KR20160112274A - Composition for inhibiting tumor cell senescence comprising ITGB4 inhibitor - Google Patents

Abstract

The present invention relates to a composition for inhibiting tumor cell senescence, comprising an integrin beta 4 (ITGB4) inhibitor, and relates to a method for controlling the senescence of tumor cells using the inhibitor. According to the present invention, the composition can inhibit the senescence of tumor cells induced by radiation by inhibiting the expression or the activation of ITGB4 in the tumor cells. Accordingly, the research of anticancer mechanism related to the enhanced sensitivity of the tumor cells with respect to the radiation can be performed by analyzing the specific substance having effects in expressing or activating ITGB4.

Description

TECHNICAL FIELD The present invention relates to a composition for inhibiting tumor cell senescence comprising an ITGB4 inhibitor,

The present invention relates to a composition for inhibiting tumor cell senescence comprising an ITGB4 (integrin beta 4) inhibitor and a method for controlling the aging of tumor cells using the inhibitor.

Early aging of tumor cells is also called stress-induced premature aging, which means aging that occurs in tumor cells by various stimuli. Unlike normal cells in which tumor cells are divided and aged only a certain number of times, the concept of the cell aging process is not common because tumor cells are infinitely dividing cells due to a change in the characteristics of replication aging in the process of carcinogenesis. Recently, it has become known that cell senescence is rapidly induced by various stimuli in tumor cells, which is called stress-induced premature senescence (Sugrue et al., Proc. Natl. Acad. Sci. USA, 94: 9648-9653, 1997; Mason et al., Oncogene, 23: 9238-9246, 2004). Genetic toxic chemicals (eg, etoposide, cyclophophamide), radiation, and ultraviolet light have been reported as sources of stress that can induce tumor cell senescence (Hemann and Narita, Genes & Dev., 21: 1-5, 2007 Chang et al., Proc Natl Acad Sci USA, 99: 389-394, 2002).

Recently, stress-induced premature aging has been proposed as an effective mechanism for the treatment of cancer patients with aging and inhibition of proliferation of cancer cells (Roninson et al., Drug Resist Updates, 4: 303-313, 2001; Campisi, Science, 886-887, 2005), it has been suggested that increasing the efficiency of cancer therapy through research on the induction of cell senescence is essential (Narita and Lowe, Nature Medicine, 11: 920-922, 2005).

In addition, tissue analysis of cancer patients with inhibited tumor metastasis showed that tumor cell senescence was efficiently induced (Collado et al., Nature, 436: 642, 2005) (Wue et al., Nature, 445: 656-660, 2007). ≪ RTI ID = 0.0 > This suggests that cell senescence may be useful for tumor therapy. Actually, activation of aging mechanism of tumor cells can improve side effects of cancer treatment by enabling lower dose of anticancer agent or radiation dose than activation of cell death mechanism and overcome cancer resistance resistance of tumor cells that have acquired resistance to apoptosis (Rebbaa, Cencer Lett, 219: 1-13, 2005).

Accordingly, the present inventors continued research on early aging of tumor cells. It was confirmed that ITGB4 phosphorylation is essential in the radiation-induced tumor cell senescence reaction, and when ITGB4 is inhibited, the tumor cell aging reaction is remarkably inhibited. Respectively.

It is an object of the present invention to provide a composition for inhibiting tumor cell senescence comprising an ITGB4 (integrin beta 4) inhibitor and a method for controlling the aging of tumor cells using the inhibitor.

It is another object of the present invention to provide a method for screening anticancer agents or anticancer adjuvant candidates using the degree of ITGB4 phosphorylation.

In order to achieve the above object, the present invention provides a composition for inhibiting tumor cell senescence comprising an integrin beta 4 (ITGB4) gene or an inhibitor against a protein encoded by the gene.

The present invention also provides a method for regulating the aging of tumor cells, comprising the step of treating the tumor cell with an integrin beta 4 (ITGB4) gene or an inhibitor for the protein encoded by the gene.

(A) measuring the degree of phosphorylation of ITGB4 (integrin beta 4) after treating a tumor cell with a sample; And (b) selecting a sample having increased degree of ITGB4 phosphorylation compared to a control group in which the sample is not treated in the tumor cells of the step (a).

The composition according to the present invention can inhibit the expression or activity of ITGB4 in tumor cells and inhibit the aging of tumor cells induced by radiation. Therefore, by analyzing the effect of a specific substance on the expression or activity of ITGB4, it is possible to study the anticancer mechanism associated with the enhancement of tumor cell sensitivity to radiation.

FIG. 1 is a graph showing the results of observing cell shape (A) and beta-galactosidase activity (B) 3 days after irradiating lung cancer cells with radiation.
FIG. 2 is a graph showing the results of analysis of the degree of phosphorylation of ITGB4 over time after irradiation of breast cancer cells with radiation. FIG.
FIG. 3 is a graph showing the results of observing cell morphology after injecting ITGB4 siRNA into lung cancer cells and irradiating it with radiation.
FIG. 4 is a graph showing the results of analysis of the degree of phosphorylation of ITGB4 over time after injecting ITGB4 siRNA into lung cancer cells and irradiating it with radiation.
FIG. 5 is a graph showing the results of observing cell shape and beta-galactosidase activity after irradiation with Asc-8, an ITGB4 antibody, in lung cancer cells. FIG.

The present invention provides a composition for inhibiting tumor cell senescence comprising an integrin beta 4 (ITGB4) gene or an inhibitor against a protein encoded by the gene.

The present invention also provides a method for regulating the aging of tumor cells, comprising the step of treating the tumor cell with an integrin beta 4 (ITGB4) gene or an inhibitor for the protein encoded by the gene.

In the present invention, " ITGB4 (integrin beta 4) " is a protein of about 200 kDa in size. Integrin is a membrane receptor protein in which alpha and beta subunits form a heterodimer. Integin beta 4 forms a heterodimer with integrin alpha 6, promoting cell-matrix or cell-cell interactions and signaling the intracellular proteins And mediates various intracellular responses such as cytoskeletal maintenance, cell growth, cell proliferation, and gene expression.

In the present invention, the ITGB4 gene is preferably derived from a human, and is a nucleotide consisting of a nucleotide sequence of NCBI registration number NM_000213 (SEQ ID NO: 1), NM_001005619 (SEQ ID NO: 2), NM_001005731 (Deletion, substitution or insertion of a base) capable of functioning. It is to be understood by those skilled in the art that the nucleotide sequence is illustrative and not limited thereto, and sequences having substantial sequence identity or substantial sequence homology to the sequence are also included in the scope of the present invention.

The protein encoded by the ITGB4 gene in the present invention includes a polypeptide consisting of the amino acid sequence of NCBI registration number NP_000204 (SEQ ID NO: 4), NP_001005619 (SEQ ID NO: 5), NP_001005731 (SEQ ID NO: 6), and functional equivalents of the protein. Is at least 70%, preferably at least 80%, more preferably at least 90%, even more preferably at least 95% sequence identity with the amino acid sequence as a result of addition, substitution or deletion of amino acids Refers to a protein having homology and exhibiting substantially the same physiological activity as the protein consisting of the amino acid sequence.

In the present invention, the inhibitor of the ITGB4 gene may be an antisense nucleotide complementary to mRNA of the gene, siRNA (short interfering RNA), shRNA (short hairpin RNA), ribozyme, or the like, but is not limited thereto. The siRNA is composed of a sense sequence of 15 to 30 mers selected in the nucleotide sequence of the mRNA of the gene and an antisense sequence complementarily binding to the sense sequence. For example, the sense sequence of SEQ ID NO: 7 And a double stranded siRNA consisting of the antisense sequence of SEQ ID < RTI ID = 0.0 > 8 < / RTI > The siRNA may have a thymine base (dTdT) bound to the 3 'end of the sense sequence and / or the antisense sequence.

In the present invention, the inhibitor of the protein encoded by the ITGB4 gene may be a compound that binds complementarily to the protein, a peptide, a mimetics, a substrate analog, an aptamer, or an antibody, but is not limited thereto. The antibody may be a monoclonal antibody, a polyclonal antibody, or a recombinant antibody capable of specifically binding to the protein, and may be, for example, Asc-8 (Anti-Integrin beta 4 antibody). The antibody can be produced by a known method known to those skilled in the art, and commercially available ones can be purchased and used.

In the present invention, the tumor cells may be cancer cells. The cancer may be selected from the group consisting of liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, colon cancer, lung cancer, ovarian cancer, rectum cancer, esophageal cancer, small intestine cancer, fallopian tube carcinoma, endometrial carcinoma, Cancer cells, central nervous system tumors, and the like. Preferably, the cancer cells are a breast cancer or a lung cancer. The term " cancer " Cells, but are not limited thereto.

In the present invention, aging is preferably induced by radiation, but is not limited thereto.

The radiation is preferably gamma ray, but is not limited thereto.

The composition for inhibiting tumor cell senescence of the present invention may comprise a pharmaceutically acceptable carrier, diluent, excipient or a combination of two or more thereof commonly used in biological preparations. In addition, it can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, oral preparations such as syrups and aerosols, external preparations, suppositories and sterilized injection solutions according to a conventional method. Suitable formulations known in the art are preferably those as disclosed in Remington ' s Pharmaceutical Science, recently, Mack Publishing Company, Easton PA. Examples of carriers, excipients and diluents that can be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose , Microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When the composition is formulated, it is prepared using a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient usually used.

(A) measuring the degree of phosphorylation of ITGB4 (integrin beta 4) after treating a tumor cell with a sample; And (b) selecting a sample having increased degree of ITGB4 phosphorylation compared to a control group in which the sample is not treated in the tumor cells of the step (a).

According to one embodiment of the present invention, phosphorylation of ITGB4 is essential in the radiation induced tumor cell senescence reaction. Therefore, when the specific sample increases the phosphorylation of ITGB4, the aging reaction of the tumor cells is promoted. As a result, the sample can be used as a candidate for anti-cancer or anti-cancer adjuvant which can enhance the sensitivity of tumor cells to radiation, It can be judged as a substance.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

Example  1. Induction of tumor cell aging by radiation

To determine whether induction of aging of tumor cells by radiation was possible, human lung cancer cell line A549 was irradiated with 6 Gy of radiation (gamma ray), and cell shape and beta-galactosidase activity were analyzed.

More specifically, ¹³⁷ Cs gamma-ray emitter 6 Gy of gamma emissions from the (Atomic Energy of Canada Ltd., Mississauga , Ontario, Canada) on lung cancer cells by exposure to radiation at a dose of 3.81 Gy / min and then, 5% CO ₂ After incubation for 3 days in a 37 ° C incubator, cell morphology was observed under a microscope (ECLIPSE TE300, Nikon).

In addition, the cells were washed twice with PBS, fixed with 3% formaldehyde at room temperature for 3-5 minutes, and fixed cells were washed again with PBS. The cells were treated with? -Galactosidase active staining solution (1 mg / ml of X-Gal, 40 mM citric acid / sodium phosphate (pH 6.0), 5 mM potassium ferrocyanide, 5 mM potassium ferricyanide, Chloride, 2 mM magnesium chloride) was added, and the mixture was reacted for 12-16 hours at 37 ° C in a constant temperature incubator. During the reaction, the culture dish was wrapped with a thin foil foil to prevent light from entering. The activity of beta - galactosidase activity was observed using a phase contrast microscope (ECLIPSE TE300, Nikon) and the number of cells stained was measured to quantify the proportion of cells showing beta - galactosidase positive.

The results are shown in Fig.

As shown in FIG. 1A, unlike the control group not exposed to radiation, lung cancer cells irradiated with radiation showed characteristics of aging cells such as a cell size becoming larger and becoming flat.

In addition, as shown in FIG. 1B, lung cancer cells irradiated with radiation as compared with the control group not exposed to radiation showed a marked increase in the proportion of cells showing positive aging-related beta-galactosidase.

Example  2. Radiation-induced tumor cell aging process ITGB4 Of phosphorylation

2-1. In human breast cancer cell lines ITGB4 Of phosphorylation

Human breast cancer cell line MCF 7 was irradiated with 6 Gy of gamma-radiation at a dose of 5% CO ₂ for 1 hour, 6 hours and 24 hours in a 37 ° C incubator. The cells were washed twice with PBS (phosphate buffered saline), and then lysed in a cell lysis buffer (50 mM Tri-HCl, 1% NP-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM PMSF, 50 mM NaF, 0.2 mM Na3VO4, 10 μg / ml aprotinin, 2 μg / ml rupeptin) to dissolve the cells. The cells were centrifuged at 11,000 rpm for 10 minutes and then the supernatant was taken to separate the proteins extracted from the cells. Using a membrane microarray (Phospho Explorer Antibody Microarray) of membrane and membrane sub-signaling phosphorylation proteins of Fullmoon BioSystems (USA) And the radiation reactivity of 1,318 phosphorylated proteins was analyzed. Table 1 shows the degree of phosphorylation of ITGB4.

Phosphorylation residue Degree of phosphorylation in radiation induced cell aging process
(Irradiation group / control group) 1 hours 6 hours 24 hours ITGB4 (Tyr1510) 2.509 1.49 1.33

As shown in Table 1, when breast cancer cells were exposed to radiation to induce senescence, it was confirmed that humanization of ITGB4 occurred from 1 hour later.

2-1. In human lung cancer cell lines ITGB4 Of phosphorylation

Human lung cancer cell line A549 was irradiated with dose of 6 Gy gamma-radiation and cultured in a 37 ° C incubator with 5% CO ₂ for 0.5 hour, 1 hour, and 6 hours. The cells were washed with PBS and incubated in a cell lysis buffer (50 mM Tri-HCl, 1% NP-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM PMSF, 50 mM NaF, 0.2 mM Na3VO4, 2 μg / ml rupeptin) to dissolve the cells. The cells were centrifuged at 11,000 rpm for 10 minutes and then the supernatant was taken to separate proteins extracted from the cells. The proteins were quantified using the Bradford method (bradford, M., Anal. Biochem. 72: 248-254 (1976)) Respectively. To 20 ug of the protein was added 2X SDS loading buffer (60 mM Tris-Cl (pH 6.8), 25% glycerol, 2% SDS, 14.4 mM mercaptoethanol, 0.1% bromophenol blue) And then electrophoresed for 2 hours at 80 V in 8% to 10% SDS polyacrylamide gel. After electrophoresis, the separated proteins were transferred to a nitrocellulose membrane (Whatman). Protein-transferred membranes were blocked in PBS solution containing 5% non-fat milk for 1 hour at room temperature, and primary antibodies diluted 1: 500 ~ 1: 1000 were added and incubated at 4 ° C for 16 hours Lt; / RTI > The primary antibodies were polyclonal anti-p21 Ab (Santa Cruz), polyclonal anti-actin Ab (Santa Cruz), and phosphorylated amino acids 1510 in the tyrosine residue of ITGB4 The anti-ITGB4 antibody (monoclonal anti-phosphoITGB4, Abcam) was used as a specific antibody and the secondary antibody was HRP-conjugated goat anti-rabbit IgG, HRP conjugated goat anti-mouse IgG, Santa Cruz). Final protein expression was confirmed by ECL (enhanced chemiluminescence) reagent (Amersham). At this time, p21, a cell-specific expression protein, was used to confirm whether normal induction of aging was induced. Actin, which is a housekeeping gene expressed in all cells at the same level, is a result of the same amount of protein It was used to confirm. The results are shown in Fig.

As shown in Fig. 2, lung cancer cells were exposed to radiation to induce senescence, and it was confirmed that ITGB4 phosphorylation occurred.

Example  3. siRNA In the aging process of tumor cells ITGB4 Expression analysis

Human lung cancer cell line A549 was cultured in an RPMI culture medium containing 10% fetal bovine serum (FBS, Welch) and an antibiotic (Gibco BRL), and cultured in a 60 mm culture medium before the injection of small interfering RNA (siRNA) (Invitrogen, Cat # 13778-075) and OptiMEM®I culture medium (Invitrogen, Cat # 31985) were mixed with siRNA {ITGB4 si; (SEQ ID NO: 7-dTdT) and 5 '= UGA UGG UGA UGU UUA CCA GdTdT-3', SEQ ID NO: 8-dTdT) (DTdT) was bound to the cells at a concentration of 100 nM. After 6 hours, the culture medium was replaced with RPMI culture medium containing 10% fetal bovine serum (FBS, Weljin) and 100 ug / ml of antibiotic streptomycin and 100 U / ml of penicillin (Gibco BRL) And then cultured in a 37 ° C incubator with 5% CO ₂ for 1 day. 137Cs gamma-ray emitter to said cell (Atomic Energy of Canada Ltd., Mississauga , Ontario, Canada) of 6 Gy gamma emitted from - after radiation exposure at a dose of 3.81 Gy / min, 37 ℃ in 5% CO ₂ constant temperature and concentration The cells were cultured in an incubator for 3 days, and the cell morphology was observed with a microscope (ECLIPSE TE300, Nikon) (Fig. 3).

In the same manner as described above, the cells were treated with 100 nM of siRNA and then cultured in a constant temperature incubator at a concentration of 5% CO ₂ for 1 day. The cells were irradiated with 6 Gy of radiation with a 137Cs gamma ray emitter and cultured in a 37 ° C incubator with 5% CO ₂ for 0.5 hour, 1 hour, and 6 hours. Cells were obtained by time of exposure to radiation, which were then washed with PBS and resuspended in cell lysis buffer (50 mM Tri-HCl, 1% NP-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM PMSF, 50 mM NaF, 0.2 mM Na3VO4 , 10 μg / ml aprotinin, 2 μg / ml rupeptin). The cells were centrifuged at 11,000 rpm for 10 minutes and then the supernatant was taken to separate proteins extracted from the cells. The proteins were quantified using the Bradford method (bradford, M., Anal. Biochem. 72: 248-254 (1976)) Respectively. After adding 2X SDS loading buffer (60 mM Tris-Cl (pH 6.8), 25% glycerol, 2% SDS, 14.4 mM mercaptoethanol, 0.1% bromophenol blue) to 20 ug of the protein, And electrophoresed at 80 V in 8% to 10% SDS polyacrylamide gel for 2 hours. After electrophoresis, the separated proteins were transferred to a nitrocellulose membrane (Whatman). Protein-transferred membranes were blocked in PBS solution containing 5% skimmed milk, incubated at room temperature for 1 hour, and incubated at 4 ° C for 16 hours at 1: 500 ~ 1: 1000 diluted with primary antibodies Lt; / RTI > The primary antibodies were polyclonal anti-p21 Ab, Santa Cruz polyclonal anti-actin Ab, Santa Cruz monoclonal anti-ITGB4 antibody, , Abcam), an anti-p-ITGB4 antibody (monoclonal anti-phosphoITGB4, manufactured by Abcam) specifically recognizing only the phosphorylated amino acid 1510 in the tyrosine residue of ITGB4 was used and the secondary antibody was a horseradish peroxidase complex anti-rabbit Or anti-mouse antibody (HRP conjugated goat anti-rabbit IgG, HRP-conjugated goat anti-mouse IgG, Santa Cruz). Final protein expression was confirmed by ECL (enhanced chemiluminescence) reagent (Amersham) (FIG. 4).

On the other hand, in the above experiment, a non-specific small interference RNA {Control si; Double-stranded siRNA consisting of the nucleotide sequence of 5'-CCU ACG CCA CCA AUU UCG UdTdT-3 '(SEQ ID NO: 9-dTdT) and 5'-ACG AAA UUG GUG GCG UAG GdTdT-3' , And the thymine dibasic base (dTdT) was bound to the 3 'end of each sequence) was used as a control.

All of the above siRNAs were prepared by using Bioneer (Korea). More specifically, siRNA was synthesized using a method of linking phosphodiester bonds forming the backbone of the DNA structure using? -Cyanoethyl phosphoramidite (see Sinha et al. , Nucleic Acids Research, 12: 4539-4557, 1984). That is, using a RNA synthesizer (Perseptive Biosystems 8909, PE Biosystems, USA), a series of oligonucleotides consisting of deblocking, coupling, oxidation and capping on a nucleotide- The procedure was repeated to obtain a reaction product containing the desired length of RNA. Next, the reaction product was applied to HPLC LC918 (Japan Analytical Industry, Japan) using Daisogel C18 (Daiso, Japan), RNA was isolated and applied to a MALDI-TOF mass spectrometer (Shimadzu, Japan) Was confirmed to match the nucleotide sequence. The sense and antisense RNA strands were then combined to produce the desired double stranded siRNAs, respectively.

The results of the above experiments are shown in FIG. 3 and FIG.

As shown in FIG. 3, when ITGB4 siRNA was injected into lung cancer cells and exposed to radiation, it was confirmed that there was no change in senescence-specific cell morphology.

As shown in FIG. 4, ITGB4 siRNA was injected into the lung cancer cells and exposed to radiation, thereby effectively suppressing ITGB4 expression and significantly reducing the expression level of p21, a cell senescence-specific expression protein.

Example  4. In the process of aging tumor cells using antibodies ITGB4 Expression analysis

Human lung cancer cell line A549 was cultured for 1 day in RPMI culture medium containing 10% fetal bovine serum (FBS, Weljin) and antibiotic (Gibco BRL) and 37 ° C incubator with 5% CO ₂ concentration . The cells were treated with 1 ug / Ml of the antibody Asc-8 (Abcam), which is an ITGB4 activation inhibitor, and then cultured in a constant temperature incubator at 37 ° C for 5 hours in a 5% CO ₂ incubator for 1 hour. The cells were irradiated with 6 Gy of radiation with a ¹³⁷ Cs gamma ray emitter, and then cultured for 3 days in a constant temperature incubator at 37 ° C with 5% CO _2. Cells were observed with a microscope (ECLIPSE TE300, Nikon).

In addition, the cells were washed twice with PBS, fixed with 3% formaldehyde at room temperature for 3-5 minutes, and fixed cells were washed again with PBS. The cells were treated with? -Galactosidase active staining solution (1 mg / ml of X-Gal, 40 mM citric acid / sodium phosphate (pH 6.0), 5 mM potassium ferrocyanide, 5 mM potassium ferricyanide, Chloride, 2 mM magnesium chloride) was added, and the mixture was reacted for 12-16 hours at 37 ° C in a constant temperature incubator. During the reaction, the culture dish was wrapped with a thin foil foil to prevent light from entering. The activity of beta - galactosidase activity was observed using a phase contrast microscope (ECLIPSE TE300, Nikon) and the number of cells stained was measured to quantify the proportion of cells showing beta - galactosidase positive.

The results are shown in Fig.

As shown in Fig. 5, when Asc-8 was treated with Asc-8 and exposed to radiation, there was no change in aging-specific cell morphology, and cells showing senescence-related beta-galactosidase positive Of the tumor cells was remarkably decreased and the tumor cell aging reaction was remarkably inhibited.

These results indicate that ITGB4 phosphorylation is essential in the course of tumor-induced tumor cell senescence, and inhibition of the expression or activity of ITGB4 significantly inhibits tumor cell senescence.

<110> INHA-INDUSTRY PARTNERSHIP INSTITUTE <120> Composition for inhibiting tumor cell senescence comprising ITGB4          inhibitor <130> 1.154P <160> 10 <170> Kopatentin 2.0 <210> 1 <211> 5925 <212> DNA <213> Homo sapiens <400> 1 gcgctgcccg cctcgtcccc acccccccaa cccccgcgcc cgccctcgga cagtccctgc 60 tcgcccgcgc gctgcagccc catctcctag cggcagccca ggcgcggagg gagcgagtcc 120 gccccgaggt aggtccagga cgggcgcaca gcagcagccg aggctggccg ggagagggag 180 gaagaggatg gcagggccac gccccagccc atgggccagg ctgctcctgg cagccttgat 240 cagcgtcagc ctctctggga ccttggcaaa ccgctgcaag aaggccccag tgaagagctg 300 cacggagtgt gtccgtgtgg ataaggactg cgcctactgc acagacgaga tgttcaggga 360 ccggcgctgc aacacccagg cggagctgct ggccgcgggc tgccagcggg agagcatcgt 420 ggtcatggag agcagcttcc aaatcacaga ggagacccag attgacacca ccctgcggcg 480 cagccagatg tccccccaag gcctgcgggt ccgtctgcgg cccggtgagg agcggcattt 540 tgagctggag gtgtttgagc cactggagag ccccgtggac ctgtacatcc tcatggactt 600 ctccaactcc atgtccgatg atctggacaa cctcaagaag atggggcaga acctggctcg 660 ggtcctgagc cagctcacca gcgactacac tattggattt ggcaagtttg tggacaaagt 720 cagcgtcccg cagacggaca tgaggcctga gaagctgaag gagccctggc ccaacagtga 780 cccccccttc tccttcaaga acgtcatcag cctgacagaa gatgtggatg agttccggaa 840 taaactgcag ggagagcgga tctcaggcaa cctggatgct cctgagggcg gcttcgatgc 900 catcctgcag acagctgtgt gcacgaggga cattggctgg cgcccggaca gcacccacct 960 gctggtcttc tccaccgagt cagccttcca ctatgaggct gatggcgcca acgtgctggc 1020 tggcatcatg agccgcaacg atgaacggtg ccacctggac accacgggca cctacaccca 1080 gtacakgaca caggactacc cgtcggtgcc caccctggtg cgcctgctcg ccaagcacaa 1140 catcatcccc atctttgctg tcaccaacta ctcctatagc tactacgaga agcttcacac 1200 ctatttccct gtctcctcac tgggggtgct gcaggaggac tcgtccaaca tcgtggagct 1260 gctggaggag gccttcaatc ggatccgctc caacctggac atccgggccc tagacagccc 1320 ccgaggcctt cggacagagg tcacctccaa gatgttccag aagacgagga ctgggtcctt 1380 tcacatccgg cggggggaag tgggtatata ccaggtgcag ctgcgggccc ttgagcacgt 1440 ggatgggacg cacgtgtgcc agctgccgga ggaccagaag ggcaacatcc atctgaaacc 1500 ttccttctcc gacggcctca agatggacgc gggcatcatc tgtgatgtgt gcacctgcga 1560 gctgcaaaaa gaggtgcggt cagctcgctg cagcttcaac ggagacttcg tgtgcggaca 1620 gtgtgtgtgc agcgagggct ggagtggcca gacctgcaac tgctccaccg gctctctgag 1680 tgacattcag ccctgcctgc gggagggcga ggacaagccg tgctccggcc gtggggagtg 1740 ccagtgcggg cactgtgtgt gctacggcga aggccgctac gagggtcagt tctgcgagta 1800 tgacaacttc cagtgtcccc gcacttccgg gttcctctgc aatgaccgag gacgctgctc 1860 catgggccag tgtgtgtgtg agcctggttg gacaggccca agctgtgact gtcccctcag 1920 caatgccacc tgcatcgaca gcaatggggg catctgtaat ggacgtggcc actgtgagtg 1980 tggccgctgc cactgccacc agcagtcgct ctacacggac accatctgcg agatcaacta 2040 cctcggcgatc cacccgggcc tctgcgagga cctacgctcc tgcgtgcagt gccaggcgtg 2100 gggcaccggc gagaagaagg ggcgcacgtg tgaggaatgc aacttcaagg tcaagatggt 2160 ggacgagctt aagagagccg aggaggtggt ggtgcgctgc tccttccggg acgaggatga 2220 cgactgcacc tacagctaca ccatggaagg tgacggcgcc cctgggccca acagcactgt 2280 cctggtgcac aagaagaagg actgccctcc gggctccttc tggtggctca tccccctgct 2340 cctcctcctc ctgccgctcc tggccctgct actgctgcta tgctggaagt actgtgcctg 2400 ctgcaaggcc tgcctggcac ttctcccgtg ctgcaaccga ggtcacatgg tgggctttaa 2460 ggaagaccac tacatgctgc gggagaacct gatggcctct gaccacttgg acacgcccat 2520 gctgcgcagc gggaacctca agggccgtga cgtggtccgc tggaaggtca ccaacaacat 2580 gcagcggcct ggctttgcca ctcatgccgc cagcatcaac cccacagagc tggtgcccta 2640 cgggctgtcc ttgcgcctgg cccgcctttg caccgagaac ctgctgaagc ctgacactcg 2700 ggagtgcgcc cagctgcgcc aggaggtgga ggagaacctg aacgaggtct acaggcagat 2760 ctccggtgta cacaagctcc agcagaccaa gttccggcag cagcccaatg ccgggaaaaa 2820 gcaagaccac accattgtgg acacagtgct gatggcgccc cgctcggcca agccggccct 2880 gctgaagctt acagagaagc aggtggaaca gagggccttc cacgacctca aggtggcccc 2940 cggctactac accctcactg cagaccagga cgcccggggc atggtggagt tccaggaggg 3000 cgtggagctg gtggacgtac gggtgcccct ctttatccgg cctgaggatg acgacgagaa 3060 gcagctgctg gtggaggcca tcgacgtgcc cgcaggcact gccaccctcg gccgccgcct 3120 ggtaaacatc accatcatca aggagcaagc cagagacgtg gtgtcctttg agcagcctga 3180 gtctcggtc agccgcgggg accaggtggc ccgcatccct gtcatccggc gtgtcctgga 3240 cggcgggaag tcccaggtct cctaccgcac acaggatggc accgcgcagg gcaaccggga 3300 ctacatcccc gtggagggtg agctgctgtt ccagcctggg gaggcctgga aagagctgca 3360 ggtgaagctc ctggagctgc aagaagttga ctccctcctg cggggccgcc aggtccgccg 3420 tttccacgtc cagctcagca accctaagtt tggggcccac ctgggccagc cccactccac 3480 caccatcatc atcagggacc cagatgaact ggaccggagc ttcacgagtc agatgttgtc 3540 atcacagcca ccccctcacg gcgacctggg cgccccgcag aaccccaatg ctaaggccgc 3600 tgggtccagg aagatccatt tcaactggct gcccccttct ggcaagccaa tggggtacag 3660 ggtaaagtac tggattcagg gtgactccga atccgaagcc cacctgctcg acagcaaggt 3720 gccctcagtg gagctcacca acctgtaccc gtattgcgac tatgagatga aggtgtgcgc 3780 ctacggggct cagggcgagg gaccctacag ctccctggtg tcctgccgca cccaccagga 3840 agtgcccagc gagccagggc gtctggcctt caatgtcgtc tcctccacgg tgacccagct 3900 gagctgggct gagccggctg agaccaacgg tgagatcaca gcctacgagg tctgctatgg 3960 cctggtcaac gatgacaacc gacctattgg gcccatgaag aaagtgctgg ttgacaaccc 4020 taagaaccgg atgctgctta ttgagaacct tcgggagtcc cagccctacc gctacacggt 4080 gaaggcgcgc aacggggccg gctgggggcc tgagcgggag gccatcatca acctggccac 4140 ccagcccaag aggcccatgt ccatccccat catccctgac atccctatcg tggacgccca 4200 gagcggggag gactacgaca gcttccttat gtacagcgat gacgttctac gctctccatc 4260 gggcagccag aggcccagcg tctccgatga cactggctgc ggctggaagt tcgagcccct 4320 gctgggggag gagctggacc tgcggcgcgt cacgtggcgg ctgcccccgg agctcatccc 4380 gcgcctgtcg gccagcagcg ggcgctcctc cgacgccgag gcgccccacg ggcccccgga 4440 cgacggcggc gcgggcggga agggcggcag cctgccccgc agtgcgacac ccgggccccc 4500 cggagagcac ctggtgaatg gccggatgga ctttgccttc ccgggcagca ccaactccct 4560 gcacaggatg accacgacca gtgctgctgc ctatggcacc cacctgagcc cacacgtgcc 4620 ccaccgcgtg ctaagcacat cctccaccct cacacgggac tacaactcac tgacccgctc 4680 agaacactca cactcgacca cactgcccag ggactactcc accctcacct ccgtctcctc 4740 ccacgactct cgcctgactg ctggtgtgcc cgacacgccc acccgcctgg tgttctctgc 4800 cctggggccc acatctctca gagtgagctg gcaggagccg cggtgcgagc ggccgctgca 4860 gggctacagt gtggagtacc agctgctgaa cggcggtgag ctgcatcggc tcaacatccc 4920 caaccctgcc cagacctcgg tggtggtgga agacctcctg cccaaccact cctacgtgtt 4980 ccgcgtgcgg gcccagagcc aggaaggctg gggccgagag cgtgagggtg tcatcaccat 5040 tgaatcccag gtgcacccgc agagcccact gtgtcccctg ccaggctccg ccttcacttt 5100 gagcactccc agtgccccag gcccgctggt gttcactgcc ctgagcccag actcgctgca 5160 gctgagctgg gagcggccac ggaggcccaa tggggatatc gtcggctacc tggtgacctg 5220 tgagatggcc caaggaggag ggccagccac cgcattccgg gtggatggag acagccccga 5280 gagccggctg accgtgccgg gcctcagcga gaacgtgccc tacaagttca aggtgcaggc 5340 caggaccact gagggcttcg ggccagagcg cgagggcatc atcaccatag agtcccagga 5400 tggaggaccc ttcccgcagc tgggcagccg tgccgggctc ttccagcacc cgctgcaaag 5460 cgagtacagc agcatcacca ccacccacac cagcgccacc gagcccttcc tagtggatgg 5520 gctgaccctg ggggcccagc acctggaggc aggcggctcc ctcacccggc atgtgaccca 5580 ggagtttgtg agccggacac tgaccaccag cggaaccctt agcacccaca tggaccaaca 5640 gttcttccaa acttgaccgc accctgcccc acccccgcca cgtcccacta ggcgtcctcc 5700 cgactcctct cccggagcct cctcagctac tccatccttg cacccctggg ggcccagccc 5760 acccgcatgc acagagcagg ggctaggtgt ctcctgggag gcatgaaggg ggcaaggtcc 5820 gtcctctgtg ggcccaaacc tatttgtaac caaagagctg ggagcagcac aaggacccag 5880 cctttgttct gcacttaata aatggttttg ctactgctaa aaaaa 5925 <210> 2 <211> 5695 <212> DNA <213> Homo sapiens <400> 2 ggaagaggat ggcagggcca cgccccagcc catgggccag gctgctcctg gcagccttga 60 tcagcgtcag cctctctggg accttggcaa accgctgcaa gaaggcccca gtgaagagct 120 gcacggagtg tgtccgtgtg gataaggact gcgcctactg cacagacgag atgttcaggg 180 accggcgctg caacacccag gcggagctgc tggccgcggg ctgccagcgg gagagcatcg 240 tggtcatgga gagcagcttc caaatcacag aggagaccca gattgacacc accctgcggc 300 gcagccagat gtccccccaa ggcctgcggg tccgtctgcg gcccggtgag gagcggcatt 360 ttgagctgga ggtgtttgag ccactggaga gccccgtgga cctgtacatc ctcatggact 420 tctccaactc catgtccgat gatctggaca acctcaagaa gatggggcag aacctggctc 480 gggtcctgag ccagctcacc agcgactaca ctattggatt tggcaagttt gtggacaaag 540 tcagcgtccc gcagacggac atgaggcctg agaagctgaa ggagccctgg cccaacagtg 600 accccccctt ctccttcaag aacgtcatca gcctgacaga agatgtggat gagttccgga 660 ataaactgca gggagagcgg atctcaggca acctggatgc tcctgagggc ggcttcgatg 720 ccatcctgca gacagctgtg tgcacgaggg acattggctg gcgcccggac agcacccacc 780 tgctggtctt ctccaccgag tcagccttcc actatgaggc tgatggcgcc aacgtgctgg 840 ctggcatcat gagccgcaac gatgaacggt gccacctgga caccacgggc acctacaccc 900 agtacaggac acaggactac ccgtcggtgc ccaccctggt gcgcctgctc gccaagcaca 960 acatcatccc catctttgct gtcaccaact actcctatag ctactacgag aagcttcaca 1020 cctatttccc tgtctcctca ctgggggtgc tgcaggagga ctcgtccaac atcgtggagc 1080 tgctggagga ggccttcaat cggatccgct ccaacctgga catccgggcc ctagacagcc 1140 cccgaggcct tcggacagag gtcacctcca agatgttcca gaagacgagg actgggtcct 1200 ttcacatccg gcggggggaa gtgggtatat accaggtgca gctgcgggcc cttgagcacg 1260 tggatgggac gcacgtgtgc cagctgccgg aggaccagaa gggcaacatc catctgaaac 1320 cttccttctc cgacggcctc aagatggacg cgggcatcat ctgtgatgtg tgcacctgcg 1380 agctgcaaaa agaggtgcgg tcagctcgct gcagcttcaa cggagacttc gtgtgcggac 1440 agtgtgtgtg cagcgagggc tggagtggcc agacctgcaa ctgctccacc ggctctctga 1500 gtgacattca gccctgcctg cgggagggcg aggacaagcc gtgctccggc cgtggggagt 1560 gccagtgcgg gcactgtgtg tgctacggcg aaggccgcta cgagggtcag ttctgcgagt 1620 atgacaactt ccagtgtccc cgcacttccg ggttcctctg caatgaccga ggacgctgct 1680 ccatgggcca gtgtgtgtgt gagcctggtt ggacaggccc aagctgtgac tgtcccctca 1740 gcaatgccac ctgcatcgac agcaatgggg gcatctgtaa tggacgtggc cactgtgagt 1800 gtggccgctg ccactgccac cagcagtcgc tctacacgga caccatctgc gagatcaact 1860 actcggcgat ccacccgggc ctctgcgagg acctacgctc ctgcgtgcag tgccaggcgt 1920 ggggcaccgg cgagaagaag gggcgcacgt gtgaggaatg caacttcaag gtcaagatgg 1980 tggacgagct taagagagcc gaggaggtgg tggtgcgctg ctccttccgg gacgaggatg 2040 acgactgcac ctacagctac accatggaag gtgacggcgc ccctgggccc aacagcactg 2100 tcctggtgca caagaagaag gactgccctc cgggctcctt ctggtggctc atccccctgc 2160 tcctcctcct cctgccgctc ctggccctgc tactgctgct atgctggaag tactgtgcct 2220 gctgcaaggc ctgcctggca cttctcccgt gctgcaaccg aggtcacatg gtgggcttta 2280 aggaagacca ctacatgctg cgggagaacc tgatggcctc tgaccacttg gacacgccca 2340 tgctgcgcag cgggaacctc aagggccgtg acgtggtccg ctggaaggtc accaacaaca 2400 tgcagcggcc tggctttgcc actcatgccg ccagcatcaa ccccacagag ctggtgccct 2460 acgggctgtc cttgcgcctg gcccgccttt gcaccgagaa cctgctgaag cctgacactc 2520 gggagtgcgc ccagctgcgc caggaggtgg aggagaacct gaacgaggtc tacaggcaga 2580 tctccggtgt acacaagctc cagcagacca agttccggca gcagcccaat gccgggaaaa 2640 agcaagacca caccattgtg gacacagtgc tgatggcgcc ccgctcggcc aagccggccc 2700 tgctgaagct tacagagaag caggtggaac agagggcctt ccacgacctc aaggtggccc 2760 ccggctacta caccctcact gcagaccagg acgcccgggg catggtggag ttccaggagg 2820 gcgtggagct ggtggacgta cgggtgcccc tctttatccg gcctgaggat gacgacgaga 2880 agcagctgct ggtggaggcc atcgacgtgc ccgcaggcac tgccaccctc ggccgccgcc 2940 tggtaaacat caccatcatc aaggagcaag ccagagacgt ggtgtccttt gagcagcctg 3000 agttctcggt cagccgcggg gaccaggtgg cccgcatccc tgtcatccgg cgtgtcctgg 3060 acggcgggaa gtcccaggtc tcctaccgca cacaggatgg caccgcgcag ggcaaccggg 3120 actacatccc cgtggagggt gagctgctgt tccagcctgg ggaggcctgg aaagagctgc 3180 aggtgaagct cctggagctg caagaagttg actccctcct gcggggccgc caggtccgcc 3240 gtttccacgt ccagctcagc aaccctaagt ttggggccca cctgggccag ccccactcca 3300 ccaccatcat catcagggac ccagatgaac tggaccggag cttcacgagt cagatgttgt 3360 catcacagcc accccctcac ggcgacctgg gcgccccgca gaaccccaat gctaaggccg 3420 ctgggtccag gaagatccat ttcaactggc tgcccccttc tggcaagcca atggggtaca 3480 gggtaaagta ctggattcag ggtgactccg aatccgaagc ccacctgctc gacagcaagg 3540 tgccctcagt ggagctcacc aacctgtacc cgtattgcga ctatgagatg aaggtgtgcg 3600 cctacggggc tcagggcgag ggaccctaca gctccctggt gtcctgccgc acccaccagg 3660 aagtgcccag cgagccaggg cgtctggcct tcaatgtcgt ctcctccacg gtgacccagc 3720 tgagctgggc tgagccggct gagaccaacg gtgagatcac agcctacgag gtctgctatg 3780 gcctggtcaa cgatgacaac cgacctattg ggcccatgaa gaaagtgctg gttgacaacc 3840 ctaagaaccg gatgctgctt attgagaacc ttcgggagtc ccagccctac cgctacacgg 3900 tgaaggcgcg caacggggcc ggctgggggc ctgagcggga ggccatcatc aacctggcca 3960 cccagcccaa gaggcccatg tccatcccca tcatccctga catccctatc gtggacgccc 4020 agagcgggga ggactacgac agcttcctta tgtacagcga tgacgttcta cgctctccat 4080 cgggcagcca gaggcccagc gtctccgatg acactgagca cctggtgaat ggccggatgg 4140 actttgcctt cccgggcagc accaactccc tgcacaggat gaccacgacc agtgctgctg 4200 cctatggcac ccacctgagc ccacacgtgc cccaccgcgt gctaagcaca tcctccaccc 4260 tcacacggga ctacaactca ctgacccgct cagaacactc acactcgacc acactgccca 4320 gggactactc caccctcacc tccgtctcct cccacggcct ccctcccatc tgggaacacg 4380 ggaggagcag gcttccgctg tcctgggccc tggggtcccg gagtcgggct cagatgaaag 4440 ggttcccccc ttccaggggc ccacgagact ctataatcct ggctgggagg ccagcagcgc 4500 cctcctgggg cccagactct cgcctgactg ctggtgtgcc cgacacgccc acccgcctgg 4560 tgttctctgc cctggggccc acatctctca gagtgagctg gcaggagccg cggtgcgagc 4620 ggccgctgca gggctacagt gtggagtacc agctgctgaa cggcggtgag ctgcatcggc 4680 tcaacatccc caaccctgcc cagacctcgg tggtggtgga agacctcctg cccaaccact 4740 cctacgtgtt ccgcgtgcgg gcccagagcc aggaaggctg gggccgagag cgtgagggtg 4800 tcatcaccat tgaatcccag gtgcacccgc agagcccact gtgtcccctg ccaggctccg 4860 ccttcacttt gagcactccc agtgccccag gcccgctggt gttcactgcc ctgagcccag 4920 actcgctgca gctgagctgg gagcggccac ggaggcccaa tggggatatc gtcggctacc 4980 tggtgacctg tgagatggcc caaggaggag ggccagccac cgcattccgg gtggatggag 5040 acagccccga gagccggctg accgtgccgg gcctcagcga gaacgtgccc tacaagttca 5100 aggtgcaggc caggaccact gagggcttcg ggccagagcg cgagggcatc atcaccatag 5160 agtcccagga tggaggaccc ttcccgcagc tgggcagccg tgccgggctc ttccagcacc 5220 cgctgcaaag cgagtacagc agcatcacca ccacccacac cagcgccacc gagcccttcc 5280 tagtggatgg gctgaccctg ggggcccagc acctggaggc aggcggctcc ctcacccggc 5340 atgtgaccca ggagtttgtg agccggacac tgaccaccag cggaaccctt agcacccaca 5400 tggaccaaca gttcttccaa acttgaccgc accctgcccc acccccgcca cgtcccacta 5460 ggcgtcctcc cgactcctct cccggagcct cctcagctac tccatccttg cacccctggg 5520 ggcccagccc acccgcatgc acagagcagg ggctaggtgt ctcctgggag gcatgaaggg 5580 ggcaaggtcc gtcctctgtg ggcccaaacc tatttgtaac caaagagctg ggagcagcac 5640 aaggacccag cctttgttct gcacttaata aatggttttg ctactgctaa aaaaa 5695 <210> 3 <211> 5715 <212> DNA <213> Homo sapiens <400> 3 gcgctgcccg cctcgtcccc acccccccaa cccccgcgcc cgccctcgga cagtccctgc 60 tcgcccgcgc gctgcagccc catctcctag cggcagccca ggcgcggagg gagcgagtcc 120 gccccgaggt aggtccagga cgggcgcaca gcagcagccg aggctggccg ggagagggag 180 gaagaggatg gcagggccac gccccagccc atgggccagg ctgctcctgg cagccttgat 240 cagcgtcagc ctctctggga ccttggcaaa ccgctgcaag aaggccccag tgaagagctg 300 cacggagtgt gtccgtgtgg ataaggactg cgcctactgc acagacgaga tgttcaggga 360 ccggcgctgc aacacccagg cggagctgct ggccgcgggc tgccagcggg agagcatcgt 420 ggtcatggag agcagcttcc aaatcacaga ggagacccag attgacacca ccctgcggcg 480 cagccagatg tccccccaag gcctgcgggt ccgtctgcgg cccggtgagg agcggcattt 540 tgagctggag gtgtttgagc cactggagag ccccgtggac ctgtacatcc tcatggactt 600 ctccaactcc atgtccgatg atctggacaa cctcaagaag atggggcaga acctggctcg 660 ggtcctgagc cagctcacca gcgactacac tattggattt ggcaagtttg tggacaaagt 720 cagcgtcccg cagacggaca tgaggcctga gaagctgaag gagccctggc ccaacagtga 780 cccccccttc tccttcaaga acgtcatcag cctgacagaa gatgtggatg agttccggaa 840 taaactgcag ggagagcgga tctcaggcaa cctggatgct cctgagggcg gcttcgatgc 900 catcctgcag acagctgtgt gcacgaggga cattggctgg cgcccggaca gcacccacct 960 gctggtcttc tccaccgagt cagccttcca ctatgaggct gatggcgcca acgtgctggc 1020 tggcatcatg agccgcaacg atgaacggtg ccacctggac accacgggca cctacaccca 1080 gtacakgaca caggactacc cgtcggtgcc caccctggtg cgcctgctcg ccaagcacaa 1140 catcatcccc atctttgctg tcaccaacta ctcctatagc tactacgaga agcttcacac 1200 ctatttccct gtctcctcac tgggggtgct gcaggaggac tcgtccaaca tcgtggagct 1260 gctggaggag gccttcaatc ggatccgctc caacctggac atccgggccc tagacagccc 1320 ccgaggcctt cggacagagg tcacctccaa gatgttccag aagacgagga ctgggtcctt 1380 tcacatccgg cggggggaag tgggtatata ccaggtgcag ctgcgggccc ttgagcacgt 1440 ggatgggacg cacgtgtgcc agctgccgga ggaccagaag ggcaacatcc atctgaaacc 1500 ttccttctcc gacggcctca agatggacgc gggcatcatc tgtgatgtgt gcacctgcga 1560 gctgcaaaaa gaggtgcggt cagctcgctg cagcttcaac ggagacttcg tgtgcggaca 1620 gtgtgtgtgc agcgagggct ggagtggcca gacctgcaac tgctccaccg gctctctgag 1680 tgacattcag ccctgcctgc gggagggcga ggacaagccg tgctccggcc gtggggagtg 1740 ccagtgcggg cactgtgtgt gctacggcga aggccgctac gagggtcagt tctgcgagta 1800 tgacaacttc cagtgtcccc gcacttccgg gttcctctgc aatgaccgag gacgctgctc 1860 catgggccag tgtgtgtgtg agcctggttg gacaggccca agctgtgact gtcccctcag 1920 caatgccacc tgcatcgaca gcaatggggg catctgtaat ggacgtggcc actgtgagtg 1980 tggccgctgc cactgccacc agcagtcgct ctacacggac accatctgcg agatcaacta 2040 cctcggcgatc cacccgggcc tctgcgagga cctacgctcc tgcgtgcagt gccaggcgtg 2100 gggcaccggc gagaagaagg ggcgcacgtg tgaggaatgc aacttcaagg tcaagatggt 2160 ggacgagctt aagagagccg aggaggtggt ggtgcgctgc tccttccggg acgaggatga 2220 cgactgcacc tacagctaca ccatggaagg tgacggcgcc cctgggccca acagcactgt 2280 cctggtgcac aagaagaagg actgccctcc gggctccttc tggtggctca tccccctgct 2340 cctcctcctc ctgccgctcc tggccctgct actgctgcta tgctggaagt actgtgcctg 2400 ctgcaaggcc tgcctggcac ttctcccgtg ctgcaaccga ggtcacatgg tgggctttaa 2460 ggaagaccac tacatgctgc gggagaacct gatggcctct gaccacttgg acacgcccat 2520 gctgcgcagc gggaacctca agggccgtga cgtggtccgc tggaaggtca ccaacaacat 2580 gcagcggcct ggctttgcca ctcatgccgc cagcatcaac cccacagagc tggtgcccta 2640 cgggctgtcc ttgcgcctgg cccgcctttg caccgagaac ctgctgaagc ctgacactcg 2700 ggagtgcgcc cagctgcgcc aggaggtgga ggagaacctg aacgaggtct acaggcagat 2760 ctccggtgta cacaagctcc agcagaccaa gttccggcag cagcccaatg ccgggaaaaa 2820 gcaagaccac accattgtgg acacagtgct gatggcgccc cgctcggcca agccggccct 2880 gctgaagctt acagagaagc aggtggaaca gagggccttc cacgacctca aggtggcccc 2940 cggctactac accctcactg cagaccagga cgcccggggc atggtggagt tccaggaggg 3000 cgtggagctg gtggacgtac gggtgcccct ctttatccgg cctgaggatg acgacgagaa 3060 gcagctgctg gtggaggcca tcgacgtgcc cgcaggcact gccaccctcg gccgccgcct 3120 ggtaaacatc accatcatca aggagcaagc cagagacgtg gtgtcctttg agcagcctga 3180 gtctcggtc agccgcgggg accaggtggc ccgcatccct gtcatccggc gtgtcctgga 3240 cggcgggaag tcccaggtct cctaccgcac acaggatggc accgcgcagg gcaaccggga 3300 ctacatcccc gtggagggtg agctgctgtt ccagcctggg gaggcctgga aagagctgca 3360 ggtgaagctc ctggagctgc aagaagttga ctccctcctg cggggccgcc aggtccgccg 3420 tttccacgtc cagctcagca accctaagtt tggggcccac ctgggccagc cccactccac 3480 caccatcatc atcagggacc cagatgaact ggaccggagc ttcacgagtc agatgttgtc 3540 atcacagcca ccccctcacg gcgacctggg cgccccgcag aaccccaatg ctaaggccgc 3600 tgggtccagg aagatccatt tcaactggct gcccccttct ggcaagccaa tggggtacag 3660 ggtaaagtac tggattcagg gtgactccga atccgaagcc cacctgctcg acagcaaggt 3720 gccctcagtg gagctcacca acctgtaccc gtattgcgac tatgagatga aggtgtgcgc 3780 ctacggggct cagggcgagg gaccctacag ctccctggtg tcctgccgca cccaccagga 3840 agtgcccagc gagccagggc gtctggcctt caatgtcgtc tcctccacgg tgacccagct 3900 gagctgggct gagccggctg agaccaacgg tgagatcaca gcctacgagg tctgctatgg 3960 cctggtcaac gatgacaacc gacctattgg gcccatgaag aaagtgctgg ttgacaaccc 4020 taagaaccgg atgctgctta ttgagaacct tcgggagtcc cagccctacc gctacacggt 4080 gaaggcgcgc aacggggccg gctgggggcc tgagcgggag gccatcatca acctggccac 4140 ccagcccaag aggcccatgt ccatccccat catccctgac atccctatcg tggacgccca 4200 gagcggggag gactacgaca gcttccttat gtacagcgat gacgttctac gctctccatc 4260 gggcagccag aggcccagcg tctccgatga cactgagcac ctggtgaatg gccggatgga 4320 ccttgccttc ccgggcagca ccaactccct gcacaggatg accacgacca gtgctgctgc 4380 ctatggcacc cacctgagcc cacacgtgcc ccaccgcgtg ctaagcacat cctccaccct 4440 cacacgggac tacaactcac tgacccgctc agaacactca cactcgacca cactgcccag 4500 ggactactcc accctcacct ccgtctcctc ccacgactct cgcctgactg ctggtgtgcc 4560 cgacacgccc acccgcctgg tgttctctgc cctggggccc acatctctca gagtgagctg 4620 gcaggagccg cggtgcgagc ggccgctgca gggctacagt gtggagtacc agctgctgaa 4680 cggcggtgag ctgcatcggc tcaacatccc caaccctgcc cagacctcgg tggtggtgga 4740 agacctcctg cccaaccact cctacgtgtt ccgcgtgcgg gcccagagcc aggaaggctg 4800 gggccgagag cgtgagggtg tcatcaccat tgaatcccag gtgcacccgc agagcccact 4860 gtgtcccctg ccaggctccg ccttcacttt gagcactccc agtgccccag gcccgctggt 4920 gttcactgcc ctgagcccag actcgctgca gctgagctgg gagcggccac ggaggcccaa 4980 tggggatatc gtcggctacc tggtgacctg tgagatggcc caaggaggag ggccagccac 5040 cgcattccgg gtggatggag acagccccga gagccggctg accgtgccgg gcctcagcga 5100 gaacgtgccc tacaagttca aggtgcaggc caggaccact gagggcttcg ggccagagcg 5160 cgagggcatc atcaccatag agtcccagga tggaggaccc ttcccgcagc tgggcagccg 5220 tgccgggctc ttccagcacc cgctgcaaag cgagtacagc agcatcacca ccacccacac 5280 cagcgccacc gagcccttcc tagtggatgg gctgaccctg ggggcccagc acctggaggc 5340 aggcggctcc ctcacccggc atgtgaccca ggagtttgtg agccggacac tgaccaccag 5400 cggaaccctt agcacccaca tggaccaaca gttcttccaa acttgaccgc accctgcccc 5460 acccccgcca cgtcccacta ggcgtcctcc cgactcctct cccggagcct cctcagctac 5520 tccatccttg cacccctggg ggcccagccc acccgcatgc acagagcagg ggctaggtgt 5580 ctcctgggag gcatgaaggg ggcaaggtcc gtcctctgtg ggcccaaacc tatttgtaac 5640 caaagagctg ggagcagcac aaggacccag cctttgttct gcacttaata aatggttttg 5700 ctactgctaa aaaaa 5715 <210> 4 <211> 1822 <212> PRT <213> Homo sapiens <400> 4 Met Ala Gly Pro Arg Pro Ser Pro Trp Ala Arg Leu Leu Leu Ala Ala   1 5 10 15 Leu Ile Ser Val Ser Leu Ser Gly Thr Leu Ala Asn Arg Cys Lys Lys              20 25 30 Ala Pro Val Lys Ser Cys Thr Glu Cys Val Arg Val Asp Lys Asp Cys          35 40 45 Ala Tyr Cys Thr Asp Glu Met Phe Arg Asp Arg Arg Cys Asn Thr Gln      50 55 60 Ala Glu Leu Leu Ala Ala Gly Cys Gln Arg Glu Ser Ile Val Val Met  65 70 75 80 Glu Ser Ser Phe Gln Ile Thr Glu Glu Thr Gln Ile Asp Thr Thr Leu                  85 90 95 Arg Arg Ser Gln Met Ser Pro Gln Gly Leu Arg Val Val Arg Leu Arg Pro             100 105 110 Gly Glu Glu Arg His Phe Glu Leu Glu Val Phe Glu Pro Leu Glu Ser         115 120 125 Pro Val Asp Leu Tyr Ile Leu Met Asp Phe Ser Asn Ser Met Ser Asp     130 135 140 Asp Leu Asp Asn Leu Lys Lys Met Gly Gln Asn Leu Ala Arg Val Leu 145 150 155 160 Ser Gln Leu Thr Ser Asp Tyr Thr Ile Gly Phe Gly Lys Phe Val Asp                 165 170 175 Lys Val Ser Val Pro Gln Thr Asp Met Arg Pro Glu Lys Leu Lys Glu             180 185 190 Pro Trp Pro Asn Ser Asp Pro Pro Phe Ser Phe Lys Asn Val Ile Ser         195 200 205 Leu Thr Glu Asp Val Asp Glu Phe Arg Asn Lys Leu Gln Gly Glu Arg     210 215 220 Ile Ser Gly Asn Leu Asp Ala Pro Glu Gly Gly Phe Asp Ala Ile Leu 225 230 235 240 Gln Thr Ala Val Cys Thr Arg Asp Ile Gly Trp Arg Pro Asp Ser Thr                 245 250 255 His Leu Leu Val Phe Ser Thr Glu Ser Ala Phe His Tyr Glu Ala Asp             260 265 270 Gly Ala Asn Val Leu Ala Gly Ile Met Ser Arg Asn Asp Glu Arg Cys         275 280 285 His Leu Asp Thr Thr Gly Thr Tyr Thr Gln Tyr Arg Thr Gln Asp Tyr     290 295 300 Pro Ser Val Pro Thr Leu Val Arg Leu Leu Ala Lys His Asn Ile Ile 305 310 315 320 Pro Ile Phe Ala Val Thr Asn Tyr Ser Tyr Ser Tyr Tyr Glu Lys Leu                 325 330 335 His Thr Tyr Phe Pro Val Ser Ser Leu Gly Val Leu Gln Glu Asp Ser             340 345 350 Ser Asn Ile Val Glu Leu Leu Glu Glu Ala Phe Asn Arg Ile Arg Ser         355 360 365 Asn Leu Asp Ile Arg Ala Leu Asp Ser Pro Arg Gly Leu Arg Thr Glu     370 375 380 Val Thr Ser Lys Met Phe Gln Lys Thr Arg Thr Gly Ser Phe His Ile 385 390 395 400 Arg Arg Gly Glu Val Gly Ile Tyr Gln Val Gln Leu Arg Ala Leu Glu                 405 410 415 His Val Asp Gly Thr His Val Cys Gln Leu Pro Glu Asp Gln Lys Gly             420 425 430 Asn Ile His Leu Lys Pro Ser Phe Ser Asp Gly Leu Lys Met Asp Ala         435 440 445 Gly Ile Ile Cys Asp Val Cys Thr Cys Glu Leu Gln Lys Glu Val Arg     450 455 460 Ser Ala Arg Cys Ser Phe Asn Gly Asp Phe Val Cys Gly Gln Cys Val 465 470 475 480 Cys Ser Glu Gly Trp Ser Gly Gln Thr Cys Asn Cys Ser Thr Gly Ser                 485 490 495 Leu Ser Asp Ile Gln Pro Cys Leu Arg Glu Gly Glu Asp Lys Pro Cys             500 505 510 Ser Gly Arg Gly Glu Cys Gln Cys Gly His Cys Val Cys Tyr Gly Glu         515 520 525 Gly Arg Tyr Glu Gly Gln Phe Cys Glu Tyr Asp Asn Phe Gln Cys Pro     530 535 540 Arg Thr Ser Gly Phe Leu Cys Asn Asp Arg Gly Arg Cys Ser Met Gly 545 550 555 560 Gln Cys Val Cys Glu Pro Gly Trp Thr Gly Pro Ser Cys Asp Cys Pro                 565 570 575 Leu Ser Asn Ala Thr Cys Ile Asp Ser Asn Gly Gly Ile Cys Asn Gly             580 585 590 Arg Gly His Cys Glu Cys Gly Arg Cys His Cys His Gln Gln Ser Leu         595 600 605 Tyr Thr Asp Thr Ile Cys Glu Ile Asn Tyr Ser Ala Ile His Pro Gly     610 615 620 Leu Cys Glu Asp Leu Arg Ser Cys Val Gln Cys Gln Ala Trp Gly Thr 625 630 635 640 Gly Glu Lys Lys Gly Arg Thr Cys Glu Glu Cys Asn Phe Lys Val Lys                 645 650 655 Met Val Asp Glu Leu Lys Arg Ala Glu Glu Val Val Val Arg Cys Ser             660 665 670 Phe Arg Asp Glu Asp Asp Asp Cys Thr Tyr Ser Tyr Thr Met Glu Gly         675 680 685 Asp Gly Ala Pro Gly Pro Asn Ser Thr Val Leu Val His Lys Lys Lys     690 695 700 Asp Cys Pro Pro Gly Ser Phe Trp Trp Leu Ile Pro Leu Leu Leu Leu 705 710 715 720 Leu Leu Pro Leu Leu Ala Leu Leu Leu Leu Leu Cys Trp Lys Tyr Cys                 725 730 735 Ala Cys Cys Lys Ala Cys Leu Ala Leu Leu Pro Cys Cys Asn Arg Gly             740 745 750 His Met Val Gly Phe Lys Glu Asp His Tyr Met Leu Arg Glu Asn Leu         755 760 765 Met Ala Ser Asp His Leu Asp Thr Pro Met Leu Arg Ser Gly Asn Leu     770 775 780 Lys Gly Arg Asp Val Val Arg Trp Lys Val Thr Asn Asn Met Gln Arg 785 790 795 800 Pro Gly Phe Ala Thr His Ala Ala Ser Ile Asn Pro Thr Glu Leu Val                 805 810 815 Pro Tyr Gly Leu Ser Leu Arg Leu Ala Arg Leu Cys Thr Glu Asn Leu             820 825 830 Leu Lys Pro Asp Thr Arg Glu Cys Ala Gln Leu Arg Gln Glu Val Glu         835 840 845 Glu Asn Leu Asn Glu Val Tyr Arg Gln Ile Ser Gly Val His Lys Leu     850 855 860 Gln Gln Thr Lys Phe Arg Gln Gln Pro Asn Ala Gly Lys Lys Gln Asp 865 870 875 880 His Thr Ile Val Asp Thr Val Leu Met Ala Pro Arg Ser Ala Lys Pro                 885 890 895 Ala Leu Leu Lys Leu Thr Glu Lys Gln Val Glu Gln Arg Ala Phe His             900 905 910 Asp Leu Lys Val Ala Pro Gly Tyr Tyr Thr Leu Thr Ala Asp Gln Asp         915 920 925 Ala Arg Gly Met Val Glu Phe Gln Glu Gly Val Glu Leu Val Asp Val     930 935 940 Arg Val Pro Leu Phe Ile Arg Pro Glu Asp Asp Asp Glu Lys Gln Leu 945 950 955 960 Leu Val Glu Ala Ile Asp Val Ala Gly Thr Ala Thr Leu Gly Arg                 965 970 975 Arg Leu Val Asn Ile Thr Ile Ile Lys Glu Gln Ala Arg Asp Val Val             980 985 990 Ser Phe Glu Gln Pro Glu Phe Ser Val Ser Arg Gly Asp Gln Val Ala         995 1000 1005 Arg Ile Pro Val Ile Arg Arg Val Leu Asp Gly Gly Lys Ser Gln Val    1010 1015 1020 Ser Tyr Arg Thr Gln Asp Gly Thr Ala Gln Gly Asn Arg Asp Tyr Ile 1025 1030 1035 1040 Pro Val Glu Gly Glu Leu Leu Phe Gln Pro Gly Glu Ala Trp Lys Glu                1045 1050 1055 Leu Gln Val Lys Leu Leu Glu Leu Gln Glu Val Asp Ser Leu Leu Arg            1060 1065 1070 Gly Arg Gln Val Arg Arg Phe His Val Gln Leu Ser Asn Pro Lys Phe        1075 1080 1085 Gly Ala His Leu Gly Gln Pro His Thr Thr Ile Ile Ile Arg Asp    1090 1095 1100 Pro Asp Glu Leu Asp Arg Ser Phe Thr Ser Gln Met Leu Ser Ser Gln 1105 1110 1115 1120 Pro Pro Pro His Gly Asp Leu Gly Ala Pro Gln Asn Pro Asn Ala Lys                1125 1130 1135 Ala Ala Gly Ser Arg Lys Ile His Phe Asn Trp Leu Pro Pro Ser Gly            1140 1145 1150 Lys Pro Met Gly Tyr Arg Val Lys Tyr Trp Ile Gln Gly Asp Ser Glu        1155 1160 1165 Ser Glu Ala His Leu Leu Asp Ser Lys Val Pro Ser Val Glu Leu Thr    1170 1175 1180 Asn Leu Tyr Pro Tyr Cys Asp Tyr Glu Met Lys Val Cys Ala Tyr Gly 1185 1190 1195 1200 Ala Gln Gly Glu Gly Pro Tyr Ser Ser Leu Val Ser Cys Arg Thr His                1205 1210 1215 Gln Glu Val Pro Ser Glu Pro Gly Arg Leu Ala Phe Asn Val Val Ser            1220 1225 1230 Ser Thr Val Thr Gln Leu Ser Trp Ala Glu Pro Ala Glu Thr Asn Gly        1235 1240 1245 Glu Ile Thr Ala Tyr Glu Val Cys Tyr Gly Leu Val Asn Asp Asp Asn    1250 1255 1260 Arg Pro Ile Gly Pro Met Lys Lys Val Leu Val Asp Asn Pro Lys Asn 1265 1270 1275 1280 Arg Met Leu Leu Ile Glu Asn Leu Arg Glu Ser Gln Pro Tyr Arg Tyr                1285 1290 1295 Thr Val Lys Ala Arg Asn Gly Ala Gly Trp Gly Pro Glu Arg Glu Ala            1300 1305 1310 Ile Ile Asn Leu Ala Thr Gln Pro Lys Arg Pro Met Ser Ile Pro Ile        1315 1320 1325 Ile Pro Asp Ile Pro Ile Val Asp Ala Gln Ser Gly Glu Asp Tyr Asp    1330 1335 1340 Ser Phe Leu Met Tyr Ser Asp Asp Val Leu Arg Ser Ser Ser Gly Ser 1345 1350 1355 1360 Gln Arg Pro Ser Val Ser Asp Asp Thr Gly Cys Gly Trp Lys Phe Glu                1365 1370 1375 Pro Leu Leu Gly Glu Glu Leu Asp Leu Arg Arg Val Thr Trp Arg Leu            1380 1385 1390 Pro Pro Glu Leu Ile Pro Arg Leu Ser Ala Ser Ser Gly Arg Ser Ser        1395 1400 1405 Asp Ala Gly Ala Pro His Gly Pro Pro Asp Asp Gly Gly Ala Gly Gly    1410 1415 1420 Lys Gly Gly Ser Leu Pro Arg Ser Ala Thr Pro Gly Pro Pro Gly Glu 1425 1430 1435 1440 His Leu Val Asn Gly Arg Met Asp Phe Ala Phe Pro Gly Ser Thr Asn                1445 1450 1455 Ser Leu His Arg Met Thr Thr Thr Ser Ala Ala Ala Tyr Gly Thr His            1460 1465 1470 Leu Ser Pro His Val Pro His Arg Val Leu Ser Thr Ser Ser Thr Leu        1475 1480 1485 Thr Arg Asp Tyr Asn Ser Leu Thr Arg Ser Glu His Ser His Ser Thr    1490 1495 1500 Thr Leu Pro Arg Asp Tyr Ser Thr Leu Thr Ser Val Ser Ser His Asp 1505 1510 1515 1520 Ser Arg Leu Thr Ala Gly Val Pro Asp Thr Pro Thr Arg Leu Val Phe                1525 1530 1535 Ser Ala Leu Gly Pro Thr Ser Leu Arg Val Ser Trp Gln Glu Pro Arg            1540 1545 1550 Cys Glu Arg Pro Leu Gln Gly Tyr Ser Val Glu Tyr Gln Leu Leu Asn        1555 1560 1565 Gly Gly Glu Leu His Arg Leu Asn Ile Pro Asn Pro Ala Gln Thr Ser    1570 1575 1580 Val Val Val Glu Asp Leu Leu Pro Asn His Ser Tyr Val Phe Arg Val 1585 1590 1595 1600 Arg Ala Gln Ser Gln Glu Gly Trp Gly Arg Glu Arg Glu Gly Val Ile                1605 1610 1615 Thr Ile Glu Ser Gln Val His Pro Gln Ser Pro Leu Cys Pro Leu Pro            1620 1625 1630 Gly Ser Ala Phe Thr Leu Ser Thr Pro Ser Ala Pro Gly Pro Leu Val        1635 1640 1645 Phe Thr Ala Leu Ser Pro Asp Ser Leu Gln Leu Ser Trp Glu Arg Pro    1650 1655 1660 Arg Arg Pro Asn Gly Asp Ile Val Gly Tyr Leu Val Thr Cys Glu Met 1665 1670 1675 1680 Ala Gln Gly Gly Gly Pro Ala Thr Ala Phe Arg Val Asp Gly Asp Ser                1685 1690 1695 Pro Glu Ser Arg Leu Thr Val Pro Gly Leu Ser Glu Asn Val Pro Tyr            1700 1705 1710 Lys Phe Lys Val Gln Ala Arg Thr Thr Glu Gly Phe Gly Pro Glu Arg        1715 1720 1725 Glu Gly Ile Ile Thr Ile Glu Ser Gln Asp Gly Gly Pro Phe Pro Gln    1730 1735 1740 Leu Gly Ser Arg Ala Gly Leu Phe Gln His Pro Leu Gln Ser Glu Tyr 1745 1750 1755 1760 Ser Ser Ile Thr Thr Thr His Thr Ser Ala Thr Glu Pro Phe Leu Val                1765 1770 1775 Asp Gly Leu Thr Leu Gly Ala Gln His Leu Glu Ala Gly Gly Ser Leu            1780 1785 1790 Thr Arg His Val Thr Gln Glu Phe Val Ser Arg Thr Leu Thr Thr Ser        1795 1800 1805 Gly Thr Leu Ser Thr His Met Asp Gln Gln Phe Phe Gln Thr    1810 1815 1820 <210> 5 <211> 1805 <212> PRT <213> Homo sapiens <400> 5 Met Ala Gly Pro Arg Pro Ser Pro Trp Ala Arg Leu Leu Leu Ala Ala   1 5 10 15 Leu Ile Ser Val Ser Leu Ser Gly Thr Leu Ala Asn Arg Cys Lys Lys              20 25 30 Ala Pro Val Lys Ser Cys Thr Glu Cys Val Arg Val Asp Lys Asp Cys          35 40 45 Ala Tyr Cys Thr Asp Glu Met Phe Arg Asp Arg Arg Cys Asn Thr Gln      50 55 60 Ala Glu Leu Leu Ala Ala Gly Cys Gln Arg Glu Ser Ile Val Val Met  65 70 75 80 Glu Ser Ser Phe Gln Ile Thr Glu Glu Thr Gln Ile Asp Thr Thr Leu                  85 90 95 Arg Arg Ser Gln Met Ser Pro Gln Gly Leu Arg Val Val Arg Leu Arg Pro             100 105 110 Gly Glu Glu Arg His Phe Glu Leu Glu Val Phe Glu Pro Leu Glu Ser         115 120 125 Pro Val Asp Leu Tyr Ile Leu Met Asp Phe Ser Asn Ser Met Ser Asp     130 135 140 Asp Leu Asp Asn Leu Lys Lys Met Gly Gln Asn Leu Ala Arg Val Leu 145 150 155 160 Ser Gln Leu Thr Ser Asp Tyr Thr Ile Gly Phe Gly Lys Phe Val Asp                 165 170 175 Lys Val Ser Val Pro Gln Thr Asp Met Arg Pro Glu Lys Leu Lys Glu             180 185 190 Pro Trp Pro Asn Ser Asp Pro Pro Phe Ser Phe Lys Asn Val Ile Ser         195 200 205 Leu Thr Glu Asp Val Asp Glu Phe Arg Asn Lys Leu Gln Gly Glu Arg     210 215 220 Ile Ser Gly Asn Leu Asp Ala Pro Glu Gly Gly Phe Asp Ala Ile Leu 225 230 235 240 Gln Thr Ala Val Cys Thr Arg Asp Ile Gly Trp Arg Pro Asp Ser Thr                 245 250 255 His Leu Leu Val Phe Ser Thr Glu Ser Ala Phe His Tyr Glu Ala Asp             260 265 270 Gly Ala Asn Val Leu Ala Gly Ile Met Ser Arg Asn Asp Glu Arg Cys         275 280 285 His Leu Asp Thr Thr Gly Thr Tyr Thr Gln Tyr Arg Thr Gln Asp Tyr     290 295 300 Pro Ser Val Pro Thr Leu Val Arg Leu Leu Ala Lys His Asn Ile Ile 305 310 315 320 Pro Ile Phe Ala Val Thr Asn Tyr Ser Tyr Ser Tyr Tyr Glu Lys Leu                 325 330 335 His Thr Tyr Phe Pro Val Ser Ser Leu Gly Val Leu Gln Glu Asp Ser             340 345 350 Ser Asn Ile Val Glu Leu Leu Glu Glu Ala Phe Asn Arg Ile Arg Ser         355 360 365 Asn Leu Asp Ile Arg Ala Leu Asp Ser Pro Arg Gly Leu Arg Thr Glu     370 375 380 Val Thr Ser Lys Met Phe Gln Lys Thr Arg Thr Gly Ser Phe His Ile 385 390 395 400 Arg Arg Gly Glu Val Gly Ile Tyr Gln Val Gln Leu Arg Ala Leu Glu                 405 410 415 His Val Asp Gly Thr His Val Cys Gln Leu Pro Glu Asp Gln Lys Gly             420 425 430 Asn Ile His Leu Lys Pro Ser Phe Ser Asp Gly Leu Lys Met Asp Ala         435 440 445 Gly Ile Ile Cys Asp Val Cys Thr Cys Glu Leu Gln Lys Glu Val Arg     450 455 460 Ser Ala Arg Cys Ser Phe Asn Gly Asp Phe Val Cys Gly Gln Cys Val 465 470 475 480 Cys Ser Glu Gly Trp Ser Gly Gln Thr Cys Asn Cys Ser Thr Gly Ser                 485 490 495 Leu Ser Asp Ile Gln Pro Cys Leu Arg Glu Gly Glu Asp Lys Pro Cys             500 505 510 Ser Gly Arg Gly Glu Cys Gln Cys Gly His Cys Val Cys Tyr Gly Glu         515 520 525 Gly Arg Tyr Glu Gly Gln Phe Cys Glu Tyr Asp Asn Phe Gln Cys Pro     530 535 540 Arg Thr Ser Gly Phe Leu Cys Asn Asp Arg Gly Arg Cys Ser Met Gly 545 550 555 560 Gln Cys Val Cys Glu Pro Gly Trp Thr Gly Pro Ser Cys Asp Cys Pro                 565 570 575 Leu Ser Asn Ala Thr Cys Ile Asp Ser Asn Gly Gly Ile Cys Asn Gly             580 585 590 Arg Gly His Cys Glu Cys Gly Arg Cys His Cys His Gln Gln Ser Leu         595 600 605 Tyr Thr Asp Thr Ile Cys Glu Ile Asn Tyr Ser Ala Ile His Pro Gly     610 615 620 Leu Cys Glu Asp Leu Arg Ser Cys Val Gln Cys Gln Ala Trp Gly Thr 625 630 635 640 Gly Glu Lys Lys Gly Arg Thr Cys Glu Glu Cys Asn Phe Lys Val Lys                 645 650 655 Met Val Asp Glu Leu Lys Arg Ala Glu Glu Val Val Val Arg Cys Ser             660 665 670 Phe Arg Asp Glu Asp Asp Asp Cys Thr Tyr Ser Tyr Thr Met Glu Gly         675 680 685 Asp Gly Ala Pro Gly Pro Asn Ser Thr Val Leu Val His Lys Lys Lys     690 695 700 Asp Cys Pro Pro Gly Ser Phe Trp Trp Leu Ile Pro Leu Leu Leu Leu 705 710 715 720 Leu Leu Pro Leu Leu Ala Leu Leu Leu Leu Leu Cys Trp Lys Tyr Cys                 725 730 735 Ala Cys Cys Lys Ala Cys Leu Ala Leu Leu Pro Cys Cys Asn Arg Gly             740 745 750 His Met Val Gly Phe Lys Glu Asp His Tyr Met Leu Arg Glu Asn Leu         755 760 765 Met Ala Ser Asp His Leu Asp Thr Pro Met Leu Arg Ser Gly Asn Leu     770 775 780 Lys Gly Arg Asp Val Val Arg Trp Lys Val Thr Asn Asn Met Gln Arg 785 790 795 800 Pro Gly Phe Ala Thr His Ala Ala Ser Ile Asn Pro Thr Glu Leu Val                 805 810 815 Pro Tyr Gly Leu Ser Leu Arg Leu Ala Arg Leu Cys Thr Glu Asn Leu             820 825 830 Leu Lys Pro Asp Thr Arg Glu Cys Ala Gln Leu Arg Gln Glu Val Glu         835 840 845 Glu Asn Leu Asn Glu Val Tyr Arg Gln Ile Ser Gly Val His Lys Leu     850 855 860 Gln Gln Thr Lys Phe Arg Gln Gln Pro Asn Ala Gly Lys Lys Gln Asp 865 870 875 880 His Thr Ile Val Asp Thr Val Leu Met Ala Pro Arg Ser Ala Lys Pro                 885 890 895 Ala Leu Leu Lys Leu Thr Glu Lys Gln Val Glu Gln Arg Ala Phe His             900 905 910 Asp Leu Lys Val Ala Pro Gly Tyr Tyr Thr Leu Thr Ala Asp Gln Asp         915 920 925 Ala Arg Gly Met Val Glu Phe Gln Glu Gly Val Glu Leu Val Asp Val     930 935 940 Arg Val Pro Leu Phe Ile Arg Pro Glu Asp Asp Asp Glu Lys Gln Leu 945 950 955 960 Leu Val Glu Ala Ile Asp Val Ala Gly Thr Ala Thr Leu Gly Arg                 965 970 975 Arg Leu Val Asn Ile Thr Ile Ile Lys Glu Gln Ala Arg Asp Val Val             980 985 990 Ser Phe Glu Gln Pro Glu Phe Ser Val Ser Arg Gly Asp Gln Val Ala         995 1000 1005 Arg Ile Pro Val Ile Arg Arg Val Leu Asp Gly Gly Lys Ser Gln Val    1010 1015 1020 Ser Tyr Arg Thr Gln Asp Gly Thr Ala Gln Gly Asn Arg Asp Tyr Ile 1025 1030 1035 1040 Pro Val Glu Gly Glu Leu Leu Phe Gln Pro Gly Glu Ala Trp Lys Glu                1045 1050 1055 Leu Gln Val Lys Leu Leu Glu Leu Gln Glu Val Asp Ser Leu Leu Arg            1060 1065 1070 Gly Arg Gln Val Arg Arg Phe His Val Gln Leu Ser Asn Pro Lys Phe        1075 1080 1085 Gly Ala His Leu Gly Gln Pro His Thr Thr Ile Ile Ile Arg Asp    1090 1095 1100 Pro Asp Glu Leu Asp Arg Ser Phe Thr Ser Gln Met Leu Ser Ser Gln 1105 1110 1115 1120 Pro Pro Pro His Gly Asp Leu Gly Ala Pro Gln Asn Pro Asn Ala Lys                1125 1130 1135 Ala Ala Gly Ser Arg Lys Ile His Phe Asn Trp Leu Pro Pro Ser Gly            1140 1145 1150 Lys Pro Met Gly Tyr Arg Val Lys Tyr Trp Ile Gln Gly Asp Ser Glu        1155 1160 1165 Ser Glu Ala His Leu Leu Asp Ser Lys Val Pro Ser Val Glu Leu Thr    1170 1175 1180 Asn Leu Tyr Pro Tyr Cys Asp Tyr Glu Met Lys Val Cys Ala Tyr Gly 1185 1190 1195 1200 Ala Gln Gly Glu Gly Pro Tyr Ser Ser Leu Val Ser Cys Arg Thr His                1205 1210 1215 Gln Glu Val Pro Ser Glu Pro Gly Arg Leu Ala Phe Asn Val Val Ser            1220 1225 1230 Ser Thr Val Thr Gln Leu Ser Trp Ala Glu Pro Ala Glu Thr Asn Gly        1235 1240 1245 Glu Ile Thr Ala Tyr Glu Val Cys Tyr Gly Leu Val Asn Asp Asp Asn    1250 1255 1260 Arg Pro Ile Gly Pro Met Lys Lys Val Leu Val Asp Asn Pro Lys Asn 1265 1270 1275 1280 Arg Met Leu Leu Ile Glu Asn Leu Arg Glu Ser Gln Pro Tyr Arg Tyr                1285 1290 1295 Thr Val Lys Ala Arg Asn Gly Ala Gly Trp Gly Pro Glu Arg Glu Ala            1300 1305 1310 Ile Ile Asn Leu Ala Thr Gln Pro Lys Arg Pro Met Ser Ile Pro Ile        1315 1320 1325 Ile Pro Asp Ile Pro Ile Val Asp Ala Gln Ser Gly Glu Asp Tyr Asp    1330 1335 1340 Ser Phe Leu Met Tyr Ser Asp Asp Val Leu Arg Ser Ser Ser Gly Ser 1345 1350 1355 1360 Gln Arg Pro Ser Val Ser Asp Asp Thr Glu His Leu Val Asn Gly Arg                1365 1370 1375 Met Asp Phe Ala Phe Pro Gly Ser Thr Asn Ser Leu His Arg Met Thr            1380 1385 1390 Thr Thr Ser Ala Ala Tyr Gly Thr His Leu Ser Pro His Val Pro        1395 1400 1405 His Arg Val Leu Ser Thr Ser Ser Thr Leu Thr Arg Asp Tyr Asn Ser    1410 1415 1420 Leu Thr Arg Ser Glu His Ser Ser Thr Thr Leu Pro Arg Asp Tyr 1425 1430 1435 1440 Ser Thr Leu Thr Ser Val Ser Ser Gly Leu Pro Pro Ile Trp Glu                1445 1450 1455 His Gly Arg Ser Ser Leu Pro Leu Ser Trp Ala Leu Gly Ser Arg Ser            1460 1465 1470 Arg Ala Gln Met Lys Gly Phe Pro Pro Ser Arg Gly Pro Arg Asp Ser        1475 1480 1485 Ile Ile Leu Ala Gly Arg Pro Ala Ala Pro Ser Trp Gly Pro Asp Ser    1490 1495 1500 Arg Leu Thr Ala Gly Val Pro Asp Thr Pro Thr Arg Leu Val Phe Ser 1505 1510 1515 1520 Ala Leu Gly Pro Thr Ser Leu Arg Val Ser Trp Gln Glu Pro Arg Cys                1525 1530 1535 Glu Arg Pro Leu Gln Gly Tyr Ser Val Glu Tyr Gln Leu Leu Asn Gly            1540 1545 1550 Gly Glu Leu His Arg Leu Asn Ile Pro Asn Pro Ala Gln Thr Ser Val        1555 1560 1565 Val Val Glu Asp Leu Leu Pro Asn His Ser Tyr Val Phe Arg Val Arg    1570 1575 1580 Ala Gln Ser Gln Glu Gly Trp Gly Arg Glu Arg Glu Gly Val Ile Thr 1585 1590 1595 1600 Ile Glu Ser Gln Val His Pro Gln Ser Pro Leu Cys Pro Leu Pro Gly                1605 1610 1615 Ser Ala Phe Thr Leu Ser Thr Pro Ser Ala Pro Gly Pro Leu Val Phe            1620 1625 1630 Thr Ala Leu Ser Pro Asp Ser Leu Gln Leu Ser Trp Glu Arg Pro Arg        1635 1640 1645 Arg Pro Asn Gly Asp Ile Val Gly Tyr Leu Val Thr Cys Glu Met Ala    1650 1655 1660 Gln Gly Gly Gly Pro Ala Thr Ala Phe Arg Val Asp Gly Asp Ser Pro 1665 1670 1675 1680 Glu Ser Arg Leu Thr Val Pro Gly Leu Ser Glu Asn Val Pro Tyr Lys                1685 1690 1695 Phe Lys Val Gln Ala Arg Thr Thr Glu Gly Phe Gly Pro Glu Arg Glu            1700 1705 1710 Gly Ile Ile Thr Ile Glu Ser Gln Asp Gly Gly Pro Phe Pro Gln Leu        1715 1720 1725 Gly Ser Arg Ala Gly Leu Phe Gln His Pro Leu Gln Ser Glu Tyr Ser    1730 1735 1740 Ser Ile Thr Thr Thr Thr Ser Ala Thr Glu Pro Phe Leu Val Asp 1745 1750 1755 1760 Gly Leu Thr Leu Gly Ala Gln His Leu Glu Ala Gly Gly Ser Leu Thr                1765 1770 1775 Arg His Val Thr Gln Glu Phe Val Ser Arg Thr Leu Thr Thr Ser Gly            1780 1785 1790 Thr Leu Ser Thr His Met Asp Gln Gln Phe Phe Gln Thr        1795 1800 1805 <210> 6 <211> 1752 <212> PRT <213> Homo sapiens <400> 6 Met Ala Gly Pro Arg Pro Ser Pro Trp Ala Arg Leu Leu Leu Ala Ala   1 5 10 15 Leu Ile Ser Val Ser Leu Ser Gly Thr Leu Ala Asn Arg Cys Lys Lys              20 25 30 Ala Pro Val Lys Ser Cys Thr Glu Cys Val Arg Val Asp Lys Asp Cys          35 40 45 Ala Tyr Cys Thr Asp Glu Met Phe Arg Asp Arg Arg Cys Asn Thr Gln      50 55 60 Ala Glu Leu Leu Ala Ala Gly Cys Gln Arg Glu Ser Ile Val Val Met  65 70 75 80 Glu Ser Ser Phe Gln Ile Thr Glu Glu Thr Gln Ile Asp Thr Thr Leu                  85 90 95 Arg Arg Ser Gln Met Ser Pro Gln Gly Leu Arg Val Val Arg Leu Arg Pro             100 105 110 Gly Glu Glu Arg His Phe Glu Leu Glu Val Phe Glu Pro Leu Glu Ser         115 120 125 Pro Val Asp Leu Tyr Ile Leu Met Asp Phe Ser Asn Ser Met Ser Asp     130 135 140 Asp Leu Asp Asn Leu Lys Lys Met Gly Gln Asn Leu Ala Arg Val Leu 145 150 155 160 Ser Gln Leu Thr Ser Asp Tyr Thr Ile Gly Phe Gly Lys Phe Val Asp                 165 170 175 Lys Val Ser Val Pro Gln Thr Asp Met Arg Pro Glu Lys Leu Lys Glu             180 185 190 Pro Trp Pro Asn Ser Asp Pro Pro Phe Ser Phe Lys Asn Val Ile Ser         195 200 205 Leu Thr Glu Asp Val Asp Glu Phe Arg Asn Lys Leu Gln Gly Glu Arg     210 215 220 Ile Ser Gly Asn Leu Asp Ala Pro Glu Gly Gly Phe Asp Ala Ile Leu 225 230 235 240 Gln Thr Ala Val Cys Thr Arg Asp Ile Gly Trp Arg Pro Asp Ser Thr                 245 250 255 His Leu Leu Val Phe Ser Thr Glu Ser Ala Phe His Tyr Glu Ala Asp             260 265 270 Gly Ala Asn Val Leu Ala Gly Ile Met Ser Arg Asn Asp Glu Arg Cys         275 280 285 His Leu Asp Thr Thr Gly Thr Tyr Thr Gln Tyr Arg Thr Gln Asp Tyr     290 295 300 Pro Ser Val Pro Thr Leu Val Arg Leu Leu Ala Lys His Asn Ile Ile 305 310 315 320 Pro Ile Phe Ala Val Thr Asn Tyr Ser Tyr Ser Tyr Tyr Glu Lys Leu                 325 330 335 His Thr Tyr Phe Pro Val Ser Ser Leu Gly Val Leu Gln Glu Asp Ser             340 345 350 Ser Asn Ile Val Glu Leu Leu Glu Glu Ala Phe Asn Arg Ile Arg Ser         355 360 365 Asn Leu Asp Ile Arg Ala Leu Asp Ser Pro Arg Gly Leu Arg Thr Glu     370 375 380 Val Thr Ser Lys Met Phe Gln Lys Thr Arg Thr Gly Ser Phe His Ile 385 390 395 400 Arg Arg Gly Glu Val Gly Ile Tyr Gln Val Gln Leu Arg Ala Leu Glu                 405 410 415 His Val Asp Gly Thr His Val Cys Gln Leu Pro Glu Asp Gln Lys Gly             420 425 430 Asn Ile His Leu Lys Pro Ser Phe Ser Asp Gly Leu Lys Met Asp Ala         435 440 445 Gly Ile Ile Cys Asp Val Cys Thr Cys Glu Leu Gln Lys Glu Val Arg     450 455 460 Ser Ala Arg Cys Ser Phe Asn Gly Asp Phe Val Cys Gly Gln Cys Val 465 470 475 480 Cys Ser Glu Gly Trp Ser Gly Gln Thr Cys Asn Cys Ser Thr Gly Ser                 485 490 495 Leu Ser Asp Ile Gln Pro Cys Leu Arg Glu Gly Glu Asp Lys Pro Cys             500 505 510 Ser Gly Arg Gly Glu Cys Gln Cys Gly His Cys Val Cys Tyr Gly Glu         515 520 525 Gly Arg Tyr Glu Gly Gln Phe Cys Glu Tyr Asp Asn Phe Gln Cys Pro     530 535 540 Arg Thr Ser Gly Phe Leu Cys Asn Asp Arg Gly Arg Cys Ser Met Gly 545 550 555 560 Gln Cys Val Cys Glu Pro Gly Trp Thr Gly Pro Ser Cys Asp Cys Pro                 565 570 575 Leu Ser Asn Ala Thr Cys Ile Asp Ser Asn Gly Gly Ile Cys Asn Gly             580 585 590 Arg Gly His Cys Glu Cys Gly Arg Cys His Cys His Gln Gln Ser Leu         595 600 605 Tyr Thr Asp Thr Ile Cys Glu Ile Asn Tyr Ser Ala Ile His Pro Gly     610 615 620 Leu Cys Glu Asp Leu Arg Ser Cys Val Gln Cys Gln Ala Trp Gly Thr 625 630 635 640 Gly Glu Lys Lys Gly Arg Thr Cys Glu Glu Cys Asn Phe Lys Val Lys                 645 650 655 Met Val Asp Glu Leu Lys Arg Ala Glu Glu Val Val Val Arg Cys Ser             660 665 670 Phe Arg Asp Glu Asp Asp Asp Cys Thr Tyr Ser Tyr Thr Met Glu Gly         675 680 685 Asp Gly Ala Pro Gly Pro Asn Ser Thr Val Leu Val His Lys Lys Lys     690 695 700 Asp Cys Pro Pro Gly Ser Phe Trp Trp Leu Ile Pro Leu Leu Leu Leu 705 710 715 720 Leu Leu Pro Leu Leu Ala Leu Leu Leu Leu Leu Cys Trp Lys Tyr Cys                 725 730 735 Ala Cys Cys Lys Ala Cys Leu Ala Leu Leu Pro Cys Cys Asn Arg Gly             740 745 750 His Met Val Gly Phe Lys Glu Asp His Tyr Met Leu Arg Glu Asn Leu         755 760 765 Met Ala Ser Asp His Leu Asp Thr Pro Met Leu Arg Ser Gly Asn Leu     770 775 780 Lys Gly Arg Asp Val Val Arg Trp Lys Val Thr Asn Asn Met Gln Arg 785 790 795 800 Pro Gly Phe Ala Thr His Ala Ala Ser Ile Asn Pro Thr Glu Leu Val                 805 810 815 Pro Tyr Gly Leu Ser Leu Arg Leu Ala Arg Leu Cys Thr Glu Asn Leu             820 825 830 Leu Lys Pro Asp Thr Arg Glu Cys Ala Gln Leu Arg Gln Glu Val Glu         835 840 845 Glu Asn Leu Asn Glu Val Tyr Arg Gln Ile Ser Gly Val His Lys Leu     850 855 860 Gln Gln Thr Lys Phe Arg Gln Gln Pro Asn Ala Gly Lys Lys Gln Asp 865 870 875 880 His Thr Ile Val Asp Thr Val Leu Met Ala Pro Arg Ser Ala Lys Pro                 885 890 895 Ala Leu Leu Lys Leu Thr Glu Lys Gln Val Glu Gln Arg Ala Phe His             900 905 910 Asp Leu Lys Val Ala Pro Gly Tyr Tyr Thr Leu Thr Ala Asp Gln Asp         915 920 925 Ala Arg Gly Met Val Glu Phe Gln Glu Gly Val Glu Leu Val Asp Val     930 935 940 Arg Val Pro Leu Phe Ile Arg Pro Glu Asp Asp Asp Glu Lys Gln Leu 945 950 955 960 Leu Val Glu Ala Ile Asp Val Ala Gly Thr Ala Thr Leu Gly Arg                 965 970 975 Arg Leu Val Asn Ile Thr Ile Ile Lys Glu Gln Ala Arg Asp Val Val             980 985 990 Ser Phe Glu Gln Pro Glu Phe Ser Val Ser Arg Gly Asp Gln Val Ala         995 1000 1005 Arg Ile Pro Val Ile Arg Arg Val Leu Asp Gly Gly Lys Ser Gln Val    1010 1015 1020 Ser Tyr Arg Thr Gln Asp Gly Thr Ala Gln Gly Asn Arg Asp Tyr Ile 1025 1030 1035 1040 Pro Val Glu Gly Glu Leu Leu Phe Gln Pro Gly Glu Ala Trp Lys Glu                1045 1050 1055 Leu Gln Val Lys Leu Leu Glu Leu Gln Glu Val Asp Ser Leu Leu Arg            1060 1065 1070 Gly Arg Gln Val Arg Arg Phe His Val Gln Leu Ser Asn Pro Lys Phe        1075 1080 1085 Gly Ala His Leu Gly Gln Pro His Thr Thr Ile Ile Ile Arg Asp    1090 1095 1100 Pro Asp Glu Leu Asp Arg Ser Phe Thr Ser Gln Met Leu Ser Ser Gln 1105 1110 1115 1120 Pro Pro Pro His Gly Asp Leu Gly Ala Pro Gln Asn Pro Asn Ala Lys                1125 1130 1135 Ala Ala Gly Ser Arg Lys Ile His Phe Asn Trp Leu Pro Pro Ser Gly            1140 1145 1150 Lys Pro Met Gly Tyr Arg Val Lys Tyr Trp Ile Gln Gly Asp Ser Glu        1155 1160 1165 Ser Glu Ala His Leu Leu Asp Ser Lys Val Pro Ser Val Glu Leu Thr    1170 1175 1180 Asn Leu Tyr Pro Tyr Cys Asp Tyr Glu Met Lys Val Cys Ala Tyr Gly 1185 1190 1195 1200 Ala Gln Gly Glu Gly Pro Tyr Ser Ser Leu Val Ser Cys Arg Thr His                1205 1210 1215 Gln Glu Val Pro Ser Glu Pro Gly Arg Leu Ala Phe Asn Val Val Ser            1220 1225 1230 Ser Thr Val Thr Gln Leu Ser Trp Ala Glu Pro Ala Glu Thr Asn Gly        1235 1240 1245 Glu Ile Thr Ala Tyr Glu Val Cys Tyr Gly Leu Val Asn Asp Asp Asn    1250 1255 1260 Arg Pro Ile Gly Pro Met Lys Lys Val Leu Val Asp Asn Pro Lys Asn 1265 1270 1275 1280 Arg Met Leu Leu Ile Glu Asn Leu Arg Glu Ser Gln Pro Tyr Arg Tyr                1285 1290 1295 Thr Val Lys Ala Arg Asn Gly Ala Gly Trp Gly Pro Glu Arg Glu Ala            1300 1305 1310 Ile Ile Asn Leu Ala Thr Gln Pro Lys Arg Pro Met Ser Ile Pro Ile        1315 1320 1325 Ile Pro Asp Ile Pro Ile Val Asp Ala Gln Ser Gly Glu Asp Tyr Asp    1330 1335 1340 Ser Phe Leu Met Tyr Ser Asp Asp Val Leu Arg Ser Ser Ser Gly Ser 1345 1350 1355 1360 Gln Arg Pro Ser Val Ser Asp Asp Thr Glu His Leu Val Asn Gly Arg                1365 1370 1375 Met Asp Phe Ala Phe Pro Gly Ser Thr Asn Ser Leu His Arg Met Thr            1380 1385 1390 Thr Thr Ser Ala Ala Tyr Gly Thr His Leu Ser Pro His Val Pro        1395 1400 1405 His Arg Val Leu Ser Thr Ser Ser Thr Leu Thr Arg Asp Tyr Asn Ser    1410 1415 1420 Leu Thr Arg Ser Glu His Ser Ser Thr Thr Leu Pro Arg Asp Tyr 1425 1430 1435 1440 Ser Thr Leu Thr Ser Val Ser Ser His His Ser Ser Leu Thr Ala Gly                1445 1450 1455 Val Pro Asp Thr Pro Thr Arg Leu Val Phe Ser Ala Leu Gly Pro Thr            1460 1465 1470 Ser Leu Arg Val Ser Trp Gln Glu Pro Arg Cys Glu Arg Pro Leu Gln        1475 1480 1485 Gly Tyr Ser Val Glu Tyr Gln Leu Leu Asn Gly Gly Glu Leu His Arg    1490 1495 1500 Leu Asn Ile Pro Asn Pro Ala Gln Thr Ser Val Val Val Glu Asp Leu 1505 1510 1515 1520 Leu Pro Asn His Ser Tyr Val Phe Arg Val Ala Gln Ser Gln Glu                1525 1530 1535 Gly Trp Gly Arg Glu Arg Glu Gly Val Ile Thr Ile Glu Ser Gln Val            1540 1545 1550 His Pro Gln Ser Pro Leu Cys Pro Leu Pro Gly Ser Ala Phe Thr Leu        1555 1560 1565 Ser Thr Pro Ser Ala Pro Gly Pro Leu Val Phe Thr Ala Leu Ser Pro    1570 1575 1580 Asp Ser Leu Gln Leu Ser Trp Glu Arg Pro Arg Arg Pro Asn Gly Asp 1585 1590 1595 1600 Ile Val Gly Tyr Leu Val Thr Cys Glu Met Ala Gln Gly Gly Gly Pro                1605 1610 1615 Ala Thr Ala Phe Arg Val Asp Gly Asp Ser Pro Glu Ser Arg Leu Thr            1620 1625 1630 Val Pro Gly Leu Ser Glu Asn Val Pro Tyr Lys Phe Lys Val Gln Ala        1635 1640 1645 Arg Thr Thr Gly Gly Phe Gly Pro Glu Arg Glu Gly Ile Ile Thr Ile    1650 1655 1660 Glu Ser Gln Asp Gly Gly Pro Phe Pro Gln Leu Gly Ser Arg Ala Gly 1665 1670 1675 1680 Leu Phe Gln His Pro Leu Gln Ser Glu Tyr Ser Ser Ile Thr Thr Thr                1685 1690 1695 His Thr Ser Ala Thr Glu Pro Phe Leu Val Asp Gly Leu Thr Leu Gly            1700 1705 1710 Ala Gln His Leu Glu Ala Gly Gly Ser Leu Thr Arg His Val Thr Gln        1715 1720 1725 Glu Phe Val Ser Arg Thr Leu Thr Thr Ser Gly Thr Leu Ser Thr His    1730 1735 1740 Met Asp Gln Gln Phe Phe Gln Thr 1745 1750 <210> 7 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> ITGB4 si <400> 7 cugguaaaca ucaccauca 19 <210> 8 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> ITGB4 si <400> 8 ugauggugau guuuaccag 19 <210> 9 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Control si <400> 9 ccuacgccac caauuucgu 19 <210> 10 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Control si <400> 10 acgaaauugg uggcguagg 19

Claims (9)

An integrin beta 4 (ITGB4) gene or a protein encoded by said gene.
The method of claim 1, wherein the inhibitor is at least one selected from the group consisting of an antisense nucleotide complementary to the mRNA of the ITGB4 gene, siRNA (short interfering RNA), shRNA (short hairpin RNA) and ribozyme , Composition for inhibiting tumor cell senescence.
The method according to claim 1, wherein the inhibitor is at least one selected from the group consisting of a compound that binds complementarily to the ITGB4 protein, a peptide, a peptide mimetic, an aptamer, a substrate analog, and an antibody. Composition.
The composition for inhibiting tumor cell senescence according to claim 3, wherein the antibody that binds complementarily to the ITGB4 protein is Asc-8.
The composition for inhibiting tumor cell senescence according to claim 1, wherein the tumor cell is a breast cancer or a lung cancer cell.
6. The composition for inhibiting tumor cell senescence according to any one of claims 1 to 5, wherein said aging is induced by radiation.
The composition for inhibiting tumor cell senescence according to claim 6, wherein the radiation is gamma rays.
A method of modulating tumor senescence comprising the step of treating an integrin beta 4 (ITGB4) gene or an inhibitor of a protein encoded by said gene in a tumor cell.
(a) measuring the degree of ITGB4 (integrin beta 4) phosphorylation after treating a sample in tumor cells; And
(b) screening the tumor cells of step (a) for increased levels of ITGB4 phosphorylation relative to a control group not treated with the sample.

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