 2940 tgctgattat atttctgagc tgctaccaca tgacagacac aaggctcaga tgaagaggtg 3000 aattaaacac gttcctgacc tcaaaaaaaa aaaaaaaaaa a 3041 <210> SEQ ID NO 5 <211> LENGTH: 1507 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/BC000533 <309> DATABASE ENTRY DATE: 2001-07-12 <313> RELEVANT RESIDUES IN SEQ ID NO: RELEVANT RESIDUES: (1)..(1507) <400> SEQUENCE: 5 ggcacgaggg ggccctgcgg tgtgactcgc gggctcagct ggtccggccg tagcacctcc 60 gcgccgtcgc catgtcgcgg tttttcacca ccggttcgga cagcgagtcc gagtcgtcct 120 tgtccgggga ggagctcgtc accaaacctg tcggaggcaa ctatggcaaa cagccattgt 180 tgctgagcga ggatgaagaa gataccaaga gagttgtccg cagtgccaag gacaagaggt 240 ttgaggagct gaccaacctt atccggacca tccgtaatgc catgaagatt cgtgatgtca 300 ccaagtgcct ggaagagttt gagctcctgg gaaaagcaca tgtgccatcc tctgccacat 360 ctaccaccat gctctgcact cgcgctggta ccaggcccgc gacctcatgc tcatgagcca 420 cttgcaggac aacattcagc atgcagaccc gccagtgcag atcctttaca accgcaccat 480 ggtgcagctg ggcatctgtg ccttccgcca aggcctgacc aaggacgcac acaacgccct 540 gctggacatc cagtcgagtg gccgagccaa ggagcttctg ggccagggcc tgctgctgcg 600 cagcctgcag gagcgcaacc aggagcagga gaaggtggag cggcgccgtc aggtcccctt 660 ccacctgcac atcaacctgg agctgctgga gtgtgtctac ctggtgtctg ccatgctcct 720 ggagatcccc tacatggccg cccatgagag cgatgcccgc cgacgcatga tcagcaagca 780 gttccaccac cagctgcgcg tgggcgagcg acagcccctg ctgggtcccc ctgagtccat 840 gcgggaacat gtggtcgctg cctccaaggc catgaagatg ggtgactgga agacctgtca 900 cagttttatc atcaatgaga agatgaatgg gaaagtgtgg gaccttttcc ccgaggctga 960 caaagtccgc accatgctgg ttaggaagat ccaggaagag tcactgagga cctacctctt 1020 cacctacagc agtgtctatg actccatcag catggagacg ctgtcagaca tgtttgagct 1080 ggatctgccc actgtgcact ccatcatcag caaaatgatc attaatgagg agctgatggc 1140 ctccctggac cagccaacac agacagtggt gatgcaccgc actgagccca ctgcccagca 1200 gaacctggct ctgcagctgg ccgagaagct gggcagcctg gtggagaaca acgaacgggt 1260 gtttgaccac aagcagggca cctacggggg ctacttccga gaccagaagg acggctaccg 1320 caaaaacgag ggctacatgc gccgcggtgg ctaccgccag cagcagtctc agacggccta 1380 ctgagctctc cactctgttt cccgcctggg ccatccaacc ttgaagtcct aaaccacacc 1440 tcagtcacta aaggtctgtt taaagttaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1500 aaaaaaa 1507 <210> SEQ ID NO 6 <211> LENGTH: 924 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 Arg Glu Glu Ser Gly Ala Gly Ala Arg Pro Arg Arg Arg Ser Ala Asp 1 5 10 15 Ser Gly Ala Ala Gly Ala Gly Arg Gly Gly Gly Gly Glu Ala Ala Gly 20 25 30 Lys Glu Glu Glu Gly Glu Ser Arg Ser Arg Arg Ala Ser Met Gly Arg 35 40 45 Leu Ala Ser Arg Pro Leu Leu Leu Ala Leu Leu Ser Leu Ala Leu Cys 50 55 60 Arg Gly Arg Val Val Arg Val Pro Thr Ala Thr Leu Val Arg Val Val 65 70 75 80 Gly Thr Glu Leu Val Ile Pro Cys Asn Val Ser Asp Tyr Asp Gly Pro 85 90 95 Ser Glu Gln Asn Phe Asp Trp Ser Phe Ser Ser Leu Gly Ser Ser Phe 100 105 110 Val Glu Leu Ala Ser Thr Trp Glu Val Gly Phe Pro Ala Gln Leu Tyr 115 120 125 Gln Glu Arg Leu Gln Arg Gly Glu Ile Leu Leu Arg Arg Thr Ala Asn 130 135 140 Asp Ala Val Glu Leu His Ile Lys Asn Val Gln Pro Ser Asp Gln Gly 145 150 155 160 His Tyr Lys Cys Ser Thr Pro Ser Thr Asp Ala Thr Val Gln Gly Asn 165 170 175 Tyr Glu Asp Thr Val Gln Val Lys Val Leu Ala Asp Ser Leu His Val 180 185 190 Gly Pro Ser Ala Arg Pro Pro Pro Ser Leu Ser Leu Arg Glu Gly Glu 195 200 205 Pro Phe Glu Leu Arg Cys Thr Ala Ala Ser Ala Ser Pro Leu His Thr 210 215 220 His Leu Ala Leu Leu Trp Glu Val His Arg Gly Pro Ala Arg Arg Ser 225 230 235 240 Val Leu Ala Leu Thr His Glu Gly Arg Phe His Pro Gly Leu Gly Tyr 245 250 255 Glu Gln Arg Tyr His Ser Gly Asp Val Arg Leu Asp Thr Val Gly Ser 260 265 270 Asp Ala Tyr Arg Leu Ser Val Ser Arg Ala Leu Ser Ala Asp Gln Gly 275 280 285 Ser Tyr Arg Cys Ile Val Ser Glu Trp Ile Ala Glu Gln Gly Asn Trp 290 295 300 Gln Glu Ile Gln Glu Lys Ala Val Glu Val Ala Thr Val Val Ile Gln 305 310 315 320 Pro Ser Val Leu Arg Ala Ala Val Pro Lys Asn Val Ser Val Ala Glu 325 330 335 Gly Lys Glu Leu Asp Leu Thr Cys Asn Ile Thr Thr Asp Arg Ala Asp 340 345 350 Asp Val Arg Pro Glu Val Thr Trp Ser Phe Ser Arg Met Pro Asp Ser 355 360 365 Thr Leu Pro Gly Ser Arg Val Leu Ala Arg Leu Asp Arg Asp Ser Leu 370 375 380 Val His Ser Ser Pro His Val Ala Leu Ser His Val Asp Ala Arg Ser 385 390 395 400 Tyr His Leu Leu Val Arg Asp Val Ser Lys Glu Asn Ser Gly Tyr Tyr 405 410 415 Tyr Cys His Val Ser Leu Trp Ala Pro Gly His Asn Arg Ser Trp His 420 425 430 Lys Val Ala Glu Ala Val Ser Ser Pro Ala Gly Val Gly Val Thr Trp 435 440 445 Leu Glu Pro Asp Tyr Gln Val Tyr Leu Asn Ala Ser Lys Val Pro Gly 450 455 460 Phe Ala Asp Asp Pro Thr Glu Leu Ala Cys Arg Val Val Asp Thr Lys 465 470 475 480 Ser Gly Glu Ala Asn Val Arg Phe Thr Val Ser Trp Tyr Tyr Arg Met 485 490 495 Asn Arg Arg Ser Asp Asn Val Val Thr Ser Glu Leu Leu Ala Val Met 500 505 510 Asp Gly Asp Trp Thr Leu Lys Tyr Gly Glu Arg Ser Lys Gln Arg Ala 515 520 525 Gln Asp Gly Asp Phe Ile Phe Ser Lys Glu His Thr Asp Thr Phe Asn 530 535 540 Phe Arg Ile Gln Arg Thr Thr Glu Glu Asp Arg Gly Asn Tyr Tyr Cys 545 550 555 560 Val Val Ser Ala Trp Thr Lys Gln Arg Asn Asn Ser Trp Val Lys Ser 565 570 575 Lys Asp Val Phe Ser Lys Pro Val Asn Ile Phe Trp Ala Leu Glu Asp 580 585 590 Ser Val Leu Val Val Lys Ala Arg Gln Pro Lys Pro Phe Phe Ala Ala 595 600 605 Gly Asn Thr Phe Glu Met Thr Cys Lys Val Ser Ser Lys Asn Ile Lys 610 615 620 Ser Pro Arg Tyr Ser Val Leu Ile Met Ala Glu Lys Pro Val Gly Asp 625 630 635 640 Leu Ser Ser Pro Asn Glu Thr Lys Tyr Ile Ile Ser Leu Asp Gln Asp 645 650 655 Ser Val Val Lys Leu Glu Asn Trp Thr Asp Ala Ser Arg Val Asp Gly 660 665 670 Val Val Leu Glu Lys Val Gln Glu Asp Glu Phe Arg Tyr Arg Met Tyr 675 680 685 Gln Thr Gln Val Ser Asp Ala Gly Leu Tyr Arg Cys Met Val Thr Ala 690 695 700 Trp Ser Pro Val Arg Gly Ser Leu Trp Arg Glu Ala Ala Thr Ser Leu 705 710 715 720 Ser Asn Pro Ile Glu Ile Asp Phe Gln Thr Ser Gly Pro Ile Phe Asn 725 730 735 Ala Ser Val His Ser Asp Thr Pro Ser Val Ile Arg Gly Asp Leu Ile 740 745 750 Lys Leu Phe Cys Ile Ile Thr Val Glu Gly Ala Ala Leu Asp Pro Asp 755 760 765 Asp Met Ala Phe Asp Val Ser Trp Phe Ala Val His Ser Phe Gly Leu 770 775 780 Asp Lys Ala Pro Val Leu Leu Ser Ser Leu Asp Arg Lys Gly Ile Val 785 790 795 800 Thr Thr Ser Arg Arg Asp Trp Lys Ser Asp Leu Ser Leu Glu Arg Val 805 810 815 Ser Val Leu Glu Phe Leu Leu Gln Val His Gly Ser Glu Asp Gln Asp 820 825 830 Phe Gly Asn Tyr Tyr Cys Ser Val Thr Pro Trp Val Lys Ser Pro Thr 835 840 845 Gly Ser Trp Gln Lys Glu Ala Glu Ile His Ser Lys Pro Val Phe Ile 850 855 860 Thr Val Lys Met Asp Val Leu Asn Ala Phe Lys Tyr Pro Leu Leu Ile 865 870 875 880 Gly Val Gly Leu Ser Thr Val Ile Gly Leu Leu Ser Cys Leu Ile Gly 885 890 895 Tyr Cys Ser Ser His Trp Cys Cys Lys Lys Glu Val Gln Glu Thr Arg 900 905 910 Arg Glu Arg Arg Arg Leu Met Ser Met Glu Met Asp 915 920 <210> SEQ ID NO 7 <211> LENGTH: 234 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 Met Leu Arg Val Pro Glu Pro Arg Pro Gly Glu Ala Lys Ala Glu Gly 1 5 10 15 Ala Ala Pro Pro Thr Pro Ser Lys Pro Leu Thr Ser Phe Leu Ile Gln 20 25 30 Asp Ile Leu Arg Asp Gly Ala Gln Arg Gln Gly Gly Arg Thr Ser Ser 35 40 45 Gln Arg Gln Arg Asp Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Gly 50 55 60 Gly Arg Ser Arg Ala Gly Ala Gln Asn Asp Gln Leu Ser Thr Gly Pro 65 70 75 80 Arg Ala Ala Pro Glu Glu Ala Glu Thr Leu Ala Glu Thr Glu Pro Glu 85 90 95 Arg His Leu Gly Ser Tyr Leu Leu Asp Ser Glu Asn Thr Ser Gly Ala 100 105 110 Leu Pro Arg Leu Pro Gln Thr Pro Lys Gln Pro Gln Lys Arg Ser Arg 115 120 125 Ala Ala Phe Ser His Thr Gln Val Ile Glu Leu Glu Arg Lys Phe Ser 130 135 140 His Gln Lys Tyr Leu Ser Ala Pro Glu Arg Ala His Leu Ala Lys Asn 145 150 155 160 Leu Lys Leu Thr Glu Thr Gln Val Lys Ile Trp Phe Gln Asn Arg Arg 165 170 175 Tyr Lys Thr Lys Arg Lys Gln Leu Ser Ser Glu Leu Gly Asp Leu Glu 180 185 190 Lys His Ser Ser Leu Pro Ala Leu Lys Glu Glu Ala Phe Ser Arg Ala 195 200 205 Ser Leu Val Ser Val Tyr Asn Ser Tyr Pro Tyr Tyr Pro Tyr Leu Tyr 210 215 220 Cys Val Gly Ser Trp Ser Pro Ala Phe Trp 225 230 <210> SEQ ID NO 8 <211> LENGTH: 2000 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Met Lys Ala Ala Asp Thr Val Ile Leu Trp Ala Arg Ser Lys Asn Asp 1 5 10 15 Gln Leu Arg Ile Ser Phe Pro Pro Gly Leu Cys Trp Gly Asp Arg Met 20 25 30 Pro Asp Lys Asp Asp Ile Arg Leu Leu Pro Ser Ala Leu Gly Val Lys 35 40 45 Lys Arg Lys Arg Gly Pro Lys Lys Gln Lys Glu Asn Lys Pro Gly Lys 50 55 60 Pro Arg Lys Arg Lys Lys Arg Asp Ser Glu Glu Glu Phe Gly Ser Glu 65 70 75 80 Arg Asp Glu Tyr Arg Glu Lys Ser Glu Ser Gly Gly Ser Glu Tyr Gly 85 90 95 Thr Gly Pro Gly Arg Lys Arg Arg Arg Lys His Arg Glu Lys Lys Glu 100 105 110 Lys Lys Thr Lys Arg Arg Lys Lys Gly Glu Gly Asp Gly Gly Gln Lys 115 120 125 Gln Val Glu Gln Lys Ser Ser Ala Thr Leu Leu Leu Thr Trp Gly Leu 130 135 140 Glu Asp Val Glu His Val Phe Ser Glu Glu Asp Tyr His Thr Leu Thr 145 150 155 160 Asn Tyr Lys Ala Phe Ser Gln Phe Met Arg Pro Leu Ile Ala Lys Lys 165 170 175 Asn Pro Lys Ile Pro Met Ser Lys Met Met Thr Ile Leu Gly Ala Lys 180 185 190 Trp Arg Glu Phe Ser Ala Asn Asn Pro Phe Lys Gly Ser Ala Ala Ala 195 200 205 Val Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Val Ala Glu Gln Val 210 215 220 Ser Ala Ala Val Ser Ser Ala Thr Pro Ile Ala Pro Ser Gly Pro Pro 225 230 235 240 Ala Leu Pro Pro Pro Pro Ala Ala Asp Ile Gln Pro Pro Pro Ile Arg 245 250 255 Arg Ala Lys Thr Lys Glu Gly Lys Gly Pro Gly His Lys Arg Arg Ser 260 265 270 Lys Ser Pro Arg Val Pro Asp Gly Arg Lys Lys Leu Arg Gly Lys Lys 275 280 285 Met Ala Pro Leu Lys Ile Lys Leu Gly Leu Leu Gly Gly Lys Arg Lys 290 295 300 Lys Gly Gly Ser Tyr Val Phe Gln Ser Asp Glu Gly Pro Glu Pro Glu 305 310 315 320 Ala Glu Glu Ser Asp Leu Asp Ser Gly Ser Val His Ser Ala Ser Gly 325 330 335 Arg Pro Asp Gly Pro Val Arg Thr Lys Lys Leu Lys Arg Gly Arg Pro 340 345 350 Gly Arg Lys Lys Lys Lys Val Leu Gly Cys Pro Ala Val Ala Gly Glu 355 360 365 Glu Glu Val Asp Gly Tyr Glu Thr Asp His Gln Asp Tyr Cys Glu Val 370 375 380 Cys Gln Gln Gly Gly Glu Ile Ile Leu Cys Asp Thr Cys Pro Arg Ala 385 390 395 400 Tyr His Leu Val Cys Leu Asp Pro Glu Leu Asp Arg Ala Pro Glu Gly 405 410 415 Lys Trp Ser Cys Pro His Cys Glu Lys Glu Gly Val Gln Trp Glu Ala 420 425 430 Lys Glu Glu Glu Glu Glu Tyr Glu Glu Glu Gly Glu Glu Glu Gly Glu 435 440 445 Lys Glu Glu Glu Asp Asp His Met Glu Tyr Cys Arg Val Cys Lys Asp 450 455 460 Gly Gly Glu Leu Leu Cys Cys Asp Ala Cys Ile Ser Ser Tyr His Ile 465 470 475 480 His Cys Leu Asn Pro Pro Leu Pro Asp Ile Pro Asn Gly Glu Trp Leu 485 490 495 Cys Pro Arg Cys Thr Cys Pro Val Leu Lys Gly Arg Val Gln Lys Ile 500 505 510 Leu His Trp Arg Trp Gly Glu Pro Pro Val Ala Val Pro Ala Pro Gln 515 520 525 Gln Ala Asp Gly Asn Pro Asp Val Pro Pro Pro Arg Pro Leu Gln Gly 530 535 540 Arg Ser Glu Arg Glu Phe Phe Val Lys Trp Val Gly Leu Ser Tyr Trp 545 550 555 560 His Cys Ser Trp Ala Lys Glu Leu Gln Leu Glu Ile Phe His Leu Val 565 570 575 Met Tyr Arg Asn Tyr Gln Arg Lys Asn Asp Met Asp Glu Pro Pro Pro 580 585 590 Leu Asp Tyr Gly Ser Gly Glu Asp Asp Gly Lys Ser Asp Lys Arg Lys 595 600 605 Val Lys Asp Pro His Tyr Ala Glu Met Glu Glu Lys Tyr Tyr Arg Phe 610 615 620 Gly Ile Lys Pro Glu Trp Met Thr Val His Arg Ile Ile Asn His Ser 625 630 635 640 Val Asp Lys Lys Gly Asn Tyr His Tyr Leu Val Lys Trp Arg Asp Leu 645 650 655 Pro Tyr Asp Gln Ser Thr Trp Glu Glu Asp Glu Met Asn Ile Pro Glu 660 665 670 Tyr Glu Glu His Lys Gln Ser Tyr Trp Arg His Arg Glu Leu Ile Met 675 680 685 Gly Glu Asp Pro Ala Gln Pro Arg Lys Tyr Lys Lys Lys Lys Lys Glu 690 695 700 Leu Gln Gly Asp Gly Pro Pro Ser Ser Pro Thr Asn Asp Pro Thr Val 705 710 715 720 Lys Tyr Glu Thr Gln Pro Arg Phe Ile Thr Ala Thr Gly Gly Thr Leu 725 730 735 His Met Tyr Gln Leu Glu Gly Leu Asn Trp Leu Arg Phe Ser Trp Ala 740 745 750 Gln Gly Thr Asp Thr Ile Leu Ala Asp Glu Met Gly Leu Gly Lys Thr 755 760 765 Ile Gln Thr Ile Val Phe Leu Tyr Ser Leu Tyr Lys Glu Gly His Thr 770 775 780 Lys Gly Pro Phe Leu Val Ser Ala Pro Leu Ser Thr Ile Ile Asn Trp 785 790 795 800 Glu Arg Glu Phe Gln Met Trp Ala Pro Lys Phe Tyr Val Val Thr Tyr 805 810 815 Thr Gly Asp Lys Asp Ser Arg Ala Ile Ile Arg Glu Asn Glu Phe Ser 820 825 830 Phe Glu Asp Asn Ala Ile Lys Gly Gly Lys Lys Ala Phe Lys Met Lys 835 840 845 Arg Glu Ala Gln Val Lys Phe His Val Leu Leu Thr Ser Tyr Glu Leu 850 855 860 Ile Thr Ile Asp Gln Ala Ala Leu Gly Ser Ile Arg Trp Ala Cys Leu 865 870 875 880 Val Val Asp Glu Ala His Arg Leu Lys Asn Asn Gln Ser Lys Phe Phe 885 890 895 Arg Val Leu Asn Gly Tyr Lys Ile Asp His Lys Leu Leu Leu Thr Gly 900 905 910 Thr Pro Leu Gln Asn Asn Leu Glu Glu Leu Phe His Leu Leu Asn Phe 915 920 925 Leu Thr Pro Glu Arg Phe Asn Asn Leu Glu Gly Phe Leu Glu Glu Phe 930 935 940 Ala Asp Ile Ser Lys Glu Asp Gln Ile Lys Lys Leu His Asp Leu Leu 945 950 955 960 Gly Pro His Met Leu Arg Arg Leu Lys Ala Asp Val Phe Lys Asn Met 965 970 975 Pro Ala Lys Thr Glu Leu Ile Val Arg Val Glu Leu Ser Pro Met Gln 980 985 990 Lys Lys Tyr Tyr Lys Tyr Ile Leu Thr Arg Asn Phe Glu Ala Leu Asn 995 1000 1005 Ser Arg Gly Gly Gly Asn Gln Val Ser Leu Leu Asn Ile Met Met 1010 1015 1020 Asp Leu Lys Lys Cys Cys Asn His Pro Tyr Leu Phe Pro Val Ala 1025 1030 1035 Ala Met Glu Ser Pro Lys Leu Pro Ser Gly Ala Tyr Glu Gly Gly 1040 1045 1050 Ala Leu Ile Lys Ser Ser Gly Lys Leu Met Leu Leu Gln Lys Met 1055 1060 1065 Leu Arg Lys Leu Lys Glu Gln Gly His Arg Val Leu Ile Phe Ser 1070 1075 1080 Gln Met Thr Lys Met Leu Asp Leu Leu Glu Asp Phe Leu Asp Tyr 1085 1090 1095 Glu Gly Tyr Lys Tyr Glu Arg Ile Asp Gly Gly Ile Thr Gly Ala 1100 1105 1110 Leu Arg Gln Glu Ala Ile Asp Arg Phe Asn Ala Pro Gly Ala Gln 1115 1120 1125 Gln Phe Cys Phe Leu Leu Ser Thr Arg Ala Gly Gly Leu Gly Ile 1130 1135 1140 Asn Leu Ala Thr Ala Asp Thr Val Ile Ile Phe Asp Ser Asp Trp 1145 1150 1155 Asn Pro His Asn Asp Ile Gln Ala Phe Ser Arg Ala His Arg Ile 1160 1165 1170 Gly Gln Ala Asn Lys Val Met Ile Tyr Arg Phe Val Thr Arg Ala 1175 1180 1185 Ser Val Glu Glu Arg Ile Thr Gln Val Ala Lys Arg Lys Met Met 1190 1195 1200 Leu Thr His Leu Val Val Arg Pro Gly Leu Gly Ser Lys Ala Gly 1205 1210 1215 Ser Met Ser Lys Gln Glu Leu Asp Asp Ile Leu Lys Phe Gly Thr 1220 1225 1230 Glu Glu Leu Phe Lys Asp Glu Asn Glu Gly Glu Asn Lys Glu Glu 1235 1240 1245 Asp Ser Ser Val Ile His Tyr Asp Asn Glu Ala Ile Ala Arg Leu 1250 1255 1260 Leu Asp Arg Asn Gln Asp Ala Thr Glu Asp Thr Asp Val Gln Asn 1265 1270 1275 Met Asn Glu Tyr Leu Ser Ser Phe Lys Val Ala Gln Tyr Val Val 1280 1285 1290 Arg Glu Glu Asp Lys Ile Glu Glu Ile Glu Arg Glu Ile Ile Lys 1295 1300 1305 Gln Glu Glu Asn Val Asp Pro Asp Tyr Trp Glu Lys Leu Leu Arg 1310 1315 1320 His His Tyr Glu Gln Gln Gln Glu Asp Leu Ala Arg Asn Leu Gly 1325 1330 1335 Lys Gly Lys Arg Val Arg Lys Gln Val Asn Tyr Asn Asp Ala Ala 1340 1345 1350 Gln Glu Asp Gln Asp Asn Gln Ser Glu Tyr Ser Val Gly Ser Glu 1355 1360 1365 Glu Glu Asp Glu Asp Phe Asp Glu Arg Pro Glu Gly Arg Arg Gln 1370 1375 1380 Ser Lys Arg Gln Leu Arg Asn Glu Lys Asp Lys Pro Leu Pro Pro 1385 1390 1395 Leu Leu Ala Arg Val Gly Gly Asn Ile Glu Val Leu Gly Phe Asn 1400 1405 1410 Thr Arg Gln Arg Lys Ala Phe Leu Asn Ala Val Met Arg Trp Gly 1415 1420 1425 Met Pro Pro Gln Asp Ala Phe Thr Thr Gln Trp Leu Val Arg Asp 1430 1435 1440 Leu Arg Gly Lys Thr Glu Lys Glu Phe Lys Ala Tyr Val Ser Leu 1445 1450 1455 Phe Met Arg His Leu Cys Glu Pro Gly Ala Asp Gly Ser Glu Thr 1460 1465 1470 Phe Ala Asp Gly Val Pro Arg Glu Gly Leu Ser Arg Gln Gln Val 1475 1480 1485 Leu Thr Arg Ile Gly Val Met Ser Leu Val Lys Lys Lys Val Gln 1490 1495 1500 Glu Phe Glu His Ile Asn Gly Arg Trp Ser Met Pro Glu Leu Met 1505 1510 1515 Pro Asp Pro Ser Ala Asp Ser Lys Arg Ser Ser Arg Ala Ser Ser 1520 1525 1530 Pro Thr Lys Thr Ser Pro Thr Thr Pro Glu Ala Ser Ala Thr Asn 1535 1540 1545 Ser Pro Cys Thr Ser Lys Pro Ala Thr Pro Ala Pro Ser Glu Lys 1550 1555 1560 Gly Glu Gly Ile Arg Thr Pro Leu Glu Lys Glu Glu Ala Glu Asn 1565 1570 1575 Gln Glu Glu Lys Pro Glu Lys Asn Ser Arg Ile Gly Glu Lys Met 1580 1585 1590 Glu Thr Glu Ala Asp Ala Pro Ser Pro Ala Pro Ser Leu Gly Glu 1595 1600 1605 Arg Leu Glu Pro Arg Lys Ile Pro Leu Glu Asp Glu Val Pro Gly 1610 1615 1620 Val Pro Gly Glu Met Glu Pro Glu Pro Gly Tyr Arg Gly Asp Arg 1625 1630 1635 Glu Lys Ser Ala Thr Glu Ser Thr Pro Gly Glu Arg Gly Glu Glu 1640 1645 1650 Lys Pro Leu Asp Gly Gln Glu His Arg Glu Arg Pro Glu Gly Glu 1655 1660 1665 Thr Gly Asp Leu Gly Lys Arg Glu Asp Val Lys Gly Asp Arg Glu 1670 1675 1680 Leu Arg Pro Gly Pro Arg Asp Glu Pro Arg Ser Asn Gly Arg Arg 1685 1690 1695 Glu Glu Lys Thr Glu Asn Pro Arg Phe Met Phe Asn Ile Ala Asp 1700 1705 1710 Gly Gly Phe Thr Glu Leu His Thr Leu Trp Gln Asn Glu Glu Arg 1715 1720 1725 Ala Ala Ile Ser Ser Gly Lys Leu Asn Glu Ile Trp His Arg Arg 1730 1735 1740 His Asp Tyr Trp Leu Leu Ala Gly Ile Val Leu His Gly Tyr Ala 1745 1750 1755 Arg Trp Gln Asp Ile Gln Asn Asp Ala Gln Phe Ala Ile Ile Asn 1760 1765 1770 Glu Pro Phe Lys Thr Glu Ala Asn Lys Gly Asn Phe Leu Glu Met 1775 1780 1785 Lys Asn Lys Phe Leu Ala Arg Arg Phe Lys Leu Leu Glu Gln Ala 1790 1795 1800 Leu Val Ile Glu Glu Gln Leu Arg Arg Ala Ala Tyr Leu Asn Leu 1805 1810 1815 Ser Gln Glu Pro Ala His Pro Ala Met Ala Leu His Ala Arg Phe 1820 1825 1830 Ala Glu Ala Glu Cys Leu Ala Glu Ser His Gln His Leu Ser Lys 1835 1840 1845 Glu Ser Leu Ala Gly Asn Lys Pro Ala Asn Ala Val Leu His Lys 1850 1855 1860 Val Leu Asn Gln Leu Glu Glu Leu Leu Ser Asp Met Lys Ala Asp 1865 1870 1875 Val Thr Arg Leu Pro Ala Thr Leu Ser Arg Ile Pro Pro Ile Ala 1880 1885 1890 Ala Arg Leu Gln Met Ser Glu Arg Ser Ile Leu Ser Arg Leu Ala 1895 1900 1905 Ser Lys Gly Thr Glu Pro His Pro Thr Pro Ala Tyr Pro Pro Gly 1910 1915 1920 Pro Tyr Ala Thr Pro Pro Gly Tyr Gly Ala Ala Phe Ser Ala Ala 1925 1930 1935 Pro Val Gly Ala Leu Ala Ala Ala Gly Ala Asn Tyr Ser Gln Met 1940 1945 1950 Pro Ala Gly Ser Phe Ile Thr Ala Ala Thr Asn Gly Pro Pro Val 1955 1960 1965 Leu Val Lys Lys Glu Lys Glu Met Val Gly Ala Leu Val Ser Asp 1970 1975 1980 Gly Leu Asp Arg Lys Glu Pro Arg Ala Gly Glu Val Ile Cys Ile 1985 1990 1995 Asp Asp 2000 <210> SEQ ID NO 9 <211> LENGTH: 913 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 Met Ser Arg Phe Phe Thr Thr Gly Ser Asp Ser Glu Ser Glu Ser Ser 1 5 10 15 Leu Ser Gly Glu Glu Leu Val Thr Lys Pro Val Gly Gly Asn Tyr Gly 20 25 30 Lys Gln Pro Leu Leu Leu Ser Glu Asp Glu Glu Asp Thr Lys Arg Val 35 40 45 Val Arg Ser Ala Lys Asp Lys Arg Phe Glu Glu Leu Thr Asn Leu Ile 50 55 60 Arg Thr Ile Arg Asn Ala Met Lys Ile Arg Asp Val Thr Lys Cys Leu 65 70 75 80 Glu Glu Phe Glu Leu Leu Gly Lys Ala Tyr Gly Lys Ala Lys Ser Ile 85 90 95 Val Asp Lys Glu Gly Val Pro Arg Phe Tyr Ile Arg Ile Leu Ala Asp 100 105 110 Leu Glu Asp Tyr Leu Asn Glu Leu Trp Glu Asp Lys Glu Gly Lys Lys 115 120 125 Lys Met Asn Lys Asn Asn Ala Lys Ala Leu Ser Thr Leu Arg Gln Lys 130 135 140 Ile Arg Lys Tyr Asn Arg Asp Phe Glu Ser His Ile Thr Ser Tyr Lys 145 150 155 160 Gln Asn Pro Glu Gln Ser Ala Asp Glu Asp Ala Glu Lys Asn Glu Glu 165 170 175 Asp Ser Glu Gly Ser Ser Asp Glu Asp Glu Asp Glu Asp Gly Val Ser 180 185 190 Ala Ala Thr Phe Leu Lys Lys Lys Ser Glu Ala Pro Ser Gly Glu Ser 195 200 205 Arg Lys Phe Leu Lys Lys Met Asp Asp Glu Asp Glu Asp Ser Glu Asp 210 215 220 Ser Glu Asp Asp Glu Asp Trp Asp Thr Gly Ser Thr Ser Ser Asp Ser 225 230 235 240 Asp Ser Glu Glu Glu Glu Gly Lys Gln Thr Ala Leu Ala Ser Arg Phe 245 250 255 Leu Lys Lys Ala Pro Thr Thr Asp Glu Asp Lys Lys Ala Ala Glu Lys 260 265 270 Lys Arg Glu Asp Lys Ala Lys Lys Lys His Asp Arg Lys Ser Lys Arg 275 280 285 Leu Asp Glu Glu Glu Glu Asp Asn Glu Gly Gly Glu Trp Glu Arg Val 290 295 300 Arg Gly Gly Val Pro Leu Val Lys Glu Lys Pro Lys Met Phe Ala Lys 305 310 315 320 Gly Thr Glu Ile Thr His Ala Val Val Ile Lys Lys Leu Asn Glu Ile 325 330 335 Leu Gln Ala Arg Gly Lys Lys Gly Thr Asp Arg Ala Ala Gln Ile Glu 340 345 350 Leu Leu Gln Leu Leu Val Gln Ile Ala Ala Glu Asn Asn Leu Gly Glu 355 360 365 Gly Val Ile Val Lys Ile Lys Phe Asn Ile Ile Ala Ser Leu Tyr Asp 370 375 380 Tyr Asn Pro Asn Leu Ala Thr Tyr Met Lys Pro Glu Met Trp Gly Lys 385 390 395 400 Cys Leu Asp Cys Ile Asn Glu Leu Met Asp Ile Leu Phe Ala Asn Pro 405 410 415 Asn Ile Phe Val Gly Glu Asn Ile Leu Glu Glu Ser Glu Asn Leu His 420 425 430 Asn Ala Asp Gln Pro Leu Arg Val Arg Gly Cys Ile Leu Thr Leu Val 435 440 445 Glu Arg Met Asp Glu Glu Phe Thr Lys Ile Met Gln Asn Thr Asp Pro 450 455 460 His Ser Gln Glu Tyr Val Glu His Leu Lys Asp Glu Ala Gln Val Cys 465 470 475 480 Ala Ile Ile Glu Arg Val Gln Arg Tyr Leu Glu Glu Lys Gly Thr Thr 485 490 495 Glu Glu Val Cys Arg Ile Tyr Leu Leu Arg Ile Leu His Thr Tyr Tyr 500 505 510 Lys Phe Asp Tyr Lys Ala His Gln Arg Gln Leu Thr Pro Pro Glu Gly 515 520 525 Ser Ser Lys Ser Glu Gln Asp Gln Ala Glu Asn Glu Gly Glu Asp Ser 530 535 540 Ala Val Leu Met Glu Arg Leu Cys Lys Tyr Ile Tyr Ala Lys Asp Arg 545 550 555 560 Thr Asp Arg Ile Arg Thr Cys Ala Ile Leu Cys His Ile Tyr His His 565 570 575 Ala Leu His Ser Arg Trp Tyr Gln Ala Arg Asp Leu Met Leu Met Ser 580 585 590 His Leu Gln Asp Asn Ile Gln His Ala Asp Pro Pro Val Gln Ile Leu 595 600 605 Tyr Asn Arg Thr Met Val Gln Leu Gly Ile Cys Ala Phe Arg Gln Gly 610 615 620 Leu Thr Lys Asp Ala His Asn Ala Leu Leu Asp Ile Gln Ser Ser Gly 625 630 635 640 Arg Ala Lys Glu Leu Leu Gly Gln Gly Leu Leu Leu Arg Ser Leu Gln 645 650 655 Glu Arg Asn Gln Glu Gln Glu Lys Val Glu Arg Arg Arg Gln Val Pro 660 665 670 Phe His Leu His Ile Asn Leu Glu Leu Leu Glu Cys Val Tyr Leu Val 675 680 685 Ser Ala Met Leu Leu Glu Ile Pro Tyr Met Ala Ala His Glu Ser Asp 690 695 700 Ala Arg Arg Arg Met Ile Ser Lys Gln Phe His His Gln Leu Arg Val 705 710 715 720 Gly Glu Arg Gln Pro Leu Leu Gly Pro Pro Glu Ser Met Arg Glu His 725 730 735 Val Val Ala Ala Ser Lys Ala Met Lys Met Gly Asp Trp Lys Thr Cys 740 745 750 His Ser Phe Ile Ile Asn Glu Lys Met Asn Gly Lys Val Trp Asp Leu 755 760 765 Phe Pro Glu Ala Asp Lys Val Arg Thr Met Leu Val Arg Lys Ile Gln 770 775 780 Glu Glu Ser Leu Arg Thr Tyr Leu Phe Thr Tyr Ser Ser Val Tyr Asp 785 790 795 800 Ser Ile Ser Met Glu Thr Leu Ser Asp Met Phe Glu Leu Asp Leu Pro 805 810 815 Thr Val His Ser Ile Ile Ser Lys Met Ile Ile Asn Glu Glu Leu Met 820 825 830 Ala Ser Leu Asp Gln Pro Thr Gln Thr Val Val Met His Arg Thr Glu 835 840 845 Pro Thr Ala Gln Gln Asn Leu Ala Leu Gln Leu Ala Glu Lys Leu Gly 850 855 860 Ser Leu Val Glu Asn Asn Glu Arg Val Phe Asp His Lys Gln Gly Thr 865 870 875 880 Tyr Gly Gly Tyr Phe Arg Asp Gln Lys Asp Gly Tyr Arg Lys Asn Glu 885 890 895 Gly Tyr Met Arg Arg Gly Gly Tyr Arg Gln Gln Gln Ser Gln Thr Ala 900 905 910 Tyr <210> SEQ ID NO 10 <211> LENGTH: 325 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 10 Met Leu Met Ser His Leu Gln Asp Asn Ile Gln His Ala Asp Pro Pro 1 5 10 15 Val Gln Ile Leu Tyr Asn Arg Thr Met Val Gln Leu Gly Ile Cys Ala 20 25 30 Phe Arg Gln Gly Leu Thr Lys Asp Ala His Asn Ala Leu Leu Asp Ile 35 40 45 Gln Ser Ser Gly Arg Ala Lys Glu Leu Leu Gly Gln Gly Leu Leu Leu 50 55 60 Arg Ser Leu Gln Glu Arg Asn Gln Glu Gln Glu Lys Val Glu Arg Arg 65 70 75 80 Arg Gln Val Pro Phe His Leu His Ile Asn Leu Glu Leu Leu Glu Cys 85 90 95 Val Tyr Leu Val Ser Ala Met Leu Leu Glu Ile Pro Tyr Met Ala Ala 100 105 110 His Glu Ser Asp Ala Arg Arg Arg Met Ile Ser Lys Gln Phe His His 115 120 125 Gln Leu Arg Val Gly Glu Arg Gln Pro Leu Leu Gly Pro Pro Glu Ser 130 135 140 Met Arg Glu His Val Val Ala Ala Ser Lys Ala Met Lys Met Gly Asp 145 150 155 160 Trp Lys Thr Cys His Ser Phe Ile Ile Asn Glu Lys Met Asn Gly Lys 165 170 175 Val Trp Asp Leu Phe Pro Glu Ala Asp Lys Val Arg Thr Met Leu Val 180 185 190 Arg Lys Ile Gln Glu Glu Ser Leu Arg Thr Tyr Leu Phe Thr Tyr Ser 195 200 205 Ser Val Tyr Asp Ser Ile Ser Met Glu Thr Leu Ser Asp Met Phe Glu 210 215 220 Leu Asp Leu Pro Thr Val His Ser Ile Ile Ser Lys Met Ile Ile Asn 225 230 235 240 Glu Glu Leu Met Ala Ser Leu Asp Gln Pro Thr Gln Thr Val Val Met 245 250 255 His Arg Thr Glu Pro Thr Ala Gln Gln Asn Leu Ala Leu Gln Leu Ala 260 265 270 Glu Lys Leu Gly Ser Leu Val Glu Asn Asn Glu Arg Val Phe Asp His 275 280 285 Lys Gln Gly Thr Tyr Gly Gly Tyr Phe Arg Asp Gln Lys Asp Gly Tyr 290 295 300 Arg Lys Asn Glu Gly Tyr Met Arg Arg Gly Gly Tyr Arg Gln Gln Gln 305 310 315 320 Ser Gln Thr Ala Tyr 325 <210> SEQ ID NO 11 <211> LENGTH: 392 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 ttcccctttg gaagagagag cagtgttaga tccttcaaag tcaagataaa agcagaggat 60 tgcaattagg gcatgagtca ccagcgagcc tcagaaaacc ctactgggat gcttccgaaa 120 ggccagtgct gtgcaggggg cgagacactt cagggagcgg gaggctccaa ggacagagct 180 tttaaagcag cagcagaagc ctgggatgtg gaagatctct gtctactctc ctattcctga 240 tgggagcagt cgggcaaagc acaccgctct tgactctgct ctacaggcca ttcacataac 300 agcaaattgc tgggtttcct tcatgtccct attaggaaag caaaacatac cacaaagtat 360 accctttctc actaaccccc tgcagtggac ct 392 <210> SEQ ID NO 12 <211> LENGTH: 250 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 ttcagaggag gggagagaaa gagtactcag tagggactga gcactaaatg cttattttaa 60 aagaaatgta aagagcagaa agcaattcag gctaccctgc cttttgtgct ggctagcact 120 ccggtcggtg tcagcagcac gtggcattga acattgcaat gtggagccca aaccacagaa 180 aatggggtga aattggccaa ctttctatta acttatgttg gcaattttgc caccaacagt 240 aagctggccc 250 <210> SEQ ID NO 13 <211> LENGTH: 359 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 tgcacgtcag tgtcctcagt tgcatcctgg ttccggtccg acagccgagc gatggcctca 60 ttgtcataat gaatcacact gctgtcctcc tccttgttct ccccctcgtt ttcatccttg 120 aatagctctt cagtgccaaa tttgagaatg tcgtcaagct cctgcttgga catggagcct 180 gccttggagc ccagcccagg ccgcacaacc aggtgtgtca gcatcatctt tctcttggcc 240 acttgtgtga ttcgctcttc cactgacgcg cgagtcacaa accggtaaat catcactttg 300 ttggcctggc caatccgatg agcccggcta aaggcctgga tgtcattatg ggggttcca 359 <210> SEQ ID NO 14 <211> LENGTH: 167 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 14 caggcgggaa acagagtgga gagctcagta ggccgtctga gactgctgct ggcggtagcc 60 accgcggcgc atgtagccct cgtttttgcg gtagccgtcc ttctggtctc ggaagtagcc 120 cccgtaggtg ccctgcttgt ggtcaaacac ccgttcgttg ttctcca 167 <210> SEQ ID NO 15 <211> LENGTH: 5852 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60 ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120 aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180 gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240 gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300 agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360 ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420 cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480 gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540 caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600 caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaacaactg 660 cgatcgcccg ccccgttgac gcaaatgggc ggtaggcgtg tacggtggga ggtctatata 720 agcagagctc gtttagtgaa ccgtcagatc actagaagct ttattgcggt agtttatcac 780 agttaaattg ctaacgcagt cagtgcttct gacacaacag tctcgaactt aagctgcagt 840 gactctctta aggtagcctt gcagaagttg gtcgtgaggc actgggcagg taagtatcaa 900 ggttacaaga caggtttaag gagaccaata gaaactgggc ttgtcgagac agagaagact 960 cttgcgtttc tgataggcac ctattggtct tactgacatc cactttgcct ttctctccac 1020 aggtgtccac tcccagttca attacagctc ttaaggctag agtacttaat acgactcact 1080 ataggctagc ctcgagaatt cacgcgtttc ccctttggaa gagagagcag tgttagatcc 1140 ttcaaagtca agataaaagc agaggattgc aattagggca tgagtcacca gcgagcctca 1200 gaaaacccta ctgggatgct tccgaaaggc cagtgctgtg cagggggcga gacacttcag 1260 ggagcgggag gctccaagga cagagctttt aaagcagcag cagaagcctg ggatgtggaa 1320 gatctctgtc tactctccta ttcctgatgg gagcagtcgg gcaaagcaca ccgctcttga 1380 ctctgctcta caggccattc acataacagc aaattgctgg gtttccttca tgtccctatt 1440 aggaaagcaa aacataccac aaagtatacc ctttctcact aaccccctgc agtggacctg 1500 tcgacccggg cggccgcttc cctttagtga gggttaatgc ttcgagcaga catgataaga 1560 tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg ctttatttgt 1620 gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa acaagttaac 1680 aacaacaatt gcattcattt tatgtttcag gttcaggggg agatgtggga ggttttttaa 1740 agcaagtaaa acctctacaa atgtggtaaa atccgataag gatcgatccg ggctggcgta 1800 atagcgaaga ggcccgcacc gatcgccctt cccaacagtt gcgcagcctg aatggcgaat 1860 ggacgcgccc tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc gcagcgtgac 1920 cgctacactt gccagcgccc tagcgcccgc tcctttcgct ttcttccctt cctttctcgc 1980 cacgttcgcc ggctttcccc gtcaagctct aaatcggggg ctccctttag ggttccgatt 2040 tagtgcttta cggcacctcg accccaaaaa acttgattag ggtgatggtt cacgtagtgg 2100 gccatcgccc tgatagacgg tttttcgccc tttgacgttg gagtccacgt tctttaatag 2160 tggactcttg ttccaaactg gaacaacact caaccctatc tcggtctatt cttttgattt 2220 ataagggatt ttgccgattt cggcctattg gttaaaaaat gagctgattt aacaaaaatt 2280 taacgcgaat tttaacaaaa tattaacgct tacaatttcc tgatgcggta ttttctcctt 2340 acgcatctgt gcggtatttc acaccgcata cgcggatctg cgcagcacca tggcctgaaa 2400 taacctctga aagaggaact tggttaggta ccttctgagg cggaaagaac cagctgtgga 2460 atgtgtgtca gttagggtgt ggaaagtccc caggctcccc agcaggcaga agtatgcaaa 2520 gcatgcatct caattagtca gcaaccaggt gtggaaagtc cccaggctcc ccagcaggca 2580 gaagtatgca aagcatgcat ctcaattagt cagcaaccat agtcccgccc ctaactccgc 2640 ccatcccgcc cctaactccg cccagttccg cccattctcc gccccatggc tgactaattt 2700 tttttattta tgcagaggcc gaggccgcct cggcctctga gctattccag aagtagtgag 2760 gaggcttttt tggaggccta ggcttttgca aaaagcttga ttcttctgac acaacagtct 2820 cgaacttaag gctagagcca ccatgattga acaagatgga ttgcacgcag gttctccggc 2880 cgcttgggtg gagaggctat tcggctatga ctgggcacaa cagacaatcg gctgctctga 2940 tgccgccgtg ttccggctgt cagcgcaggg gcgcccggtt ctttttgtca agaccgacct 3000 gtccggtgcc ctgaatgaac tgcaggacga ggcagcgcgg ctatcgtggc tggccacgac 3060 gggcgttcct tgcgcagctg tgctcgacgt tgtcactgaa gcgggaaggg actggctgct 3120 attgggcgaa gtgccggggc aggatctcct gtcatctcac cttgctcctg ccgagaaagt 3180 atccatcatg gctgatgcaa tgcggcggct gcatacgctt gatccggcta cctgcccatt 3240 cgaccaccaa gcgaaacatc gcatcgagcg agcacgtact cggatggaag ccggtcttgt 3300 cgatcaggat gatctggacg aagagcatca ggggctcgcg ccagccgaac tgttcgccag 3360 gctcaaggcg cgcatgcccg acggcgagga tctcgtcgtg acccatggcg atgcctgctt 3420 gccgaatatc atggtggaaa atggccgctt ttctggattc atcgactgtg gccggctggg 3480 tgtggcggac cgctatcagg acatagcgtt ggctacccgt gatattgctg aagagcttgg 3540 cggcgaatgg gctgaccgct tcctcgtgct ttacggtatc gccgctcccg attcgcagcg 3600 catcgccttc tatcgccttc ttgacgagtt cttctgagcg ggactctggg gttcgaaatg 3660 accgaccaag cgacgcccaa cctgccatca cgatggccgc aataaaatat ctttattttc 3720 attacatctg tgtgttggtt ttttgtgtga atcgatagcg ataaggatcc gcgtatggtg 3780 cactctcagt acaatctgct ctgatgccgc atagttaagc cagccccgac acccgccaac 3840 acccgctgac gcgccctgac gggcttgtct gctcccggca tccgcttaca gacaagctgt 3900 gaccgtctcc gggagctgca tgtgtcagag gttttcaccg tcatcaccga aacgcgcgag 3960 acgaaagggc ctcgtgatac gcctattttt ataggttaat gtcatgataa taatggtttc 4020 ttagacgtca ggtggcactt ttcggggaaa tgtgcgcgga acccctattt gtttattttt 4080 ctaaatacat tcaaatatgt atccgctcat gagacaataa ccctgataaa tgcttcaata 4140 atattgaaaa aggaagagta tgagtattca acatttccgt gtcgccctta ttcccttttt 4200 tgcggcattt tgccttcctg tttttgctca cccagaaacg ctggtgaaag taaaagatgc 4260 tgaagatcag ttgggtgcac gagtgggtta catcgaactg gatctcaaca gcggtaagat 4320 ccttgagagt tttcgccccg aagaacgttt tccaatgatg agcactttta aagttctgct 4380 atgtggcgcg gtattatccc gtattgacgc cgggcaagag caactcggtc gccgcataca 4440 ctattctcag aatgacttgg ttgagtactc accagtcaca gaaaagcatc ttacggatgg 4500 catgacagta agagaattat gcagtgctgc cataaccatg agtgataaca ctgcggccaa 4560 cttacttctg acaacgatcg gaggaccgaa ggagctaacc gcttttttgc acaacatggg 4620 ggatcatgta actcgccttg atcgttggga accggagctg aatgaagcca taccaaacga 4680 cgagcgtgac accacgatgc ctgtagcaat ggcaacaacg ttgcgcaaac tattaactgg 4740 cgaactactt actctagctt cccggcaaca attaatagac tggatggagg cggataaagt 4800 tgcaggacca cttctgcgct cggcccttcc ggctggctgg tttattgctg ataaatctgg 4860 agccggtgag cgtgggtctc gcggtatcat tgcagcactg gggccagatg gtaagccctc 4920 ccgtatcgta gttatctaca cgacggggag tcaggcaact atggatgaac gaaatagaca 4980 gatcgctgag ataggtgcct cactgattaa gcattggtaa ctgtcagacc aagtttactc 5040 atatatactt tagattgatt taaaacttca tttttaattt aaaaggatct aggtgaagat 5100 cctttttgat aatctcatga ccaaaatccc ttaacgtgag ttttcgttcc actgagcgtc 5160 agaccccgta gaaaagatca aaggatcttc ttgagatcct ttttttctgc gcgtaatctg 5220 ctgcttgcaa acaaaaaaac caccgctacc agcggtggtt tgtttgccgg atcaagagct 5280 accaactctt tttccgaagg taactggctt cagcagagcg cagataccaa atactgttct 5340 tctagtgtag ccgtagttag gccaccactt caagaactct gtagcaccgc ctacatacct 5400 cgctctgcta atcctgttac cagtggctgc tgccagtggc gataagtcgt gtcttaccgg 5460 gttggactca agacgatagt taccggataa ggcgcagcgg tcgggctgaa cggggggttc 5520 gtgcacacag cccagcttgg agcgaacgac ctacaccgaa ctgagatacc tacagcgtga 5580 gctatgagaa agcgccacgc ttcccgaagg gagaaaggcg gacaggtatc cggtaagcgg 5640 cagggtcgga acaggagagc gcacgaggga gcttccaggg ggaaacgcct ggtatcttta 5700 tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat gctcgtcagg 5760 ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc tggccttttg 5820 ctggcctttt gctcacatgg ctcgacagat ct 5852 <210> SEQ ID NO 16 <211> LENGTH: 5710 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60 ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120 aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180 gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240 gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300 agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360 ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420 cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480 gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540 caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600 caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaacaactg 660 cgatcgcccg ccccgttgac gcaaatgggc ggtaggcgtg tacggtggga ggtctatata 720 agcagagctc gtttagtgaa ccgtcagatc actagaagct ttattgcggt agtttatcac 780 agttaaattg ctaacgcagt cagtgcttct gacacaacag tctcgaactt aagctgcagt 840 gactctctta aggtagcctt gcagaagttg gtcgtgaggc actgggcagg taagtatcaa 900 ggttacaaga caggtttaag gagaccaata gaaactgggc ttgtcgagac agagaagact 960 cttgcgtttc tgataggcac ctattggtct tactgacatc cactttgcct ttctctccac 1020 aggtgtccac tcccagttca attacagctc ttaaggctag agtacttaat acgactcact 1080 ataggctagc ctcgagaatt cacgcgtttc agaggagggg agagaaagag tactcagtag 1140 ggactgagca ctaaatgctt attttaaaag aaatgtaaag agcagaaagc aattcaggct 1200 accctgcctt ttgtgctggc tagcactccg gtcggtgtca gcagcacgtg gcattgaaca 1260 ttgcaatgtg gagcccaaac cacagaaaat ggggtgaaat tggccaactt tctattaact 1320 tatgttggca attttgccac caacagtaag ctggcccgtc gacccgggcg gccgcttccc 1380 tttagtgagg gttaatgctt cgagcagaca tgataagata cattgatgag tttggacaaa 1440 ccacaactag aatgcagtga aaaaaatgct ttatttgtga aatttgtgat gctattgctt 1500 tatttgtaac cattataagc tgcaataaac aagttaacaa caacaattgc attcatttta 1560 tgtttcaggt tcagggggag atgtgggagg ttttttaaag caagtaaaac ctctacaaat 1620 gtggtaaaat ccgataagga tcgatccggg ctggcgtaat agcgaagagg cccgcaccga 1680 tcgcccttcc caacagttgc gcagcctgaa tggcgaatgg acgcgccctg tagcggcgca 1740 ttaagcgcgg cgggtgtggt ggttacgcgc agcgtgaccg ctacacttgc cagcgcccta 1800 gcgcccgctc ctttcgcttt cttcccttcc tttctcgcca cgttcgccgg ctttccccgt 1860 caagctctaa atcgggggct ccctttaggg ttccgattta gtgctttacg gcacctcgac 1920 cccaaaaaac ttgattaggg tgatggttca cgtagtgggc catcgccctg atagacggtt 1980 tttcgccctt tgacgttgga gtccacgttc tttaatagtg gactcttgtt ccaaactgga 2040 acaacactca accctatctc ggtctattct tttgatttat aagggatttt gccgatttcg 2100 gcctattggt taaaaaatga gctgatttaa caaaaattta acgcgaattt taacaaaata 2160 ttaacgctta caatttcctg atgcggtatt ttctccttac gcatctgtgc ggtatttcac 2220 accgcatacg cggatctgcg cagcaccatg gcctgaaata acctctgaaa gaggaacttg 2280 gttaggtacc ttctgaggcg gaaagaacca gctgtggaat gtgtgtcagt tagggtgtgg 2340 aaagtcccca ggctccccag caggcagaag tatgcaaagc atgcatctca attagtcagc 2400 aaccaggtgt ggaaagtccc caggctcccc agcaggcaga agtatgcaaa gcatgcatct 2460 caattagtca gcaaccatag tcccgcccct aactccgccc atcccgcccc taactccgcc 2520 cagttccgcc cattctccgc cccatggctg actaattttt tttatttatg cagaggccga 2580 ggccgcctcg gcctctgagc tattccagaa gtagtgagga ggcttttttg gaggcctagg 2640 cttttgcaaa aagcttgatt cttctgacac aacagtctcg aacttaaggc tagagccacc 2700 atgattgaac aagatggatt gcacgcaggt tctccggccg cttgggtgga gaggctattc 2760 ggctatgact gggcacaaca gacaatcggc tgctctgatg ccgccgtgtt ccggctgtca 2820 gcgcaggggc gcccggttct ttttgtcaag accgacctgt ccggtgccct gaatgaactg 2880 caggacgagg cagcgcggct atcgtggctg gccacgacgg gcgttccttg cgcagctgtg 2940 ctcgacgttg tcactgaagc gggaagggac tggctgctat tgggcgaagt gccggggcag 3000 gatctcctgt catctcacct tgctcctgcc gagaaagtat ccatcatggc tgatgcaatg 3060 cggcggctgc atacgcttga tccggctacc tgcccattcg accaccaagc gaaacatcgc 3120 atcgagcgag cacgtactcg gatggaagcc ggtcttgtcg atcaggatga tctggacgaa 3180 gagcatcagg ggctcgcgcc agccgaactg ttcgccaggc tcaaggcgcg catgcccgac 3240 ggcgaggatc tcgtcgtgac ccatggcgat gcctgcttgc cgaatatcat ggtggaaaat 3300 ggccgctttt ctggattcat cgactgtggc cggctgggtg tggcggaccg ctatcaggac 3360 atagcgttgg ctacccgtga tattgctgaa gagcttggcg gcgaatgggc tgaccgcttc 3420 ctcgtgcttt acggtatcgc cgctcccgat tcgcagcgca tcgccttcta tcgccttctt 3480 gacgagttct tctgagcggg actctggggt tcgaaatgac cgaccaagcg acgcccaacc 3540 tgccatcacg atggccgcaa taaaatatct ttattttcat tacatctgtg tgttggtttt 3600 ttgtgtgaat cgatagcgat aaggatccgc gtatggtgca ctctcagtac aatctgctct 3660 gatgccgcat agttaagcca gccccgacac ccgccaacac ccgctgacgc gccctgacgg 3720 gcttgtctgc tcccggcatc cgcttacaga caagctgtga ccgtctccgg gagctgcatg 3780 tgtcagaggt tttcaccgtc atcaccgaaa cgcgcgagac gaaagggcct cgtgatacgc 3840 ctatttttat aggttaatgt catgataata atggtttctt agacgtcagg tggcactttt 3900 cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc aaatatgtat 3960 ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag gaagagtatg 4020 agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg ccttcctgtt 4080 tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt gggtgcacga 4140 gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt tcgccccgaa 4200 gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt attatcccgt 4260 attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa tgacttggtt 4320 gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag agaattatgc 4380 agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac aacgatcgga 4440 ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac tcgccttgat 4500 cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac cacgatgcct 4560 gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac tctagcttcc 4620 cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact tctgcgctcg 4680 gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg tgggtctcgc 4740 ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt tatctacacg 4800 acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat aggtgcctca 4860 ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta gattgattta 4920 aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa tctcatgacc 4980 aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa 5040 ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca 5100 ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta 5160 actggcttca gcagagcgca gataccaaat actgttcttc tagtgtagcc gtagttaggc 5220 caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca 5280 gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta 5340 ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag 5400 cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt 5460 cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc 5520 acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg gtttcgccac 5580 ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac 5640 gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc tcacatggct 5700 cgacagatct 5710 <210> SEQ ID NO 17 <211> LENGTH: 5819 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60 ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120 aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180 gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240 gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300 agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360 ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420 cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480 gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540 caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600 caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaacaactg 660 cgatcgcccg ccccgttgac gcaaatgggc ggtaggcgtg tacggtggga ggtctatata 720 agcagagctc gtttagtgaa ccgtcagatc actagaagct ttattgcggt agtttatcac 780 agttaaattg ctaacgcagt cagtgcttct gacacaacag tctcgaactt aagctgcagt 840 gactctctta aggtagcctt gcagaagttg gtcgtgaggc actgggcagg taagtatcaa 900 ggttacaaga caggtttaag gagaccaata gaaactgggc ttgtcgagac agagaagact 960 cttgcgtttc tgataggcac ctattggtct tactgacatc cactttgcct ttctctccac 1020 aggtgtccac tcccagttca attacagctc ttaaggctag agtacttaat acgactcact 1080 ataggctagc ctcgagaatt cacgcgttgc acgtcagtgt cctcagttgc atcctggttc 1140 cggtccgaca gccgagcgat ggcctcattg tcataatgaa tcacactgct gtcctcctcc 1200 ttgttctccc cctcgttttc atccttgaat agctcttcag tgccaaattt gagaatgtcg 1260 tcaagctcct gcttggacat ggagcctgcc ttggagccca gcccaggccg cacaaccagg 1320 tgtgtcagca tcatctttct cttggccact tgtgtgattc gctcttccac tgacgcgcga 1380 gtcacaaacc ggtaaatcat cactttgttg gcctggccaa tccgatgagc ccggctaaag 1440 gcctggatgt cattatgggg gttccagtcg acccgggcgg ccgcttccct ttagtgaggg 1500 ttaatgcttc gagcagacat gataagatac attgatgagt ttggacaaac cacaactaga 1560 atgcagtgaa aaaaatgctt tatttgtgaa atttgtgatg ctattgcttt atttgtaacc 1620 attataagct gcaataaaca agttaacaac aacaattgca ttcattttat gtttcaggtt 1680 cagggggaga tgtgggaggt tttttaaagc aagtaaaacc tctacaaatg tggtaaaatc 1740 cgataaggat cgatccgggc tggcgtaata gcgaagaggc ccgcaccgat cgcccttccc 1800 aacagttgcg cagcctgaat ggcgaatgga cgcgccctgt agcggcgcat taagcgcggc 1860 gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag cgcccgctcc 1920 tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc aagctctaaa 1980 tcgggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc ccaaaaaact 2040 tgattagggt gatggttcac gtagtgggcc atcgccctga tagacggttt ttcgcccttt 2100 gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa caacactcaa 2160 ccctatctcg gtctattctt ttgatttata agggattttg ccgatttcgg cctattggtt 2220 aaaaaatgag ctgatttaac aaaaatttaa cgcgaatttt aacaaaatat taacgcttac 2280 aatttcctga tgcggtattt tctccttacg catctgtgcg gtatttcaca ccgcatacgc 2340 ggatctgcgc agcaccatgg cctgaaataa cctctgaaag aggaacttgg ttaggtacct 2400 tctgaggcgg aaagaaccag ctgtggaatg tgtgtcagtt agggtgtgga aagtccccag 2460 gctccccagc aggcagaagt atgcaaagca tgcatctcaa ttagtcagca accaggtgtg 2520 gaaagtcccc aggctcccca gcaggcagaa gtatgcaaag catgcatctc aattagtcag 2580 caaccatagt cccgccccta actccgccca tcccgcccct aactccgccc agttccgccc 2640 attctccgcc ccatggctga ctaatttttt ttatttatgc agaggccgag gccgcctcgg 2700 cctctgagct attccagaag tagtgaggag gcttttttgg aggcctaggc ttttgcaaaa 2760 agcttgattc ttctgacaca acagtctcga acttaaggct agagccacca tgattgaaca 2820 agatggattg cacgcaggtt ctccggccgc ttgggtggag aggctattcg gctatgactg 2880 ggcacaacag acaatcggct gctctgatgc cgccgtgttc cggctgtcag cgcaggggcg 2940 cccggttctt tttgtcaaga ccgacctgtc cggtgccctg aatgaactgc aggacgaggc 3000 agcgcggcta tcgtggctgg ccacgacggg cgttccttgc gcagctgtgc tcgacgttgt 3060 cactgaagcg ggaagggact ggctgctatt gggcgaagtg ccggggcagg atctcctgtc 3120 atctcacctt gctcctgccg agaaagtatc catcatggct gatgcaatgc ggcggctgca 3180 tacgcttgat ccggctacct gcccattcga ccaccaagcg aaacatcgca tcgagcgagc 3240 acgtactcgg atggaagccg gtcttgtcga tcaggatgat ctggacgaag agcatcaggg 3300 gctcgcgcca gccgaactgt tcgccaggct caaggcgcgc atgcccgacg gcgaggatct 3360 cgtcgtgacc catggcgatg cctgcttgcc gaatatcatg gtggaaaatg gccgcttttc 3420 tggattcatc gactgtggcc ggctgggtgt ggcggaccgc tatcaggaca tagcgttggc 3480 tacccgtgat attgctgaag agcttggcgg cgaatgggct gaccgcttcc tcgtgcttta 3540 cggtatcgcc gctcccgatt cgcagcgcat cgccttctat cgccttcttg acgagttctt 3600 ctgagcggga ctctggggtt cgaaatgacc gaccaagcga cgcccaacct gccatcacga 3660 tggccgcaat aaaatatctt tattttcatt acatctgtgt gttggttttt tgtgtgaatc 3720 gatagcgata aggatccgcg tatggtgcac tctcagtaca atctgctctg atgccgcata 3780 gttaagccag ccccgacacc cgccaacacc cgctgacgcg ccctgacggg cttgtctgct 3840 cccggcatcc gcttacagac aagctgtgac cgtctccggg agctgcatgt gtcagaggtt 3900 ttcaccgtca tcaccgaaac gcgcgagacg aaagggcctc gtgatacgcc tatttttata 3960 ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc ggggaaatgt 4020 gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag 4080 acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattcaaca 4140 tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc 4200 agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag tgggttacat 4260 cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag aacgttttcc 4320 aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgta ttgacgccgg 4380 gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg agtactcacc 4440 agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca gtgctgccat 4500 aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag gaccgaagga 4560 gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc gttgggaacc 4620 ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg tagcaatggc 4680 aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc ggcaacaatt 4740 aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg cccttccggc 4800 tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg gtatcattgc 4860 agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga cggggagtca 4920 ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac tgattaagca 4980 ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa aacttcattt 5040 ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca aaatccctta 5100 acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag gatcttcttg 5160 agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac cgctaccagc 5220 ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa ctggcttcag 5280 cagagcgcag ataccaaata ctgttcttct agtgtagccg tagttaggcc accacttcaa 5340 gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag tggctgctgc 5400 cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac cggataaggc 5460 gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc gaacgaccta 5520 caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc ccgaagggag 5580 aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca cgagggagct 5640 tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc tctgacttga 5700 gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg ccagcaacgc 5760 ggccttttta cggttcctgg ccttttgctg gccttttgct cacatggctc gacagatct 5819 <210> SEQ ID NO 18 <211> LENGTH: 5627 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60 ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120 aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180 gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240 gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300 agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360 ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420 cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480 gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540 caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600 caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaacaactg 660 cgatcgcccg ccccgttgac gcaaatgggc ggtaggcgtg tacggtggga ggtctatata 720 agcagagctc gtttagtgaa ccgtcagatc actagaagct ttattgcggt agtttatcac 780 agttaaattg ctaacgcagt cagtgcttct gacacaacag tctcgaactt aagctgcagt 840 gactctctta aggtagcctt gcagaagttg gtcgtgaggc actgggcagg taagtatcaa 900 ggttacaaga caggtttaag gagaccaata gaaactgggc ttgtcgagac agagaagact 960 cttgcgtttc tgataggcac ctattggtct tactgacatc cactttgcct ttctctccac 1020 aggtgtccac tcccagttca attacagctc ttaaggctag agtacttaat acgactcact 1080 ataggctagc ctcgagaatt cacgcgtcag gcgggaaaca gagtggagag ctcagtaggc 1140 cgtctgagac tgctgctggc ggtagccacc gcggcgcatg tagccctcgt ttttgcggta 1200 gccgtccttc tggtctcgga agtagccccc gtaggtgccc tgcttgtggt caaacacccg 1260 ttcgttgttc tccagtcgac ccgggcggcc gcttcccttt agtgagggtt aatgcttcga 1320 gcagacatga taagatacat tgatgagttt ggacaaacca caactagaat gcagtgaaaa 1380 aaatgcttta tttgtgaaat ttgtgatgct attgctttat ttgtaaccat tataagctgc 1440 aataaacaag ttaacaacaa caattgcatt cattttatgt ttcaggttca gggggagatg 1500 tgggaggttt tttaaagcaa gtaaaacctc tacaaatgtg gtaaaatccg ataaggatcg 1560 atccgggctg gcgtaatagc gaagaggccc gcaccgatcg cccttcccaa cagttgcgca 1620 gcctgaatgg cgaatggacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt 1680 tacgcgcagc gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt 1740 cccttccttt ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc 1800 tttagggttc cgatttagtg ctttacggca cctcgacccc aaaaaacttg attagggtga 1860 tggttcacgt agtgggccat cgccctgata gacggttttt cgccctttga cgttggagtc 1920 cacgttcttt aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggt 1980 ctattctttt gatttataag ggattttgcc gatttcggcc tattggttaa aaaatgagct 2040 gatttaacaa aaatttaacg cgaattttaa caaaatatta acgcttacaa tttcctgatg 2100 cggtattttc tccttacgca tctgtgcggt atttcacacc gcatacgcgg atctgcgcag 2160 caccatggcc tgaaataacc tctgaaagag gaacttggtt aggtaccttc tgaggcggaa 2220 agaaccagct gtggaatgtg tgtcagttag ggtgtggaaa gtccccaggc tccccagcag 2280 gcagaagtat gcaaagcatg catctcaatt agtcagcaac caggtgtgga aagtccccag 2340 gctccccagc aggcagaagt atgcaaagca tgcatctcaa ttagtcagca accatagtcc 2400 cgcccctaac tccgcccatc ccgcccctaa ctccgcccag ttccgcccat tctccgcccc 2460 atggctgact aatttttttt atttatgcag aggccgaggc cgcctcggcc tctgagctat 2520 tccagaagta gtgaggaggc ttttttggag gcctaggctt ttgcaaaaag cttgattctt 2580 ctgacacaac agtctcgaac ttaaggctag agccaccatg attgaacaag atggattgca 2640 cgcaggttct ccggccgctt gggtggagag gctattcggc tatgactggg cacaacagac 2700 aatcggctgc tctgatgccg ccgtgttccg gctgtcagcg caggggcgcc cggttctttt 2760 tgtcaagacc gacctgtccg gtgccctgaa tgaactgcag gacgaggcag cgcggctatc 2820 gtggctggcc acgacgggcg ttccttgcgc agctgtgctc gacgttgtca ctgaagcggg 2880 aagggactgg ctgctattgg gcgaagtgcc ggggcaggat ctcctgtcat ctcaccttgc 2940 tcctgccgag aaagtatcca tcatggctga tgcaatgcgg cggctgcata cgcttgatcc 3000 ggctacctgc ccattcgacc accaagcgaa acatcgcatc gagcgagcac gtactcggat 3060 ggaagccggt cttgtcgatc aggatgatct ggacgaagag catcaggggc tcgcgccagc 3120 cgaactgttc gccaggctca aggcgcgcat gcccgacggc gaggatctcg tcgtgaccca 3180 tggcgatgcc tgcttgccga atatcatggt ggaaaatggc cgcttttctg gattcatcga 3240 ctgtggccgg ctgggtgtgg cggaccgcta tcaggacata gcgttggcta cccgtgatat 3300 tgctgaagag cttggcggcg aatgggctga ccgcttcctc gtgctttacg gtatcgccgc 3360 tcccgattcg cagcgcatcg ccttctatcg ccttcttgac gagttcttct gagcgggact 3420 ctggggttcg aaatgaccga ccaagcgacg cccaacctgc catcacgatg gccgcaataa 3480 aatatcttta ttttcattac atctgtgtgt tggttttttg tgtgaatcga tagcgataag 3540 gatccgcgta tggtgcactc tcagtacaat ctgctctgat gccgcatagt taagccagcc 3600 ccgacacccg ccaacacccg ctgacgcgcc ctgacgggct tgtctgctcc cggcatccgc 3660 ttacagacaa gctgtgaccg tctccgggag ctgcatgtgt cagaggtttt caccgtcatc 3720 accgaaacgc gcgagacgaa agggcctcgt gatacgccta tttttatagg ttaatgtcat 3780 gataataatg gtttcttaga cgtcaggtgg cacttttcgg ggaaatgtgc gcggaacccc 3840 tatttgttta tttttctaaa tacattcaaa tatgtatccg ctcatgagac aataaccctg 3900 ataaatgctt caataatatt gaaaaaggaa gagtatgagt attcaacatt tccgtgtcgc 3960 ccttattccc ttttttgcgg cattttgcct tcctgttttt gctcacccag aaacgctggt 4020 gaaagtaaaa gatgctgaag atcagttggg tgcacgagtg ggttacatcg aactggatct 4080 caacagcggt aagatccttg agagttttcg ccccgaagaa cgttttccaa tgatgagcac 4140 ttttaaagtt ctgctatgtg gcgcggtatt atcccgtatt gacgccgggc aagagcaact 4200 cggtcgccgc atacactatt ctcagaatga cttggttgag tactcaccag tcacagaaaa 4260 gcatcttacg gatggcatga cagtaagaga attatgcagt gctgccataa ccatgagtga 4320 taacactgcg gccaacttac ttctgacaac gatcggagga ccgaaggagc taaccgcttt 4380 tttgcacaac atgggggatc atgtaactcg ccttgatcgt tgggaaccgg agctgaatga 4440 agccatacca aacgacgagc gtgacaccac gatgcctgta gcaatggcaa caacgttgcg 4500 caaactatta actggcgaac tacttactct agcttcccgg caacaattaa tagactggat 4560 ggaggcggat aaagttgcag gaccacttct gcgctcggcc cttccggctg gctggtttat 4620 tgctgataaa tctggagccg gtgagcgtgg gtctcgcggt atcattgcag cactggggcc 4680 agatggtaag ccctcccgta tcgtagttat ctacacgacg gggagtcagg caactatgga 4740 tgaacgaaat agacagatcg ctgagatagg tgcctcactg attaagcatt ggtaactgtc 4800 agaccaagtt tactcatata tactttagat tgatttaaaa cttcattttt aatttaaaag 4860 gatctaggtg aagatccttt ttgataatct catgaccaaa atcccttaac gtgagttttc 4920 gttccactga gcgtcagacc ccgtagaaaa gatcaaagga tcttcttgag atcctttttt 4980 tctgcgcgta atctgctgct tgcaaacaaa aaaaccaccg ctaccagcgg tggtttgttt 5040 gccggatcaa gagctaccaa ctctttttcc gaaggtaact ggcttcagca gagcgcagat 5100 accaaatact gttcttctag tgtagccgta gttaggccac cacttcaaga actctgtagc 5160 accgcctaca tacctcgctc tgctaatcct gttaccagtg gctgctgcca gtggcgataa 5220 gtcgtgtctt accgggttgg actcaagacg atagttaccg gataaggcgc agcggtcggg 5280 ctgaacgggg ggttcgtgca cacagcccag cttggagcga acgacctaca ccgaactgag 5340 atacctacag cgtgagctat gagaaagcgc cacgcttccc gaagggagaa aggcggacag 5400 gtatccggta agcggcaggg tcggaacagg agagcgcacg agggagcttc cagggggaaa 5460 cgcctggtat ctttatagtc ctgtcgggtt tcgccacctc tgacttgagc gtcgattttt 5520 gtgatgctcg tcaggggggc ggagcctatg gaaaaacgcc agcaacgcgg cctttttacg 5580 gttcctggcc ttttgctggc cttttgctca catggctcga cagatct 5627 <210> SEQ ID NO 19 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 cgggtcgaca ggtccactgc agggggtta 29 <210> SEQ ID NO 20 <211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 cgcacgcgtt tcccctttgg aagagagagc a 31 <210> SEQ ID NO 21 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 cgggtcgacg ggccagctta ctgttggtg 29 <210> SEQ ID NO 22 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 22 cgcacgcgtt tcagaggagg ggagagaaag ag 32 <210> SEQ ID NO 23 <211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 cgggtcgact ggaaccccca taatgacatc c 31 <210> SEQ ID NO 24 <211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 24 cgcacgcgtt gcacgtcagt gtcctcagtt g 31 <210> SEQ ID NO 25 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 cgggtcgact ggagaacaac gaacgggtgt 30 <210> SEQ ID NO 26 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 26 cgcacgcgtc aggcgggaaa cagagtgga 29 <210> SEQ ID NO 27 <211> LENGTH: 5975 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/XM_040709 <309> DATABASE ENTRY DATE: 2002-02-07 <313> RELEVANT RESIDUES IN SEQ ID NO: RELEVANT RESIDUES: (1)..(5975) <400> SEQUENCE: 27 gctctttgcc gagggcgtgt ggtgagagtc cccacagcga ccctggttcg agtggtgggc 60 actgagctgg tcatcccctg caacgtcagt gactatgatg gccccagcga gcaaaacttt 120 gactggagct tctcatcttt ggggagcagc tttgtggagc ttgcaagcac ctgggaggtg 180 gggttcccag cccagctgta ccaggagcgg ctgcagaggg gcgagatcct gttaaggcgg 240 actgccaacg acgccgtgga gctccacata aagaacgtcc agccttcaga ccaaggccac 300 tacaaatgtt caacccccag cacagatgcc actgtccagg gaaactatga ggacacagtg 360 caggttaaag tgctggccga ctccctgcac gtgggcccca gcgcgcggcc cccgccgagc 420 ctgagcctgc gggaggggga gcccttcgag ctgcgctgca ccgccgcctc cgcctcgccg 480 ctgcacacgc acctggcgct gctgtgggag gtgcaccgcg gcccggccag gcggagcgtc 540 ctcgccctga cccacgaggg caggttccac ccgggcctgg ggtacgagca gcgctaccac 600 agtggggacg tgcgcctcga caccgtgggc agcgacgcct accgcctctc agtgtcccgg 660 gctctgtctg ccgaccaggg ctcctacagg tgtatcgtca gcgagtggat cgccgagcag 720 ggcaactggc aggaaatcca agaaaaggcc gtggaagttg ccaccgtggt gatccagcca 780 tcagttctgc gagcagctgt gcccaagaat gtgtctgtgg ctgaaggaaa ggaactggac 840 ctgacctgta acatcacaac agaccgagcc gatgacgtcc ggcccgaggt gacgtggtcc 900 ttcagcagga tgcctgacag caccctacct ggctcccgcg tgttggcgcg gcttgaccgt 960 gattccctgg tgcacagctc gcctcatgtt gctttgagtc atgtggatgc acgctcctac 1020 catttactgg ttcgggatgt tagcaaagaa aactctggct actattactg ccacgtgtcc 1080 ctgtgggcac ccggacacaa caggagctgg cacaaagtgg cagaggccgt gtcttcccca 1140 gctggtgtgg gtgtgacctg gctagaacca gactaccagg tgtacctgaa tgcttccaag 1200 gtccccgggt ttgcggatga ccccacagag ctggcatgcc gggtggtgga cacgaagagt 1260 ggggaggcga atgtccgatt cacggtttcg tggtactaca ggatgaaccg gcgcagcgac 1320 aatgtggtga ccagcgagct gcttgcagtc atggacgggg actggacgct aaaatatgga 1380 gagaggagca agcagcgggc ccaggatgga gactttattt tttctaagga acatacagac 1440 acgttcaatt tccggatcca aaggactaca gaggaagaca gaggcaatta ttactgtgtt 1500 gtgtctgcct ggaccaaaca gcggaacaac agctgggtga aaagcaagga tgtcttctcc 1560 aagcctgtta acatattttg ggcattagaa gattccgtgc ttgtggtgaa ggcgaggcag 1620 ccaaagcctt tctttgctgc cggaaataca tttgagatga cttgcaaagt atcttccaag 1680 aatattaagt cgccacgcta ctctgttctc atcatggctg agaagcctgt cggcgacctc 1740 tccagtccca atgaaacgaa gtacatcatc tctctggacc aggattctgt ggtgaagctg 1800 gagaattgga cagatgcatc acgggtggat ggcgttgttt tagaaaaagt gcaggaggat 1860 gagttccgct atcgaatgta ccagactcag gtctcagacg cagggctgta ccgctgcatg 1920 gtgacagcct ggtctcctgt caggggcagc ctttggcgag aagcagcaac cagtctctcc 1980 aatcctattg agatagactt ccaaacctca ggtcctatat ttaatgcttc tgtgcattca 2040 gacacaccat cagtaattcg gggagatctg atcaaattgt tctgtatcat cactgtcgag 2100 ggagcagcac tggatccaga tgacatggcc tttgatgtgt cctggtttgc ggtgcactct 2160 tttggcctgg acaaggctcc tgtgctcctg tcttccctgg atcggaaggg catcgtgacc 2220 acctcccgga gggactggaa gagcgacctc agcctggagc gcgtgagtgt gctggaattc 2280 ttgctgcaag tgcatggctc cgaggaccag gactttggca actactactg ttccgtgact 2340 ccatgggtga agtcaccaac aggttcctgg cagaaggagg cagagatcca ctccaagccc 2400 gtttttataa ctgtgaagat ggatgtgctg aacgccttca agtatccctt gctgatcggc 2460 gtcggtctgt ccacggtcat cgggctcctg tcctgtctca tcgggtactg cagctcccac 2520 tggtgttgta agaaggaggt tcaggagaca cggcgcgagc gccgcaggct catgtcgatg 2580 gagatggact aggctggccc gggaggggag tgacagaggg acgttctagg agcaattggg 2640 gcaagaagag gacagtgata ttttaaaaca aagtgtgtta cactaaaaac cagtcctctc 2700 taatctcagg tgggacttgg cgctctctct tttctgcatg tcaagttctg agcgcggaca 2760 tgtttaccag cacacggctc ttcttcccac ggcactttct gatgtaacaa tcgagtgtgt 2820 gttttcccaa ctgcagcttt ttaatggtta accttcatct aatttttttt ctcccactgg 2880 tttatagatc ctctgacttg tgtgtgttta tagcttttgt ttcgcggggt tgtggtgagg 2940 aaggggtgat ggcatgcgga gttctttatc ttcagtgaga atgtgcctgc ccgcctgaga 3000 gccagcttcc gcgttggagg cacgtgttca gagagctgct gagcgccacc ctctacccgg 3060 ctgacagaca acacagacct gtgccgaagg ctaatttgtg gcttttacga ccctacccca 3120 ccccctgttt tcaggggttt agactacatt tgaaatccaa acttggagta tataacttct 3180 tattgagccc aactgctttt tttttttttt tttttgcttc tctgcccctt ttccatttct 3240 tttgtatttg ttttctgtga gagcactgaa atggcagccc tggaatctac aatttggctc 3300 tccactgagc accttatctt gccaccttag ccttaagaat gaatatgaag aaaaatacac 3360 agccacctct gtccagggca gtaagaaggg ctgcaaggaa ggggaggatg gggacaagga 3420 aaggatcaga tacctgctcc agtagttgtg aggccactgt gtctcagggg actccaggag 3480 gagcagaaga gggatcccac gaagttattc ttacgcagct ggggccagga gggtcagagt 3540 ggtgccaggt gcaagttagg ctaaagaagc caccactatt cctctctctt gcccattgtg 3600 gggggcaaag gcattggtca ccaagagtct tgcaggggga cccacagata tgccatgtcc 3660 ttcacacgtg cttgggctcc ttaacctgaa ggcaaattgc tacttgcaag actgactgac 3720 ttcaaggaat cagaaattac ctagaagcac catgtttttt ctatgacctt ttcagtcctt 3780 caggtcattt taaggtccac tgcagggggt tagtgagaaa gggtatactt tgtggtatgt 3840 tttgctttcc taatagggac atgaaggaaa cccagcaatt tgctgttatg tgaatggcct 3900 gtagagcaga gtcaagagcg gtgtgctttg cccgactgct cccatcagga ataggagagt 3960 agacagagat cttccacatc ccaggcttct gctgctgctt taaaagctct gtccttggag 4020 cctcccgctc cctgaagtgt ctcgccccct gcacagcact ggcctttcgg aagcatccca 4080 gtagggtttt ctgaggctcg ctggtgactc atgccctaat tgcaatcctc tgcttttatc 4140 ttgactttga aggatctaac actgctctct cttccaaagg ggaaaaaaag attcatttgt 4200 tttgagcaat aaactaatac aaaatgatgg ccattcatgt gcagctcttt gtcaccatgg 4260 gccggatgag ttgtgctcct cctggctcac catttccccc tgctccccca cagccggttc 4320 tgcacttatc accgagtcgc ccctggaagc agattcccat tgagttttcc ccaccaaggg 4380 gaccatgcac atggtagaaa cattagattc tgcattgaca gtagcctttc cttggcccgg 4440 gcctgtggtg ggaagacggg caacaagtat accccaccag ggcctgagtg actagaggaa 4500 gaggacgagg ccttgttggc actagatttg ggtattttct gcatgtcata acatatccta 4560 actgctattt cagaagaggc agcttgtagg tgattgtaca agtgagaatt aaagagagaa 4620 cagatattta aacaggtgct gtattagtaa cagccagtgc cctttcagcc cttgcatcta 4680 ttaaaaggag attcaggatt ttattggcac aggcccttct tagtaggaag aaagggtgct 4740 tagctttgga cctgaccggg tgtgtgtaaa accatggact gagtcacagc agacactcga 4800 tggtggtaaa tgtgatgggt gcttacacac tgtacctttt cctttcatac tgatgctgca 4860 gttcagggct ggagttgtta aggcattgac ctccacccac ctgccccatg tccactgggc 4920 tgcccaagct gcatgtcacc tgagggctgg caggaagggg cgagaaatcc cagggcattg 4980 taccaaggac ctagttcctt ctagggatat aaatttccag gaatgtgtat ttttaatgtg 5040 gtgagatgca ctcttttgtt gtaccaaata gggctcccca ccccacccct gcgacaagtg 5100 ctcttctaga acaggttcct accagcagca ctggtgtgaa tgaaagagag acccagccgc 5160 gtctcacaca ggtggaattg cacttcttaa caaaaaggaa ctttataaaa gtttgggatt 5220 ttttttccta atcataaaaa tagccccaga aagagcctaa gctatgttca gatagaagcc 5280 tcgaaattcc tgtaaattgt ttactttatg atgtttacat acacgtttca ctttgaaaaa 5340 aaatgcaaat cgacttttta acaactgttg agatgtttca tgggacagta gaactctgac 5400 tcaccaactg ggctaaattt taatttaaaa atgtatttat ttgagtgtct ttccccccct 5460 caccctcacc atctgagggg ctccctgaga tcttggtaga ggaggcccct cctgcccaga 5520 ccttcgtttg tttccccggt ggcccttgct tcttgctttg cagactgcct gcagccatga 5580 ttttgtcact gacatctgtg agccaaagac tgagcctttt tggcaggaat aataagcaat 5640 actacacaac ttgctacttt cagaaaactt ttttttagct tcaccgatga caacagagga 5700 agaagggaac tgggatttgg gtaagttctc ctccactgtt tgaccaaatt ctcagtgata 5760 aatatgtgtg cagatcccta gaagagaaaa cgctgacttt ctttttaagt gtggcacata 5820 aggatctgca gaattttccg tagacaaaga aaggatcttg tgtatttttg tccatatcca 5880 atgttatatg aactaattgt attgttttat actgtgacca caaatattat gcaatgcacc 5940 atttgttttt tatttcatta aaggaagttt aattt 5975 <210> SEQ ID NO 28 <211> LENGTH: 2197 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1037)..(1037) <223> OTHER INFORMATION: a, t, c or g <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1236)..(1236) <223> OTHER INFORMATION: a, t, c or g <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AB014734 <309> DATABASE ENTRY DATE: 2001-01-06 <313> RELEVANT RESIDUES IN SEQ ID NO: RELEVANT RESIDUES: (1)..(2197) <400> SEQUENCE: 28 gtgcattcag acacaccatc agtaattcgg ggagatctga tcaaattgtt ctgtatcatc 60 actgtcgagg gagcagcact ggatccagat gacatggcct ttgatgtgtc ctggtttgcg 120 gtgcactctt ttggcctgga caaggctcct gtgctcctgt cttccctgga tcggaagggc 180 atcgtgacca cctcccggag ggactggaag agcgacctca gcctggagcg cgtgagtgtg 240 ctggaattct tgctgcaagt gcatggctcc gaggaccagg actttggcaa ctactactgt 300 tccgtgactc catgggtgaa gtcaccaaca ggttcctggc agaaggaggc agagatccac 360 tccaagcccg tttttataac tgtgaagatg gatgtgctga acgccttcaa gtatcccttg 420 ctgatcggcg tcggtctgtc cacggtcatc gggctcctgt cctgtctcat cgggtactgc 480 agctcccact ggtgttgtaa gaaggaggtt caggagacac ggcgcgagcg ccgcaggctc 540 atgtcgatgg agatggacta ggctggcccg ggaggggagt gacagaggga cgttctagga 600 gcaattgggg caagaagagg acagtgatat tttaaaacaa agtgtgttac actaaaaacc 660 agtcctctct aatctcaggt gggacttggc gctctctctt ttctgcatgt caagttctga 720 gcgcggacat gtttaccagc acacggctct tcttcccacg gcactttctg atgtaacaat 780 cgagtgtgtg ttttcccaac tgcagctttt taatggttaa ccttcatcta attttttttc 840 tcccactggt ttatagatcc tctgacttgt gtgtgtttat agcttttgtt tcgcggggtt 900 gtggtgagga aggggtgatg gcatgcggag ttctttatct tcagtgagaa tgtgcctgcc 960 cgcctgagag ccagcttccg cgttggaggc acgtgttcag agagctgctg agcgccaccc 1020 tctacccggc tgacagncaa cacagacctg tgccgaaggc taatttgtgg cttttacgac 1080 cctaccccac cccctgtttt caggggttta gactacattt gaaatccaaa cttggagtat 1140 ataacttctt attgagccca actgcttttt tttttttttt ttttttgctt ctctgcccct 1200 tttccatttc ttttgtattt gttttctgtg agagcnctga aatggcagcc ctggaatcta 1260 caatttggct ctccactgag caccttatct tgccacctta gccttaagaa tgaatatgaa 1320 gaaaaataca cagccacctc tgtccagggc agtaagaagg gctgcaagga aggggaggat 1380 ggggacaagg aaaggatcag atacctgctc cagtagttgt gaggccactg tgtctcaggg 1440 gactccagga ggagcagaag agggatccca cgaagttatt cttacgcagc tggggccagg 1500 agggtcagag tggtgccagg tgcaagttag gctaaagaag ccaccactat tcctctctct 1560 tgcccattgt ggggggcaaa ggcattggtc accaagagtc ttgcaggggg acccacagat 1620 atgccatgtc cttcacacgt gcttgggctc cttaacctga aggcaaattg ctacttgcaa 1680 gactgactga cttcaaggaa tcagaaatta cctagaagca ccatgttttt tctatgacct 1740 tttcagtcct tcaggtcatt ttaaggtcca ctgcaggggg ttagtgagaa agggtatact 1800 ttgtggtatg ttttgctttc ctaataggga catgaaggaa acccagcaat ttgctgttat 1860 gtgaatggcc tgtagagcag agtcaagagc ggtgtgcttt gcccgactgc tcccatcagg 1920 aataggagag tagacagaga tcttccacat cccaggcttc tgctgctgct ttaaaagctc 1980 tgtccttgga gcctcccgct ccctgaagtg tctcgccccc tgcacagcac tggcctttcg 2040 gaagcatccc agtagggttt tctgaggctc gctggtgact catgccctaa ttgcaatcct 2100 ctgcttttat cttgactttg aaggatctaa cactgctctc tcttccaaag gggaaaaaaa 2160 gattcatttg ttttgagcaa taaactaata caaaatg 2197 <210> SEQ ID NO 29 <211> LENGTH: 6331 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AF006515 <309> DATABASE ENTRY DATE: 1997-11-27 <313> RELEVANT RESIDUES IN SEQ ID NO: RELEVANT RESIDUES: (1)..(6331) <400> SEQUENCE: 29 atctttgttt gggtctccca tactgcgtat agatgaatgg gtcaggatat ctggaacaaa 60 atatggaggt gaagggtgag atcgggaaac aaagggtatg gccccctagt tcccaaaggg 120 agcagggaga tgggaataga attgaaggta ggttttaggc tacttgggag gaggaatatt 180 taggtaattg tggagacttt ctcctgtgtg atgaaggcgg cagacactgt gatcctgtgg 240 gcaagaagta aaaatgacca gctgaggatt tcttttcctc caggactgtg ttggggtgac 300 aggatgcctg ataaggatga cattcggctg ctgccgtcag cattgggtgt gaagaagaga 360 aaacgaggac ccaagaagca gaaggagaac aagccaggaa aaccccgaaa acgcaagaag 420 cgtgacagtg aggaggaatt tggttctgag cgagatgagt accgggagaa gtcagagagt 480 gggggcagtg aatatggaac cggaccgggt cggaaacgaa gaaggaagca ccgagaaaaa 540 aaggagaaga agacaaagcg gcggaaaaag ggggagggag atggggggca aaagcaagtg 600 gaacagaagt catcagcaac tctgcttctg acctggggcc tggaggatgt ggagcatgtg 660 ttctctgagg aggattacca cacgctcacc aactacaaag ccttcagcca gttcatgagg 720 cccctaattg ctaagaagaa tcctaagatc ccaatgtcta agatgatgac catccttggg 780 gccaaatgga gagagttcag tgccaacaac cccttcaagg ggtcagcagc tgctgtggcg 840 gcggcagcgg cagcagcagc agcagctgta gctgagcagg tgtcagctgc tgtctcgtcg 900 gccaccccca tagcaccctc cggacccccc gcccttccac caccccctgc tgctgatatc 960 cagcccccac ccatccgaag agccaaaacc aaagagggca aaggtccagg ccataagagg 1020 cggagtaaga gcccccgagt gcctgatgga cgcaagaagc ttcggggaaa gaaaatggca 1080 ccactcaaaa taaaactagg gcttctgggt ggcaagagga agaaaggagg ctcgtatgtt 1140 tttcagagcg acgaaggtcc tgaaccagag gctgaggaat cagacctgga cagtggcagt 1200 gtccacagtg cctcaggccg gcctgatggc cctgtccgca ccaagaaact aaagagaggc 1260 cggccaggaa ggaagaagaa gaaggtcctg ggctgtcctg cagtggccgg ggaggaggag 1320 gttgatggct acgagacgga tcaccaggat tactgtgagg tgtgccagca gggtggggaa 1380 attattctgt gtgacacctg ccctcgtgcc taccacctcg tctgccttga tcctgagctt 1440 gaccgggctc cagagggcaa atggagctgc cctcactgtg agaaggaggg ggtccagtgg 1500 gaggccaagg aggaagaaga agaatacgaa gaggagggag aggaagaagg ggagaaggag 1560 gaggaggatg atcacatgga gtactgccgc gtatgcaagg acggcgggga gctcctgtgc 1620 tgtgacgcgt gcatctcctc ctaccacatt cattgtctaa accctcccct gcctgacatt 1680 cccaatggtg aatggctgtg tccccgatgc acatgccccg tgctgaaggg tcgagtgcag 1740 aagatcctac attggcggtg gggggagcca cctgtagcag tgccagcccc tcaacaggca 1800 gatggaaatc cagatgtccc acccccccgt cctcttcaag gcagatcaga gcgagagttc 1860 tttgtcaagt gggtaggact atcctactgg cactgctcct gggccaagga gcttcagctg 1920 gaaatcttcc atttggttat gtatcgaaac taccagcgga agaatgacat ggatgagccc 1980 ccacccctgg actatggctc cggcgaggat gatgggaaga gcgacaagcg taaagtgaaa 2040 gacccgcact atgctgagat ggaggagaag tactatcgtt ttggcatcaa gccagagtgg 2100 atgaccgtcc accgcatcat caaccacagt gtggataaaa aggggaatta ccactatcta 2160 gtaaaatgga gggacttacc atatgaccag tccacgtggg aggaagatga aatgaatatc 2220 cctgaatacg aagaacataa gcaaagctac tggagacacc gagaactaat tatgggggaa 2280 gaccctgccc agccccgcaa gtataagaag aagaagaagg agctacaggg tgatgggcct 2340 cccagttctc ccactaatga tcctaccgtg aaatatgaga ctcagccacg gtttatcaca 2400 gccactggag gcaccctgca catgtatcag ttggaagggc tgaactggct acgcttctcc 2460 tgggcccagg gcactgacac cattctagct gatgagatgg ggctaggcaa gaccatacaa 2520 accatcgtct tcctctactc actctacaag gagggccaca caaaaggtcc cttcctggtg 2580 agtgccccac tctctaccat cattaactgg gagcgggagt tccagatgtg ggcacccaaa 2640 ttctatgtgg tgacatacac gggtgacaag gacagccggg ccatcattcg tgagaatgaa 2700 ttctcctttg aggacaatgc catcaaaggg ggcaagaaag cttttaagat gaaaagggag 2760 gcacaggtga agttccatgt tctcctgaca tcgtatgagc tgatcaccat tgatcaggca 2820 gcacttggtt ccatccgctg ggcctgtctt gtggtagatg aggcccatcg actcaagaac 2880 aaccagtcca agtttttcag ggttctcaat ggttacaaga tagatcataa gttgctgctg 2940 acaggaaccc cattgcagaa taatctggag gagctcttcc atctcctgaa cttcctcacc 3000 ccagagagat ttaacaactt ggagggcttc ctggaggagt ttgctgacat atccaaagag 3060 gaccagatca agaaactgca tgatttgctg gggccacaca tgctgcggag actcaaggca 3120 gatgtcttta agaacatgcc agccaagaca gagctcatcg ttcgggtgga gctaagcccc 3180 atgcagaaga aatactacaa atacatcctg actcgaaatt ttgaggcctt gaattcacga 3240 ggtggtggga accaggtgtc gctgcttaat atcatgatgg atcttaagaa gtgctgcaac 3300 catccatacc tttttcccgt ggctgctatg gagtccccca aactccccag tggggcttat 3360 gagggtgggg cacttattaa gtcgtctggg aagctcatgc tgctccagaa gatgctgcga 3420 aagctgaagg agcaaggaca ccgagtgctc atcttctcgc agatgaccaa aatgttagac 3480 ttgcttgagg acttcttaga ctatgaaggc tacaagtatg agcgcatcga tggtggtatc 3540 acgggtgccc tgaggcagga ggccatcgat cggtttaatg ctcctggggc ccaacaattc 3600 tgcttcctcc tgtccacccg agctgggggc ctgggcatca atctggccac tgctgacact 3660 gtcatcatct ttgattctga ctggaacccc cataatgaca tccaggcctt tagccgggct 3720 catcggattg gccaggccaa caaagtgatg atttaccggt ttgtgactcg cgcgtcagtg 3780 gaagagcgaa tcacacaagt ggccaagaga aagatgatgc tgacacacct ggttgtgcgg 3840 cctgggctgg gctccaaggc aggctccatg tccaagcagg agcttgacga cattctcaaa 3900 tttggcactg aagagctatt caaggatgaa aacgaggggg agaacaagga ggaggacagc 3960 agtgtgattc attatgacaa tgaggccatc gctcggctgt tggaccggaa ccaggatgca 4020 actgaggaca ctgacgtgca gaacatgaat gagtatctca gctccttcaa ggtggcacag 4080 tacgtcgtgc gggaagaaga caagattgag gaaattgagc gagagatcat caagcaggag 4140 gagaatgtgg accctgacta ctgggagaag ctgctgaggc atcactatga gcaacagcag 4200 gaagacctag cccggaatct aggcaagggc aagcgggttc gcaagcaagt taactacaat 4260 gatgctgctc aggaagacca agacaaccag tcagagtact cggtgggttc agaggaggag 4320 gatgaagact tcgatgaacg tcctgaaggg cgtagacagt caaagaggca gctccggaat 4380 gagaaagata agccactgcc tccactgctg gcccgagtcg ggggcaacat tgaggtgctg 4440 ggcttcaaca cccgtcagcg gaaggctttc ctcaatgctg tgatgcgctg ggggatgcca 4500 ccacaggatg ccttcaccac acagtggctg gtgcgggacc tgaggggcaa gactgagaag 4560 gagtttaagg cctatgtgtc tttgttcatg cgccatctgt gtgagcctgg ggcagacggc 4620 tctgaaacct ttgccgatgg ggtccctcgg gagggactga gtcgccagca ggtgttgacc 4680 cgcattggag tcatgtctct cgtcaaaaag aaggtgcagg agtttgagca catcaatggg 4740 cgttggtcaa tgccggaact gatgcctgac cccagcgccg attctaagcg ctcctccaga 4800 gcctcctctc ctaccaaaac gtctcccacc actcctgagg cttctgctac caacagtccc 4860 tgcacctcta aacctgctac tccagctcca agtgagaaag gagaaggcat aaggacacct 4920 cttgagaagg aggaagctga aaaccaggag gaaaagccag agaagaacag cagaattggg 4980 gagaagatgg agacagaggc tgatgccccc agcccagccc catcacttgg ggagcggctg 5040 gagccaagga agattcctct agaggatgag gtgccagggg tgcctggaga gatggagcct 5100 gaacctgggt accgtgggga cagagagaag tcagaagatg taaaaggtga ccgggagctt 5160 cgaccagggc ctcgagatga gccacggtcc aatgggcgac gagaggaaaa gacagagaag 5220 ccccggttca tgttcaatat cgccgatggt ggcttcacag agcttcacac actgtggcag 5280 aatgaggaac gggcagctat ttcctcgggg aaactcaatg agatctggca cagaagacat 5340 gactattggc ttctggctgg gattgtcctc catggctatg cacggtggca ggacatccag 5400 aatgatgctc aatttgccat tatcaacgag ccatttaaaa ctgaagccaa taaggggaac 5460 tttctggaga tgaaaaataa gttcctggcc cggaggttca agctcctgga gcaggcgctg 5520 gtgattgagg agcagctgcg gcgggcggcc tacctgaacc tgtcgcagga gccggcgcac 5580 cccgccatgg ccctccacgc ccgcttcgcc gaggccgagt gcctggccga gagccaccag 5640 cacctctcca aggagtcgct ggcggggaac aagccggcca acgccgtcct gcacaaggtt 5700 ctgaaccagc tggaggagtt gctgagcgac atgaaggcgg acgtgacccg cctgccagcc 5760 acgctgtccc gaataccccc catcgcagcc cgccttcaga tgtccgagcg cagcatcctc 5820 agccggctgg ccagcaaggg cacggagcct caccccacac cggcctaccc gccgggtccc 5880 tacgctacac ctccggggta cggggcggcc ttcagcgccg cacccgtagg ggccctggcc 5940 gccgcaggcg ccaattacag ccagatgcct gcagggtcct tcatcacagc cgccaccaac 6000 ggcccaattc accgattttt taaaaaagtt ccagaaatcc agtgacgaat gtggtataca 6060 aaaaaatata taaattcttt caacttagaa taattaagtc ataaaataca tagggtacaa 6120 ataccacatt ccgttctaaa atgatatctt aggatcatca aaagaaaaag aggatttgga 6180 ttatgcaaaa aatgattcct atatatataa tcaattatct aactgacatt tttgcaaatc 6240 taccacaact tcgcctttta ttgcatatgc taaacaagca gatgctaagt ctgtaaactg 6300 tgaattaacc tcctttttaa ttaattgttc g 6331 <210> SEQ ID NO 30 <211> LENGTH: 6331 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/NM_001272 <309> DATABASE ENTRY DATE: 2001-02-03 <313> RELEVANT RESIDUES IN SEQ ID NO: RELEVANT RESIDUES: (1)..(6331) <400> SEQUENCE: 30 atctttgttt gggtctccca tactgcgtat agatgaatgg gtcaggatat ctggaacaaa 60 atatggaggt gaagggtgag atcgggaaac aaagggtatg gccccctagt tcccaaaggg 120 agcagggaga tgggaataga attgaaggta ggttttaggc tacttgggag gaggaatatt 180 taggtaattg tggagacttt ctcctgtgtg atgaaggcgg cagacactgt gatcctgtgg 240 gcaagaagta aaaatgacca gctgaggatt tcttttcctc caggactgtg ttggggtgac 300 aggatgcctg ataaggatga cattcggctg ctgccgtcag cattgggtgt gaagaagaga 360 aaacgaggac ccaagaagca gaaggagaac aagccaggaa aaccccgaaa acgcaagaag 420 cgtgacagtg aggaggaatt tggttctgag cgagatgagt accgggagaa gtcagagagt 480 gggggcagtg aatatggaac cggaccgggt cggaaacgaa gaaggaagca ccgagaaaaa 540 aaggagaaga agacaaagcg gcggaaaaag ggggagggag atggggggca aaagcaagtg 600 gaacagaagt catcagcaac tctgcttctg acctggggcc tggaggatgt ggagcatgtg 660 ttctctgagg aggattacca cacgctcacc aactacaaag ccttcagcca gttcatgagg 720 cccctaattg ctaagaagaa tcctaagatc ccaatgtcta agatgatgac catccttggg 780 gccaaatgga gagagttcag tgccaacaac cccttcaagg ggtcagcagc tgctgtggcg 840 gcggcagcgg cagcagcagc agcagctgta gctgagcagg tgtcagctgc tgtctcgtcg 900 gccaccccca tagcaccctc cggacccccc gcccttccac caccccctgc tgctgatatc 960 cagcccccac ccatccgaag agccaaaacc aaagagggca aaggtccagg ccataagagg 1020 cggagtaaga gcccccgagt gcctgatgga cgcaagaagc ttcggggaaa gaaaatggca 1080 ccactcaaaa taaaactagg gcttctgggt ggcaagagga agaaaggagg ctcgtatgtt 1140 tttcagagcg acgaaggtcc tgaaccagag gctgaggaat cagacctgga cagtggcagt 1200 gtccacagtg cctcaggccg gcctgatggc cctgtccgca ccaagaaact aaagagaggc 1260 cggccaggaa ggaagaagaa gaaggtcctg ggctgtcctg cagtggccgg ggaggaggag 1320 gttgatggct acgagacgga tcaccaggat tactgtgagg tgtgccagca gggtggggaa 1380 attattctgt gtgacacctg ccctcgtgcc taccacctcg tctgccttga tcctgagctt 1440 gaccgggctc cagagggcaa atggagctgc cctcactgtg agaaggaggg ggtccagtgg 1500 gaggccaagg aggaagaaga agaatacgaa gaggagggag aggaagaagg ggagaaggag 1560 gaggaggatg atcacatgga gtactgccgc gtatgcaagg acggcgggga gctcctgtgc 1620 tgtgacgcgt gcatctcctc ctaccacatt cattgtctaa accctcccct gcctgacatt 1680 cccaatggtg aatggctgtg tccccgatgc acatgccccg tgctgaaggg tcgagtgcag 1740 aagatcctac attggcggtg gggggagcca cctgtagcag tgccagcccc tcaacaggca 1800 gatggaaatc cagatgtccc acccccccgt cctcttcaag gcagatcaga gcgagagttc 1860 tttgtcaagt gggtaggact atcctactgg cactgctcct gggccaagga gcttcagctg 1920 gaaatcttcc atttggttat gtatcgaaac taccagcgga agaatgacat ggatgagccc 1980 ccacccctgg actatggctc cggcgaggat gatgggaaga gcgacaagcg taaagtgaaa 2040 gacccgcact atgctgagat ggaggagaag tactatcgtt ttggcatcaa gccagagtgg 2100 atgaccgtcc accgcatcat caaccacagt gtggataaaa aggggaatta ccactatcta 2160 gtaaaatgga gggacttacc atatgaccag tccacgtggg aggaagatga aatgaatatc 2220 cctgaatacg aagaacataa gcaaagctac tggagacacc gagaactaat tatgggggaa 2280 gaccctgccc agccccgcaa gtataagaag aagaagaagg agctacaggg tgatgggcct 2340 cccagttctc ccactaatga tcctaccgtg aaatatgaga ctcagccacg gtttatcaca 2400 gccactggag gcaccctgca catgtatcag ttggaagggc tgaactggct acgcttctcc 2460 tgggcccagg gcactgacac cattctagct gatgagatgg ggctaggcaa gaccatacaa 2520 accatcgtct tcctctactc actctacaag gagggccaca caaaaggtcc cttcctggtg 2580 agtgccccac tctctaccat cattaactgg gagcgggagt tccagatgtg ggcacccaaa 2640 ttctatgtgg tgacatacac gggtgacaag gacagccggg ccatcattcg tgagaatgaa 2700 ttctcctttg aggacaatgc catcaaaggg ggcaagaaag cttttaagat gaaaagggag 2760 gcacaggtga agttccatgt tctcctgaca tcgtatgagc tgatcaccat tgatcaggca 2820 gcacttggtt ccatccgctg ggcctgtctt gtggtagatg aggcccatcg actcaagaac 2880 aaccagtcca agtttttcag ggttctcaat ggttacaaga tagatcataa gttgctgctg 2940 acaggaaccc cattgcagaa taatctggag gagctcttcc atctcctgaa cttcctcacc 3000 ccagagagat ttaacaactt ggagggcttc ctggaggagt ttgctgacat atccaaagag 3060 gaccagatca agaaactgca tgatttgctg gggccacaca tgctgcggag actcaaggca 3120 gatgtcttta agaacatgcc agccaagaca gagctcatcg ttcgggtgga gctaagcccc 3180 atgcagaaga aatactacaa atacatcctg actcgaaatt ttgaggcctt gaattcacga 3240 ggtggtggga accaggtgtc gctgcttaat atcatgatgg atcttaagaa gtgctgcaac 3300 catccatacc tttttcccgt ggctgctatg gagtccccca aactccccag tggggcttat 3360 gagggtgggg cacttattaa gtcgtctggg aagctcatgc tgctccagaa gatgctgcga 3420 aagctgaagg agcaaggaca ccgagtgctc atcttctcgc agatgaccaa aatgttagac 3480 ttgcttgagg acttcttaga ctatgaaggc tacaagtatg agcgcatcga tggtggtatc 3540 acgggtgccc tgaggcagga ggccatcgat cggtttaatg ctcctggggc ccaacaattc 3600 tgcttcctcc tgtccacccg agctgggggc ctgggcatca atctggccac tgctgacact 3660 gtcatcatct ttgattctga ctggaacccc cataatgaca tccaggcctt tagccgggct 3720 catcggattg gccaggccaa caaagtgatg atttaccggt ttgtgactcg cgcgtcagtg 3780 gaagagcgaa tcacacaagt ggccaagaga aagatgatgc tgacacacct ggttgtgcgg 3840 cctgggctgg gctccaaggc aggctccatg tccaagcagg agcttgacga cattctcaaa 3900 tttggcactg aagagctatt caaggatgaa aacgaggggg agaacaagga ggaggacagc 3960 agtgtgattc attatgacaa tgaggccatc gctcggctgt tggaccggaa ccaggatgca 4020 actgaggaca ctgacgtgca gaacatgaat gagtatctca gctccttcaa ggtggcacag 4080 tacgtcgtgc gggaagaaga caagattgag gaaattgagc gagagatcat caagcaggag 4140 gagaatgtgg accctgacta ctgggagaag ctgctgaggc atcactatga gcaacagcag 4200 gaagacctag cccggaatct aggcaagggc aagcgggttc gcaagcaagt taactacaat 4260 gatgctgctc aggaagacca agacaaccag tcagagtact cggtgggttc agaggaggag 4320 gatgaagact tcgatgaacg tcctgaaggg cgtagacagt caaagaggca gctccggaat 4380 gagaaagata agccactgcc tccactgctg gcccgagtcg ggggcaacat tgaggtgctg 4440 ggcttcaaca cccgtcagcg gaaggctttc ctcaatgctg tgatgcgctg ggggatgcca 4500 ccacaggatg ccttcaccac acagtggctg gtgcgggacc tgaggggcaa gactgagaag 4560 gagtttaagg cctatgtgtc tttgttcatg cgccatctgt gtgagcctgg ggcagacggc 4620 tctgaaacct ttgccgatgg ggtccctcgg gagggactga gtcgccagca ggtgttgacc 4680 cgcattggag tcatgtctct cgtcaaaaag aaggtgcagg agtttgagca catcaatggg 4740 cgttggtcaa tgccggaact gatgcctgac cccagcgccg attctaagcg ctcctccaga 4800 gcctcctctc ctaccaaaac gtctcccacc actcctgagg cttctgctac caacagtccc 4860 tgcacctcta aacctgctac tccagctcca agtgagaaag gagaaggcat aaggacacct 4920 cttgagaagg aggaagctga aaaccaggag gaaaagccag agaagaacag cagaattggg 4980 gagaagatgg agacagaggc tgatgccccc agcccagccc catcacttgg ggagcggctg 5040 gagccaagga agattcctct agaggatgag gtgccagggg tgcctggaga gatggagcct 5100 gaacctgggt accgtgggga cagagagaag tcagaagatg taaaaggtga ccgggagctt 5160 cgaccagggc ctcgagatga gccacggtcc aatgggcgac gagaggaaaa gacagagaag 5220 ccccggttca tgttcaatat cgccgatggt ggcttcacag agcttcacac actgtggcag 5280 aatgaggaac gggcagctat ttcctcgggg aaactcaatg agatctggca cagaagacat 5340 gactattggc ttctggctgg gattgtcctc catggctatg cacggtggca ggacatccag 5400 aatgatgctc aatttgccat tatcaacgag ccatttaaaa ctgaagccaa taaggggaac 5460 tttctggaga tgaaaaataa gttcctggcc cggaggttca agctcctgga gcaggcgctg 5520 gtgattgagg agcagctgcg gcgggcggcc tacctgaacc tgtcgcagga gccggcgcac 5580 cccgccatgg ccctccacgc ccgcttcgcc gaggccgagt gcctggccga gagccaccag 5640 cacctctcca aggagtcgct ggcggggaac aagccggcca acgccgtcct gcacaaggtt 5700 ctgaaccagc tggaggagtt gctgagcgac atgaaggcgg acgtgacccg cctgccagcc 5760 acgctgtccc gaataccccc catcgcagcc cgccttcaga tgtccgagcg cagcatcctc 5820 agccggctgg ccagcaaggg cacggagcct caccccacac cggcctaccc gccgggtccc 5880 tacgctacac ctccggggta cggggcggcc ttcagcgccg cacccgtagg ggccctggcc 5940 gccgcaggcg ccaattacag ccagatgcct gcagggtcct tcatcacagc cgccaccaac 6000 ggcccaattc accgattttt taaaaaagtt ccagaaatcc agtgacgaat gtggtataca 6060 aaaaaatata taaattcttt caacttagaa taattaagtc ataaaataca tagggtacaa 6120 ataccacatt ccgttctaaa atgatatctt aggatcatca aaagaaaaag aggatttgga 6180 ttatgcaaaa aatgattcct atatatataa tcaattatct aactgacatt tttgcaaatc 6240 taccacaact tcgcctttta ttgcatatgc taaacaagca gatgctaagt ctgtaaactg 6300 tgaattaacc tcctttttaa ttaattgttc g 6331 <210> SEQ ID NO 31 <211> LENGTH: 560 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 Met Pro Asp Ser Thr Leu Pro Gly Ser Arg Val Leu Ala Arg Leu Asp 1 5 10 15 Arg Asp Ser Leu Val His Ser Ser Pro His Val Ala Leu Ser His Val 20 25 30 Asp Ala Arg Ser Tyr His Leu Leu Val Arg Asp Val Ser Lys Glu Asn 35 40 45 Ser Gly Tyr Tyr Tyr Cys His Val Ser Leu Trp Ala Pro Gly His Asn 50 55 60 Arg Ser Trp His Lys Val Ala Glu Ala Val Ser Ser Pro Ala Gly Val 65 70 75 80 Gly Val Thr Trp Leu Glu Pro Asp Tyr Gln Val Tyr Leu Asn Ala Ser 85 90 95 Lys Val Pro Gly Phe Ala Asp Asp Pro Thr Glu Leu Ala Cys Arg Val 100 105 110 Val Asp Thr Lys Ser Gly Glu Ala Asn Val Arg Phe Thr Val Ser Trp 115 120 125 Tyr Tyr Arg Met Asn Arg Arg Ser Asp Asn Val Val Thr Ser Glu Leu 130 135 140 Leu Ala Val Met Asp Gly Asp Trp Thr Leu Lys Tyr Gly Glu Arg Ser 145 150 155 160 Lys Gln Arg Ala Gln Asp Gly Asp Phe Ile Phe Ser Lys Glu His Thr 165 170 175 Asp Thr Phe Asn Phe Arg Ile Gln Arg Thr Thr Glu Glu Asp Arg Gly 180 185 190 Asn Tyr Tyr Cys Val Val Ser Ala Trp Thr Lys Gln Arg Asn Asn Ser 195 200 205 Trp Val Lys Ser Lys Asp Val Phe Ser Lys Pro Val Asn Ile Phe Trp 210 215 220 Ala Leu Glu Asp Ser Val Leu Val Val Lys Ala Arg Gln Pro Lys Pro 225 230 235 240 Phe Phe Ala Ala Gly Asn Thr Phe Glu Met Thr Cys Lys Val Ser Ser 245 250 255 Lys Asn Ile Lys Ser Pro Arg Tyr Ser Val Leu Ile Met Ala Glu Lys 260 265 270 Pro Val Gly Asp Leu Ser Ser Pro Asn Glu Thr Lys Tyr Ile Ile Ser 275 280 285 Leu Asp Gln Asp Ser Val Val Lys Leu Glu Asn Trp Thr Asp Ala Ser 290 295 300 Arg Val Asp Gly Val Val Leu Glu Lys Val Gln Glu Asp Glu Phe Arg 305 310 315 320 Tyr Arg Met Tyr Gln Thr Gln Val Ser Asp Ala Gly Leu Tyr Arg Cys 325 330 335 Met Val Thr Ala Trp Ser Pro Val Arg Gly Ser Leu Trp Arg Glu Ala 340 345 350 Ala Thr Ser Leu Ser Asn Pro Ile Glu Ile Asp Phe Gln Thr Ser Gly 355 360 365 Pro Ile Phe Asn Ala Ser Val His Ser Asp Thr Pro Ser Val Ile Arg 370 375 380 Gly Asp Leu Ile Lys Leu Phe Cys Ile Ile Thr Val Glu Gly Ala Ala 385 390 395 400 Leu Asp Pro Asp Asp Met Ala Phe Asp Val Ser Trp Phe Ala Val His 405 410 415 Ser Phe Gly Leu Asp Lys Ala Pro Val Leu Leu Ser Ser Leu Asp Arg 420 425 430 Lys Gly Ile Val Thr Thr Ser Arg Arg Asp Trp Lys Ser Asp Leu Ser 435 440 445 Leu Glu Arg Val Ser Val Leu Glu Phe Leu Leu Gln Val His Gly Ser 450 455 460 Glu Asp Gln Asp Phe Gly Asn Tyr Tyr Cys Ser Val Thr Pro Trp Val 465 470 475 480 Lys Ser Pro Thr Gly Ser Trp Gln Lys Glu Ala Glu Ile His Ser Lys 485 490 495 Pro Val Phe Ile Thr Val Lys Met Asp Val Leu Asn Ala Phe Lys Tyr 500 505 510 Pro Leu Leu Ile Gly Val Gly Leu Ser Thr Val Ile Gly Leu Leu Ser 515 520 525 Cys Leu Ile Gly Tyr Cys Ser Ser His Trp Cys Cys Lys Lys Glu Val 530 535 540 Gln Glu Thr Arg Arg Glu Arg Arg Arg Leu Met Ser Met Glu Met Asp 545 550 555 560 <210> SEQ ID NO 32 <211> LENGTH: 186 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 32 Val His Ser Asp Thr Pro Ser Val Ile Arg Gly Asp Leu Ile Lys Leu 1 5 10 15 Phe Cys Ile Ile Thr Val Glu Gly Ala Ala Leu Asp Pro Asp Asp Met 20 25 30 Ala Phe Asp Val Ser Trp Phe Ala Val His Ser Phe Gly Leu Asp Lys 35 40 45 Ala Pro Val Leu Leu Ser Ser Leu Asp Arg Lys Gly Ile Val Thr Thr 50 55 60 Ser Arg Arg Asp Trp Lys Ser Asp Leu Ser Leu Glu Arg Val Ser Val 65 70 75 80 Leu Glu Phe Leu Leu Gln Val His Gly Ser Glu Asp Gln Asp Phe Gly 85 90 95 Asn Tyr Tyr Cys Ser Val Thr Pro Trp Val Lys Ser Pro Thr Gly Ser 100 105 110 Trp Gln Lys Glu Ala Glu Ile His Ser Lys Pro Val Phe Ile Thr Val 115 120 125 Lys Met Asp Val Leu Asn Ala Phe Lys Tyr Pro Leu Leu Ile Gly Val 130 135 140 Gly Leu Ser Thr Val Ile Gly Leu Leu Ser Cys Leu Ile Gly Tyr Cys 145 150 155 160 Ser Ser His Trp Cys Cys Lys Lys Glu Val Gln Glu Thr Arg Arg Glu 165 170 175 Arg Arg Arg Leu Met Ser Met Glu Met Asp 180 185 <210> SEQ ID NO 33 <211> LENGTH: 1944 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 Met Lys Ala Ala Asp Thr Val Ile Leu Trp Ala Arg Ser Lys Asn Asp 1 5 10 15 Gln Leu Arg Ile Ser Phe Pro Pro Gly Leu Cys Trp Gly Asp Arg Met 20 25 30 Pro Asp Lys Asp Asp Ile Arg Leu Leu Pro Ser Ala Leu Gly Val Lys 35 40 45 Lys Arg Lys Arg Gly Pro Lys Lys Gln Lys Glu Asn Lys Pro Gly Lys 50 55 60 Pro Arg Lys Arg Lys Lys Arg Asp Ser Glu Glu Glu Phe Gly Ser Glu 65 70 75 80 Arg Asp Glu Tyr Arg Glu Lys Ser Glu Ser Gly Gly Ser Glu Tyr Gly 85 90 95 Thr Gly Pro Gly Arg Lys Arg Arg Arg Lys His Arg Glu Lys Lys Glu 100 105 110 Lys Lys Thr Lys Arg Arg Lys Lys Gly Glu Gly Asp Gly Gly Gln Lys 115 120 125 Gln Val Glu Gln Lys Ser Ser Ala Thr Leu Leu Leu Thr Trp Gly Leu 130 135 140 Glu Asp Val Glu His Val Phe Ser Glu Glu Asp Tyr His Thr Leu Thr 145 150 155 160 Asn Tyr Lys Ala Phe Ser Gln Phe Met Arg Pro Leu Ile Ala Lys Lys 165 170 175 Asn Pro Lys Ile Pro Met Ser Lys Met Met Thr Ile Leu Gly Ala Lys 180 185 190 Trp Arg Glu Phe Ser Ala Asn Asn Pro Phe Lys Gly Ser Ala Ala Ala 195 200 205 Val Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Val Ala Glu Gln Val 210 215 220 Ser Ala Ala Val Ser Ser Ala Thr Pro Ile Ala Pro Ser Gly Pro Pro 225 230 235 240 Ala Leu Pro Pro Pro Pro Ala Ala Asp Ile Gln Pro Pro Pro Ile Arg 245 250 255 Arg Ala Lys Thr Lys Glu Gly Lys Gly Pro Gly His Lys Arg Arg Ser 260 265 270 Lys Ser Pro Arg Val Pro Asp Gly Arg Lys Lys Leu Arg Gly Lys Lys 275 280 285 Met Ala Pro Leu Lys Ile Lys Leu Gly Leu Leu Gly Gly Lys Arg Lys 290 295 300 Lys Gly Gly Ser Tyr Val Phe Gln Ser Asp Glu Gly Pro Glu Pro Glu 305 310 315 320 Ala Glu Glu Ser Asp Leu Asp Ser Gly Ser Val His Ser Ala Ser Gly 325 330 335 Arg Pro Asp Gly Pro Val Arg Thr Lys Lys Leu Lys Arg Gly Arg Pro 340 345 350 Gly Arg Lys Lys Lys Lys Val Leu Gly Cys Pro Ala Val Ala Gly Glu 355 360 365 Glu Glu Val Asp Gly Tyr Glu Thr Asp His Gln Asp Tyr Cys Glu Val 370 375 380 Cys Gln Gln Gly Gly Glu Ile Ile Leu Cys Asp Thr Cys Pro Arg Ala 385 390 395 400 Tyr His Leu Val Cys Leu Asp Pro Glu Leu Asp Arg Ala Pro Glu Gly 405 410 415 Lys Trp Ser Cys Pro His Cys Glu Lys Glu Gly Val Gln Trp Glu Ala 420 425 430 Lys Glu Glu Glu Glu Glu Tyr Glu Glu Glu Gly Glu Glu Glu Gly Glu 435 440 445 Lys Glu Glu Glu Asp Asp His Met Glu Tyr Cys Arg Val Cys Lys Asp 450 455 460 Gly Gly Glu Leu Leu Cys Cys Asp Ala Cys Ile Ser Ser Tyr His Ile 465 470 475 480 His Cys Leu Asn Pro Pro Leu Pro Asp Ile Pro Asn Gly Glu Trp Leu 485 490 495 Cys Pro Arg Cys Thr Cys Pro Val Leu Lys Gly Arg Val Gln Lys Ile 500 505 510 Leu His Trp Arg Trp Gly Glu Pro Pro Val Ala Val Pro Ala Pro Gln 515 520 525 Gln Ala Asp Gly Asn Pro Asp Val Pro Pro Pro Arg Pro Leu Gln Gly 530 535 540 Arg Ser Glu Arg Glu Phe Phe Val Lys Trp Val Gly Leu Ser Tyr Trp 545 550 555 560 His Cys Ser Trp Ala Lys Glu Leu Gln Leu Glu Ile Phe His Leu Val 565 570 575 Met Tyr Arg Asn Tyr Gln Arg Lys Asn Asp Met Asp Glu Pro Pro Pro 580 585 590 Leu Asp Tyr Gly Ser Gly Glu Asp Asp Gly Lys Ser Asp Lys Arg Lys 595 600 605 Val Lys Asp Pro His Tyr Ala Glu Met Glu Glu Lys Tyr Tyr Arg Phe 610 615 620 Gly Ile Lys Pro Glu Trp Met Thr Val His Arg Ile Ile Asn His Ser 625 630 635 640 Val Asp Lys Lys Gly Asn Tyr His Tyr Leu Val Lys Trp Arg Asp Leu 645 650 655 Pro Tyr Asp Gln Ser Thr Trp Glu Glu Asp Glu Met Asn Ile Pro Glu 660 665 670 Tyr Glu Glu His Lys Gln Ser Tyr Trp Arg His Arg Glu Leu Ile Met 675 680 685 Gly Glu Asp Pro Ala Gln Pro Arg Lys Tyr Lys Lys Lys Lys Lys Glu 690 695 700 Leu Gln Gly Asp Gly Pro Pro Ser Ser Pro Thr Asn Asp Pro Thr Val 705 710 715 720 Lys Tyr Glu Thr Gln Pro Arg Phe Ile Thr Ala Thr Gly Gly Thr Leu 725 730 735 His Met Tyr Gln Leu Glu Gly Leu Asn Trp Leu Arg Phe Ser Trp Ala 740 745 750 Gln Gly Thr Asp Thr Ile Leu Ala Asp Glu Met Gly Leu Gly Lys Thr 755 760 765 Ile Gln Thr Ile Val Phe Leu Tyr Ser Leu Tyr Lys Glu Gly His Thr 770 775 780 Lys Gly Pro Phe Leu Val Ser Ala Pro Leu Ser Thr Ile Ile Asn Trp 785 790 795 800 Glu Arg Glu Phe Gln Met Trp Ala Pro Lys Phe Tyr Val Val Thr Tyr 805 810 815 Thr Gly Asp Lys Asp Ser Arg Ala Ile Ile Arg Glu Asn Glu Phe Ser 820 825 830 Phe Glu Asp Asn Ala Ile Lys Gly Gly Lys Lys Ala Phe Lys Met Lys 835 840 845 Arg Glu Ala Gln Val Lys Phe His Val Leu Leu Thr Ser Tyr Glu Leu 850 855 860 Ile Thr Ile Asp Gln Ala Ala Leu Gly Ser Ile Arg Trp Ala Cys Leu 865 870 875 880 Val Val Asp Glu Ala His Arg Leu Lys Asn Asn Gln Ser Lys Phe Phe 885 890 895 Arg Val Leu Asn Gly Tyr Lys Ile Asp His Lys Leu Leu Leu Thr Gly 900 905 910 Thr Pro Leu Gln Asn Asn Leu Glu Glu Leu Phe His Leu Leu Asn Phe 915 920 925 Leu Thr Pro Glu Arg Phe Asn Asn Leu Glu Gly Phe Leu Glu Glu Phe 930 935 940 Ala Asp Ile Ser Lys Glu Asp Gln Ile Lys Lys Leu His Asp Leu Leu 945 950 955 960 Gly Pro His Met Leu Arg Arg Leu Lys Ala Asp Val Phe Lys Asn Met 965 970 975 Pro Ala Lys Thr Glu Leu Ile Val Arg Val Glu Leu Ser Pro Met Gln 980 985 990 Lys Lys Tyr Tyr Lys Tyr Ile Leu Thr Arg Asn Phe Glu Ala Leu Asn 995 1000 1005 Ser Arg Gly Gly Gly Asn Gln Val Ser Leu Leu Asn Ile Met Met 1010 1015 1020 Asp Leu Lys Lys Cys Cys Asn His Pro Tyr Leu Phe Pro Val Ala 1025 1030 1035 Ala Met Glu Ser Pro Lys Leu Pro Ser Gly Ala Tyr Glu Gly Gly 1040 1045 1050 Ala Leu Ile Lys Ser Ser Gly Lys Leu Met Leu Leu Gln Lys Met 1055 1060 1065 Leu Arg Lys Leu Lys Glu Gln Gly His Arg Val Leu Ile Phe Ser 1070 1075 1080 Gln Met Thr Lys Met Leu Asp Leu Leu Glu Asp Phe Leu Asp Tyr 1085 1090 1095 Glu Gly Tyr Lys Tyr Glu Arg Ile Asp Gly Gly Ile Thr Gly Ala 1100 1105 1110 Leu Arg Gln Glu Ala Ile Asp Arg Phe Asn Ala Pro Gly Ala Gln 1115 1120 1125 Gln Phe Cys Phe Leu Leu Ser Thr Arg Ala Gly Gly Leu Gly Ile 1130 1135 1140 Asn Leu Ala Thr Ala Asp Thr Val Ile Ile Phe Asp Ser Asp Trp 1145 1150 1155 Asn Pro His Asn Asp Ile Gln Ala Phe Ser Arg Ala His Arg Ile 1160 1165 1170 Gly Gln Ala Asn Lys Val Met Ile Tyr Arg Phe Val Thr Arg Ala 1175 1180 1185 Ser Val Glu Glu Arg Ile Thr Gln Val Ala Lys Arg Lys Met Met 1190 1195 1200 Leu Thr His Leu Val Val Arg Pro Gly Leu Gly Ser Lys Ala Gly 1205 1210 1215 Ser Met Ser Lys Gln Glu Leu Asp Asp Ile Leu Lys Phe Gly Thr 1220 1225 1230 Glu Glu Leu Phe Lys Asp Glu Asn Glu Gly Glu Asn Lys Glu Glu 1235 1240 1245 Asp Ser Ser Val Ile His Tyr Asp Asn Glu Ala Ile Ala Arg Leu 1250 1255 1260 Leu Asp Arg Asn Gln Asp Ala Thr Glu Asp Thr Asp Val Gln Asn 1265 1270 1275 Met Asn Glu Tyr Leu Ser Ser Phe Lys Val Ala Gln Tyr Val Val 1280 1285 1290 Arg Glu Glu Asp Lys Ile Glu Glu Ile Glu Arg Glu Ile Ile Lys 1295 1300 1305 Gln Glu Glu Asn Val Asp Pro Asp Tyr Trp Glu Lys Leu Leu Arg 1310 1315 1320 His His Tyr Glu Gln Gln Gln Glu Asp Leu Ala Arg Asn Leu Gly 1325 1330 1335 Lys Gly Lys Arg Val Arg Lys Gln Val Asn Tyr Asn Asp Ala Ala 1340 1345 1350 Gln Glu Asp Gln Asp Asn Gln Ser Glu Tyr Ser Val Gly Ser Glu 1355 1360 1365 Glu Glu Asp Glu Asp Phe Asp Glu Arg Pro Glu Gly Arg Arg Gln 1370 1375 1380 Ser Lys Arg Gln Leu Arg Asn Glu Lys Asp Lys Pro Leu Pro Pro 1385 1390 1395 Leu Leu Ala Arg Val Gly Gly Asn Ile Glu Val Leu Gly Phe Asn 1400 1405 1410 Thr Arg Gln Arg Lys Ala Phe Leu Asn Ala Val Met Arg Trp Gly 1415 1420 1425 Met Pro Pro Gln Asp Ala Phe Thr Thr Gln Trp Leu Val Arg Asp 1430 1435 1440 Leu Arg Gly Lys Thr Glu Lys Glu Phe Lys Ala Tyr Val Ser Leu 1445 1450 1455 Phe Met Arg His Leu Cys Glu Pro Gly Ala Asp Gly Ser Glu Thr 1460 1465 1470 Phe Ala Asp Gly Val Pro Arg Glu Gly Leu Ser Arg Gln Gln Val 1475 1480 1485 Leu Thr Arg Ile Gly Val Met Ser Leu Val Lys Lys Lys Val Gln 1490 1495 1500 Glu Phe Glu His Ile Asn Gly Arg Trp Ser Met Pro Glu Leu Met 1505 1510 1515 Pro Asp Pro Ser Ala Asp Ser Lys Arg Ser Ser Arg Ala Ser Ser 1520 1525 1530 Pro Thr Lys Thr Ser Pro Thr Thr Pro Glu Ala Ser Ala Thr Asn 1535 1540 1545 Ser Pro Cys Thr Ser Lys Pro Ala Thr Pro Ala Pro Ser Glu Lys 1550 1555 1560 Gly Glu Gly Ile Arg Thr Pro Leu Glu Lys Glu Glu Ala Glu Asn 1565 1570 1575 Gln Glu Glu Lys Pro Glu Lys Asn Ser Arg Ile Gly Glu Lys Met 1580 1585 1590 Glu Thr Glu Ala Asp Ala Pro Ser Pro Ala Pro Ser Leu Gly Glu 1595 1600 1605 Arg Leu Glu Pro Arg Lys Ile Pro Leu Glu Asp Glu Val Pro Gly 1610 1615 1620 Val Pro Gly Glu Met Glu Pro Glu Pro Gly Tyr Arg Gly Asp Arg 1625 1630 1635 Glu Lys Ser Glu Asp Val Lys Gly Asp Arg Glu Leu Arg Pro Gly 1640 1645 1650 Pro Arg Asp Glu Pro Arg Ser Asn Gly Arg Arg Glu Glu Lys Thr 1655 1660 1665 Glu Lys Pro Arg Phe Met Phe Asn Ile Ala Asp Gly Gly Phe Thr 1670 1675 1680 Glu Leu His Thr Leu Trp Gln Asn Glu Glu Arg Ala Ala Ile Ser 1685 1690 1695 Ser Gly Lys Leu Asn Glu Ile Trp His Arg Arg His Asp Tyr Trp 1700 1705 1710 Leu Leu Ala Gly Ile Val Leu His Gly Tyr Ala Arg Trp Gln Asp 1715 1720 1725 Ile Gln Asn Asp Ala Gln Phe Ala Ile Ile Asn Glu Pro Phe Lys 1730 1735 1740 Thr Glu Ala Asn Lys Gly Asn Phe Leu Glu Met Lys Asn Lys Phe 1745 1750 1755 Leu Ala Arg Arg Phe Lys Leu Leu Glu Gln Ala Leu Val Ile Glu 1760 1765 1770 Glu Gln Leu Arg Arg Ala Ala Tyr Leu Asn Leu Ser Gln Glu Pro 1775 1780 1785 Ala His Pro Ala Met Ala Leu His Ala Arg Phe Ala Glu Ala Glu 1790 1795 1800 Cys Leu Ala Glu Ser His Gln His Leu Ser Lys Glu Ser Leu Ala 1805 1810 1815 Gly Asn Lys Pro Ala Asn Ala Val Leu His Lys Val Leu Asn Gln 1820 1825 1830 Leu Glu Glu Leu Leu Ser Asp Met Lys Ala Asp Val Thr Arg Leu 1835 1840 1845 Pro Ala Thr Leu Ser Arg Ile Pro Pro Ile Ala Ala Arg Leu Gln 1850 1855 1860 Met Ser Glu Arg Ser Ile Leu Ser Arg Leu Ala Ser Lys Gly Thr 1865 1870 1875 Glu Pro His Pro Thr Pro Ala Tyr Pro Pro Gly Pro Tyr Ala Thr 1880 1885 1890 Pro Pro Gly Tyr Gly Ala Ala Phe Ser Ala Ala Pro Val Gly Ala 1895 1900 1905 Leu Ala Ala Ala Gly Ala Asn Tyr Ser Gln Met Pro Ala Gly Ser 1910 1915 1920 Phe Ile Thr Ala Ala Thr Asn Gly Pro Ile His Arg Phe Phe Lys 1925 1930 1935 Lys Val Pro Glu Ile Gln 1940 <210> SEQ ID NO 34 <211> LENGTH: 1944 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34 Met Lys Ala Ala Asp Thr Val Ile Leu Trp Ala Arg Ser Lys Asn Asp 1 5 10 15 Gln Leu Arg Ile Ser Phe Pro Pro Gly Leu Cys Trp Gly Asp Arg Met 20 25 30 Pro Asp Lys Asp Asp Ile Arg Leu Leu Pro Ser Ala Leu Gly Val Lys 35 40 45 Lys Arg Lys Arg Gly Pro Lys Lys Gln Lys Glu Asn Lys Pro Gly Lys 50 55 60 Pro Arg Lys Arg Lys Lys Arg Asp Ser Glu Glu Glu Phe Gly Ser Glu 65 70 75 80 Arg Asp Glu Tyr Arg Glu Lys Ser Glu Ser Gly Gly Ser Glu Tyr Gly 85 90 95 Thr Gly Pro Gly Arg Lys Arg Arg Arg Lys His Arg Glu Lys Lys Glu 100 105 110 Lys Lys Thr Lys Arg Arg Lys Lys Gly Glu Gly Asp Gly Gly Gln Lys 115 120 125 Gln Val Glu Gln Lys Ser Ser Ala Thr Leu Leu Leu Thr Trp Gly Leu 130 135 140 Glu Asp Val Glu His Val Phe Ser Glu Glu Asp Tyr His Thr Leu Thr 145 150 155 160 Asn Tyr Lys Ala Phe Ser Gln Phe Met Arg Pro Leu Ile Ala Lys Lys 165 170 175 Asn Pro Lys Ile Pro Met Ser Lys Met Met Thr Ile Leu Gly Ala Lys 180 185 190 Trp Arg Glu Phe Ser Ala Asn Asn Pro Phe Lys Gly Ser Ala Ala Ala 195 200 205 Val Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Val Ala Glu Gln Val 210 215 220 Ser Ala Ala Val Ser Ser Ala Thr Pro Ile Ala Pro Ser Gly Pro Pro 225 230 235 240 Ala Leu Pro Pro Pro Pro Ala Ala Asp Ile Gln Pro Pro Pro Ile Arg 245 250 255 Arg Ala Lys Thr Lys Glu Gly Lys Gly Pro Gly His Lys Arg Arg Ser 260 265 270 Lys Ser Pro Arg Val Pro Asp Gly Arg Lys Lys Leu Arg Gly Lys Lys 275 280 285 Met Ala Pro Leu Lys Ile Lys Leu Gly Leu Leu Gly Gly Lys Arg Lys 290 295 300 Lys Gly Gly Ser Tyr Val Phe Gln Ser Asp Glu Gly Pro Glu Pro Glu 305 310 315 320 Ala Glu Glu Ser Asp Leu Asp Ser Gly Ser Val His Ser Ala Ser Gly 325 330 335 Arg Pro Asp Gly Pro Val Arg Thr Lys Lys Leu Lys Arg Gly Arg Pro 340 345 350 Gly Arg Lys Lys Lys Lys Val Leu Gly Cys Pro Ala Val Ala Gly Glu 355 360 365 Glu Glu Val Asp Gly Tyr Glu Thr Asp His Gln Asp Tyr Cys Glu Val 370 375 380 Cys Gln Gln Gly Gly Glu Ile Ile Leu Cys Asp Thr Cys Pro Arg Ala 385 390 395 400 Tyr His Leu Val Cys Leu Asp Pro Glu Leu Asp Arg Ala Pro Glu Gly 405 410 415 Lys Trp Ser Cys Pro His Cys Glu Lys Glu Gly Val Gln Trp Glu Ala 420 425 430 Lys Glu Glu Glu Glu Glu Tyr Glu Glu Glu Gly Glu Glu Glu Gly Glu 435 440 445 Lys Glu Glu Glu Asp Asp His Met Glu Tyr Cys Arg Val Cys Lys Asp 450 455 460 Gly Gly Glu Leu Leu Cys Cys Asp Ala Cys Ile Ser Ser Tyr His Ile 465 470 475 480 His Cys Leu Asn Pro Pro Leu Pro Asp Ile Pro Asn Gly Glu Trp Leu 485 490 495 Cys Pro Arg Cys Thr Cys Pro Val Leu Lys Gly Arg Val Gln Lys Ile 500 505 510 Leu His Trp Arg Trp Gly Glu Pro Pro Val Ala Val Pro Ala Pro Gln 515 520 525 Gln Ala Asp Gly Asn Pro Asp Val Pro Pro Pro Arg Pro Leu Gln Gly 530 535 540 Arg Ser Glu Arg Glu Phe Phe Val Lys Trp Val Gly Leu Ser Tyr Trp 545 550 555 560 His Cys Ser Trp Ala Lys Glu Leu Gln Leu Glu Ile Phe His Leu Val 565 570 575 Met Tyr Arg Asn Tyr Gln Arg Lys Asn Asp Met Asp Glu Pro Pro Pro 580 585 590 Leu Asp Tyr Gly Ser Gly Glu Asp Asp Gly Lys Ser Asp Lys Arg Lys 595 600 605 Val Lys Asp Pro His Tyr Ala Glu Met Glu Glu Lys Tyr Tyr Arg Phe 610 615 620 Gly Ile Lys Pro Glu Trp Met Thr Val His Arg Ile Ile Asn His Ser 625 630 635 640 Val Asp Lys Lys Gly Asn Tyr His Tyr Leu Val Lys Trp Arg Asp Leu 645 650 655 Pro Tyr Asp Gln Ser Thr Trp Glu Glu Asp Glu Met Asn Ile Pro Glu 660 665 670 Tyr Glu Glu His Lys Gln Ser Tyr Trp Arg His Arg Glu Leu Ile Met 675 680 685 Gly Glu Asp Pro Ala Gln Pro Arg Lys Tyr Lys Lys Lys Lys Lys Glu 690 695 700 Leu Gln Gly Asp Gly Pro Pro Ser Ser Pro Thr Asn Asp Pro Thr Val 705 710 715 720 Lys Tyr Glu Thr Gln Pro Arg Phe Ile Thr Ala Thr Gly Gly Thr Leu 725 730 735 His Met Tyr Gln Leu Glu Gly Leu Asn Trp Leu Arg Phe Ser Trp Ala 740 745 750 Gln Gly Thr Asp Thr Ile Leu Ala Asp Glu Met Gly Leu Gly Lys Thr 755 760 765 Ile Gln Thr Ile Val Phe Leu Tyr Ser Leu Tyr Lys Glu Gly His Thr 770 775 780 Lys Gly Pro Phe Leu Val Ser Ala Pro Leu Ser Thr Ile Ile Asn Trp 785 790 795 800 Glu Arg Glu Phe Gln Met Trp Ala Pro Lys Phe Tyr Val Val Thr Tyr 805 810 815 Thr Gly Asp Lys Asp Ser Arg Ala Ile Ile Arg Glu Asn Glu Phe Ser 820 825 830 Phe Glu Asp Asn Ala Ile Lys Gly Gly Lys Lys Ala Phe Lys Met Lys 835 840 845 Arg Glu Ala Gln Val Lys Phe His Val Leu Leu Thr Ser Tyr Glu Leu 850 855 860 Ile Thr Ile Asp Gln Ala Ala Leu Gly Ser Ile Arg Trp Ala Cys Leu 865 870 875 880 Val Val Asp Glu Ala His Arg Leu Lys Asn Asn Gln Ser Lys Phe Phe 885 890 895 Arg Val Leu Asn Gly Tyr Lys Ile Asp His Lys Leu Leu Leu Thr Gly 900 905 910 Thr Pro Leu Gln Asn Asn Leu Glu Glu Leu Phe His Leu Leu Asn Phe 915 920 925 Leu Thr Pro Glu Arg Phe Asn Asn Leu Glu Gly Phe Leu Glu Glu Phe 930 935 940 Ala Asp Ile Ser Lys Glu Asp Gln Ile Lys Lys Leu His Asp Leu Leu 945 950 955 960 Gly Pro His Met Leu Arg Arg Leu Lys Ala Asp Val Phe Lys Asn Met 965 970 975 Pro Ala Lys Thr Glu Leu Ile Val Arg Val Glu Leu Ser Pro Met Gln 980 985 990 Lys Lys Tyr Tyr Lys Tyr Ile Leu Thr Arg Asn Phe Glu Ala Leu Asn 995 1000 1005 Ser Arg Gly Gly Gly Asn Gln Val Ser Leu Leu Asn Ile Met Met 1010 1015 1020 Asp Leu Lys Lys Cys Cys Asn His Pro Tyr Leu Phe Pro Val Ala 1025 1030 1035 Ala Met Glu Ser Pro Lys Leu Pro Ser Gly Ala Tyr Glu Gly Gly 1040 1045 1050 Ala Leu Ile Lys Ser Ser Gly Lys Leu Met Leu Leu Gln Lys Met 1055 1060 1065 Leu Arg Lys Leu Lys Glu Gln Gly His Arg Val Leu Ile Phe Ser 1070 1075 1080 Gln Met Thr Lys Met Leu Asp Leu Leu Glu Asp Phe Leu Asp Tyr 1085 1090 1095 Glu Gly Tyr Lys Tyr Glu Arg Ile Asp Gly Gly Ile Thr Gly Ala 1100 1105 1110 Leu Arg Gln Glu Ala Ile Asp Arg Phe Asn Ala Pro Gly Ala Gln 1115 1120 1125 Gln Phe Cys Phe Leu Leu Ser Thr Arg Ala Gly Gly Leu Gly Ile 1130 1135 1140 Asn Leu Ala Thr Ala Asp Thr Val Ile Ile Phe Asp Ser Asp Trp 1145 1150 1155 Asn Pro His Asn Asp Ile Gln Ala Phe Ser Arg Ala His Arg Ile 1160 1165 1170 Gly Gln Ala Asn Lys Val Met Ile Tyr Arg Phe Val Thr Arg Ala 1175 1180 1185 Ser Val Glu Glu Arg Ile Thr Gln Val Ala Lys Arg Lys Met Met 1190 1195 1200 Leu Thr His Leu Val Val Arg Pro Gly Leu Gly Ser Lys Ala Gly 1205 1210 1215 Ser Met Ser Lys Gln Glu Leu Asp Asp Ile Leu Lys Phe Gly Thr 1220 1225 1230 Glu Glu Leu Phe Lys Asp Glu Asn Glu Gly Glu Asn Lys Glu Glu 1235 1240 1245 Asp Ser Ser Val Ile His Tyr Asp Asn Glu Ala Ile Ala Arg Leu 1250 1255 1260 Leu Asp Arg Asn Gln Asp Ala Thr Glu Asp Thr Asp Val Gln Asn 1265 1270 1275 Met Asn Glu Tyr Leu Ser Ser Phe Lys Val Ala Gln Tyr Val Val 1280 1285 1290 Arg Glu Glu Asp Lys Ile Glu Glu Ile Glu Arg Glu Ile Ile Lys 1295 1300 1305 Gln Glu Glu Asn Val Asp Pro Asp Tyr Trp Glu Lys Leu Leu Arg 1310 1315 1320 His His Tyr Glu Gln Gln Gln Glu Asp Leu Ala Arg Asn Leu Gly 1325 1330 1335 Lys Gly Lys Arg Val Arg Lys Gln Val Asn Tyr Asn Asp Ala Ala 1340 1345 1350 Gln Glu Asp Gln Asp Asn Gln Ser Glu Tyr Ser Val Gly Ser Glu 1355 1360 1365 Glu Glu Asp Glu Asp Phe Asp Glu Arg Pro Glu Gly Arg Arg Gln 1370 1375 1380 Ser Lys Arg Gln Leu Arg Asn Glu Lys Asp Lys Pro Leu Pro Pro 1385 1390 1395 Leu Leu Ala Arg Val Gly Gly Asn Ile Glu Val Leu Gly Phe Asn 1400 1405 1410 Thr Arg Gln Arg Lys Ala Phe Leu Asn Ala Val Met Arg Trp Gly 1415 1420 1425 Met Pro Pro Gln Asp Ala Phe Thr Thr Gln Trp Leu Val Arg Asp 1430 1435 1440 Leu Arg Gly Lys Thr Glu Lys Glu Phe Lys Ala Tyr Val Ser Leu 1445 1450 1455 Phe Met Arg His Leu Cys Glu Pro Gly Ala Asp Gly Ser Glu Thr 1460 1465 1470 Phe Ala Asp Gly Val Pro Arg Glu Gly Leu Ser Arg Gln Gln Val 1475 1480 1485 Leu Thr Arg Ile Gly Val Met Ser Leu Val Lys Lys Lys Val Gln 1490 1495 1500 Glu Phe Glu His Ile Asn Gly Arg Trp Ser Met Pro Glu Leu Met 1505 1510 1515 Pro Asp Pro Ser Ala Asp Ser Lys Arg Ser Ser Arg Ala Ser Ser 1520 1525 1530 Pro Thr Lys Thr Ser Pro Thr Thr Pro Glu Ala Ser Ala Thr Asn 1535 1540 1545 Ser Pro Cys Thr Ser Lys Pro Ala Thr Pro Ala Pro Ser Glu Lys 1550 1555 1560 Gly Glu Gly Ile Arg Thr Pro Leu Glu Lys Glu Glu Ala Glu Asn 1565 1570 1575 Gln Glu Glu Lys Pro Glu Lys Asn Ser Arg Ile Gly Glu Lys Met 1580 1585 1590 Glu Thr Glu Ala Asp Ala Pro Ser Pro Ala Pro Ser Leu Gly Glu 1595 1600 1605 Arg Leu Glu Pro Arg Lys Ile Pro Leu Glu Asp Glu Val Pro Gly 1610 1615 1620 Val Pro Gly Glu Met Glu Pro Glu Pro Gly Tyr Arg Gly Asp Arg 1625 1630 1635 Glu Lys Ser Glu Asp Val Lys Gly Asp Arg Glu Leu Arg Pro Gly 1640 1645 1650 Pro Arg Asp Glu Pro Arg Ser Asn Gly Arg Arg Glu Glu Lys Thr 1655 1660 1665 Glu Lys Pro Arg Phe Met Phe Asn Ile Ala Asp Gly Gly Phe Thr 1670 1675 1680 Glu Leu His Thr Leu Trp Gln Asn Glu Glu Arg Ala Ala Ile Ser 1685 1690 1695 Ser Gly Lys Leu Asn Glu Ile Trp His Arg Arg His Asp Tyr Trp 1700 1705 1710 Leu Leu Ala Gly Ile Val Leu His Gly Tyr Ala Arg Trp Gln Asp 1715 1720 1725 Ile Gln Asn Asp Ala Gln Phe Ala Ile Ile Asn Glu Pro Phe Lys 1730 1735 1740 Thr Glu Ala Asn Lys Gly Asn Phe Leu Glu Met Lys Asn Lys Phe 1745 1750 1755 Leu Ala Arg Arg Phe Lys Leu Leu Glu Gln Ala Leu Val Ile Glu 1760 1765 1770 Glu Gln Leu Arg Arg Ala Ala Tyr Leu Asn Leu Ser Gln Glu Pro 1775 1780 1785 Ala His Pro Ala Met Ala Leu His Ala Arg Phe Ala Glu Ala Glu 1790 1795 1800 Cys Leu Ala Glu Ser His Gln His Leu Ser Lys Glu Ser Leu Ala 1805 1810 1815 Gly Asn Lys Pro Ala Asn Ala Val Leu His Lys Val Leu Asn Gln 1820 1825 1830 Leu Glu Glu Leu Leu Ser Asp Met Lys Ala Asp Val Thr Arg Leu 1835 1840 1845 Pro Ala Thr Leu Ser Arg Ile Pro Pro Ile Ala Ala Arg Leu Gln 1850 1855 1860 Met Ser Glu Arg Ser Ile Leu Ser Arg Leu Ala Ser Lys Gly Thr 1865 1870 1875 Glu Pro His Pro Thr Pro Ala Tyr Pro Pro Gly Pro Tyr Ala Thr 1880 1885 1890 Pro Pro Gly Tyr Gly Ala Ala Phe Ser Ala Ala Pro Val Gly Ala 1895 1900 1905 Leu Ala Ala Ala Gly Ala Asn Tyr Ser Gln Met Pro Ala Gly Ser 1910 1915 1920 Phe Ile Thr Ala Ala Thr Asn Gly Pro Ile His Arg Phe Phe Lys 1925 1930 1935 Lys Val Pro Glu Ile Gln 1940

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an active agent comprising at least one substance selected from the group consisting of: (i) a nucleic acid molecule, the expression of which is induced in an endothelial cell by an angiostatic agent, or a complementary sequence or a fragment or derivative thereof; (ii) a polypeptide sequence coded by said nucleic acid molecule or the complement fragment or derivative thereof, (iii) an antisense nucleic acid molecule that inhibits the expression of a nucleic acid molecule according to (i); and (iv) an antibody capable of binding to a polypeptide sequence according to (ii).

2. The pharmaceutical composition according to claim 1, wherein the nucleic acid molecule is selected from among the group consisting of SEQ ID No. 1, SEQ ID No. 2, SEQ ID No. 3, SEQ ID No. 4, SEQ ID No. 5, SEQ ID No. 27, SEQ ID No. 28, SEQ ID No. 29 and SEQ ID No. 30.

3. The pharmaceutical composition according to claim 1, wherein the antisense nucleic acid molecule is an angiogenesis inhibitory sequence and comprises a nucleic acid sequence selected from among the group consisting of SEQ ID No. 1, SEQ ID No. 2, SEQ ID No. 3, SEQ ID No. 4, SEQ ID No. 5, SEQ ID No. 27, SEQ ID No. 28, SEQ ID No. 29 and SEQ ID No. 30.

4. The pharmaceutical composition according to claim 1, wherein the antisense sequence is selected from the group consisting of SEQ ID No. 11, SEQ ID NO. 12, SEQ ID No. 13 and SEQ ID No.

5. The pharmaceutical composition according to claim 1, wherein the polypeptide sequence is selected from the group consisting of SEQ ID No. 7, SEQ ID No. 8, SEQ ID No. 9, SEQ ID No. 10, SEQ ID No. 31, SEQ ID No. 33 and SEQ ID No. 34.

6. The pharmaceutical composition according to claim 1, comprising at least one antibody having an affinity for one or more polypeptide sequences identified by the numbers SEQ ID. No. 6 to SEQ ID. No. 10 or by the numbers SEQ ID. No. 31 to SEQ ID No. 34, or fragments of said one or more polypeptide sequences.

7. An antisense nucleotide sequence comprising at least 10 nucleotides of a nucleotide sequence selected from among the sequences identified by the numbers SEQ ID. No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30.

8. The antisense sequence according to claim 7 having an identity of at least about 85%, wherein the antisense sequence is selected from the group consisting of SEQ ID. No. 11, SEQ ID No. 12, SEQ ID No. 13 and SEQ ID No. 14.

9. A mammalian expression vector comprising at least one antisense sequence according to claim 7.

10. The mammalian expression vector according to claim 9, wherein the vector is selected from the group consisting of vectors GS-V1, GS-V2, GS-V3 and GS-V4.

11. A diagnostic and/or prognostic method for an angiogenic pathology in a mammal, comprising detecting in vitro in cells from said mammal the overexpression or the underexpression of one or more nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 or one or more polypeptide sequences identified by the numbers SEQ ID No. 6 to SEQ ID No. 10 or SEQ ID No. 31 to SEQ ID No. 34.

12. The method according to claim 11, further comprising: detecting the expression of one or more of said nucleotide sequences SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 or one or more of said polypeptide sequences SEQ ID No. 6 to SEQ ID No. 10 or SEQ ID No. 31 to SEQ ID No. 34 in a mammalian cell population; detecting the expression of one or more of said nucleotide sequences in a reference cell population, the angiogenic state of which is known; and identifying the differences in the level of expression of said nucleotide sequences in the mammalian and reference cell populations.

13. The diagnostic or prognostic method according to claim 11, wherein the angiogenic disorder is selected from the group consisting of: tumor vascularization, retinopathies, rheumatoid arthritis, Crohn's disease, atherosclerosis, hyperstimulation of the ovary, psoriasis, endometriosis associated with neovascularization, restenosis due to balloon angioplasty, tissue overproduction due to cicatrization, peripheral vascular disease, hypertension, vascular inflammation, Raynaud's disease and phenomena, aneurism, arterial restenosis, thrombophlebitis, lymphangitis, lymphedema, tissue cicatrization and repair, ischemia, angina, myocardial infarction, chronic heart disease, cardiac insufficiencies such as congestive heart failure, age-related macular degeneration and osteoporosis.

14. The diagnostic and/or prognostic method according to claim 11, wherein the detection of the expression of the nucleotide sequences is performed after contacting the endothelial cells with a biological fluid from a patient.

15. A method for the verification of the therapeutic efficacy of an angiogenic treatment in a mammal, comprising identifying in vitro in a cell population from said mammal the overexpression or the underexpression of at least one gene implicated in an angiogenic disorder, wherein said gene is identified by one of the nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30.

16. The method for the verification of therapeutic efficacy according to claim 15, further comprising the following steps: detecting the expression of one or more of said nucleotide sequences in a cell population isolated from a mammal, to which mammal was administered a composition comprising a test compound intended to treat an angiogenic disorder; detecting the expression of said nucleotide sequences in a reference cell population, the angiogenic state of which is known; and identifying the differences in the level of expression of said sequences in the mammalian and reference cell populations.

17. The method for the verification of therapeutic efficacy according to claim 15, wherein the angiogenic disorder is selected from the group consisting of: tumor vascularization, retinopathies, rheumatoid arthritis, Crohn's disease, atherosclerosis, hyperstimulation of the ovary, psoriasis, endometriosis associated with neovascularization, restenosis due to balloon angioplasty, tissue overproduction due to cicatrization, peripheral vascular disease, hypertension, vascular inflammation, Raynaud's disease and phenomena, aneurism, arterial restenosis, thrombophlebitis, lymphangitis, lymphedema, tissue cicatrization and repair, ischemia, angina, myocardial infarction, chronic heart disease, cardiac insufficiencies such as congestive heart failure, age-related macular degeneration and osteoporosis.

18. The method for the verification therapeutic efficacy according to claim 15, wherein the detection of the expression of the sequences is performed after contacting the endothelial cells with a biological fluid from a patient.

19. A method for screening for compounds useful for the treatment of an angiogenic disorder of a mammal, comprising: a) detecting the expression of one or more nucleotide sequences SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID No. 27 to SEQ ID No. 30 in a mammalian cell population contacted with a test compound; b) detecting the expression of said nucleotide sequences in a reference cell population, the angiogenic state of which is known; c) identifying the differences in the level of expression of said nucleotide sequences in the mammalian and reference cell populations, wherein a difference in expression of said nucleotide sequences in the mammalian and reference cell population indicates that the test compound has a therapeutic effect on an angiogenic disorder.

20. The screening method according to claim 19, wherein the detection of the expression of the sequences is performed after contacting the endothelial cells with a biological fluid from a patient.

21. A device comprising a support comprising one or more specific probes of one or more nucleotide sequences identified by the numbers SEQ ID No. 1 to SEQ ID No. 5 and SEQ ID. No. 27 to SEQ ID. No. 30.

22. A kit for measuring the differential display of genes implicated in angiogenic disorders, comprising a device according to claim 21; and specific primers and accessories required for the amplification of the sequences extracted from a sample, hybridization with the probes of the device and the performance of differential display measurements.

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