WO1999063083A1 - Nouveau gene et proteine codee par ce gene - Google Patents

Nouveau gene et proteine codee par ce gene Download PDF

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Publication number
WO1999063083A1
WO1999063083A1 PCT/JP1999/002813 JP9902813W WO9963083A1 WO 1999063083 A1 WO1999063083 A1 WO 1999063083A1 JP 9902813 W JP9902813 W JP 9902813W WO 9963083 A1 WO9963083 A1 WO 9963083A1
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WIPO (PCT)
Prior art keywords
sequence
gene
hair
protein
derp2
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PCT/JP1999/002813
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English (en)
Japanese (ja)
Inventor
Akiko Ikeda
Megumi Yamashita
Katsuki Tsuritani
Makoto Yoshimoto
Seiji Arase
Original Assignee
Taisho Pharmaceutical Co., Ltd.
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Publication date
Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU39550/99A priority Critical patent/AU3955099A/en
Publication of WO1999063083A1 publication Critical patent/WO1999063083A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity

Definitions

  • the present invention relates to a novel protein having a function of regulating hair growth, such as DERP (dermalpapilladel erotein) 2, and a gene derp2 encoding the protein.
  • DERP dermalpapilladel erotein
  • Human hair follicles contain various epithelial and dermal cells such as keratinocytes, dermal papilla cells, fibroblasts and sebaceous cells, and the hair cycle (hair growth cycle) Is regulated through cell-cell interactions.
  • hair follicle keratinocytes produce the hair fibers
  • hair papilla cells are thought to play a central role in regulating the proliferation and differentiation of these cells. Have been. In other words, it is thought that the papilla cells function as a controller of the hair cycle.
  • the analysis of the mechanism of hair cycle regulation centering on the dermal papilla is currently being actively conducted, but the molecular mechanism of hair growth has not yet been elucidated.
  • Hair papilla cells express high levels of the andorogen receptor and the testosterone-metabolizing enzyme 5a-reductase, and the expression of androgen receptors in hair papilla cells is higher than that of the hair growth area. Due to high levels in the cervix, the major target cell for androgens in hair follicles is thought to be the dermal papilla cells. In other words, androgen is thought to act on the hair papilla and regulate hair growth by altering the production of factors such as hair papilla cell-derived factors.
  • An object of the present invention is to provide a novel protein and a gene thereof capable of regulating such hair growth in the process of elucidating the molecular mechanism related to hair growth. Disclosure of the invention
  • the present inventors aimed to identify factors involved in hair growth, and as a result of intensive studies to determine the desired protein from genes highly expressed in human hair papilla cells, the novel protein DERP 2
  • the present inventors succeeded in isolating the gene derp 2 encoding the gene and completed the present invention.
  • the present invention relates to (a) a protein comprising the amino acid sequence of SEQ ID NO: 1, or (b) an amino acid in which one or several amino acids have been deleted, substituted or added in the amino acid sequence of SEQ ID NO: 1.
  • the present invention relates to a protein comprising a sequence and having a function of regulating hair growth.
  • the present invention relates to (c) a gene comprising the DNA of SEQ ID NO: 2 or (d) a DNA that hybridizes with the DNA of SEQ ID NO: 2 under stringent conditions and regulates hair growth.
  • the present invention relates to a gene comprising DNA encoding a protein having
  • DERP2 of the present invention is a protein having a molecular weight of 37 kilodaltons (kd) consisting of 345 amino acid residues as shown in SEQ ID NO: 1.
  • kd kilodaltons
  • SEQ ID NO: 1 As a feature of the amino acid sequence, a region rich in hydrophobic amino acids is observed at a plurality of sites, and it is presumed that the region is a type of membrane protein.
  • derp2 of the present invention is a gene consisting of 130 base pairs (bp) as shown in SEQ ID NO: 2.
  • the gene derp2 can be isolated as a cDNA fragment containing the gene from a cDNA library derived from human dermal papilla cells.
  • the cDNA library used by the present inventors was prepared by extracting mRNA extracted from human papillary cells isolated according to the method of Messenger et al. (Br. J. Dermatol. 114, 425, 1986) according to a general method. Although prepared on the basis of cDNA, cDNA can also be prepared in the same manner based on human cerebral cortex mRNA commercially available from Clonetech.
  • Human mRNA was derived from human dermal papilla cells, and the cDNA was synthesized using type I as the primer, oligo dT bound to one end of plasmid, which was opened with an appropriate restriction enzyme. Cleavage with restriction enzymes MboI and BamHI. Since this vector was prepared using dam methylase-positive Escherichia coli as a host, the A residue of “GATC”, which is the recognition sequence of Mb0I, is methylated. Thus, Mbol only cleaves the newly synthesized cDNA portion.
  • the enzyme cuts the vector at one position and If the BamHI recognition sequence is present in the cDNA portion synthesized in step 2, the site is also cleaved.
  • BamH I and Mbo I are composed of the sequence ⁇ GATC '' and generate the same cohesive end.Cleavage with both enzymes and then closing of plasmid by the action of DNA ligase. be able to.
  • Escherichia coli was transformed to construct a 3′-end cDNA library.
  • the library includes a region from the poly A site at the 3 ′ end of each mRNA to the site where the base sequence GATC first appears in the 5 ′ side thereof.
  • An appropriate number of recombinants are randomly selected from the 3′-end cDNA library, and the entire nucleotide sequence of the cDNA fragment in each recombinant is determined.
  • An organ-specific gene and a high-expressing gene can be identified based on how many of the cDNA fragments having the specific sequence determined in this way are confirmed from randomly selected recombinants.
  • the total number of recombinants selected at random is suitably several hundreds to about 1,000, but if necessary, more recombinants may be processed.
  • the present inventors carried out the above method, determined all the nucleotide sequences of the cDNA fragments in the 789 recombinants, and determined from them the frequency of appearance as cDNA having the same sequence.
  • the cDNA fragment of 37989 was selected as a candidate for a DNA fragment of a gene highly expressed in human papillary cells.
  • the cDNA fragment contains only a part of the 3 ′ end region of mRNA. Therefore, the present inventors based on the nucleotide sequence information of the region (hereinafter, 3 ′ fragment). Then, the total chain length cDNA was obtained.
  • a human cerebral cortex cDNA library commercially available from Clonetech is a rust type, and an oligonucleotide of an appropriate length having the sequence in the 3 ′ fragment and a comparable length having a sequence in the vector are used. Each oligonucleotide was synthesized, and PCR was performed using these as primers. As a result, a DNA fragment of about 1.5 kb could be amplified. At this time, it can also be carried out by using mRNA extracted from human cultured hair papilla cells according to a conventional method as type III and using a 5 'RACE kit of Clonetech or Gibco. In addition, screening of the human cerebral cortex or dermal papilla cell cDNA library by colony hybridization or plaque hybridization using the above 3 ′ fragment as a probe in accordance with a standard method. Can also be performed.
  • the cDNA fragment amplified by the above method was incorporated into vector pGEM-T commercially available from Promega, and the entire nucleotide sequence was determined. At this time, the sequence was confirmed by independently obtaining two clones of the recombinant DNA and determining the nucleotide sequence of each cDNA fragment.
  • One protein translation region Open Reading Flame, ORF was found in this sequence, the gene was designated as derp2, and the protein encoded by the gene was designated as DERP2.
  • the gene derp 2 can be made into a recombinant gene by a general gene recombination technique using an appropriate host vector system.
  • Suitable vectors include plasmids derived from Escherichia coli (eg, pBR322, pUC118, etc.), and plasmids derived from Bacillus subtilis (eg, pUB110, pC194). Others), yeast-derived plasmids (eg, pSH19 and others), and animal viruses such as bacteriophages, retroviruses and vaccinia viruses can be used.
  • a translation initiation codon and a translation termination codon can be added using an appropriate synthetic DNA adapter.
  • an appropriate expression promoter is connected upstream of the gene.
  • the promoter to be used may be appropriately selected depending on the host. For example, when the host is Escherichia coli, the T7 promoter, 1 ac promoter, trp promoter, and ⁇ PL promoter are used, and when the host is Bacillus, the S ⁇ 0 promoter is used. If the host is yeast, the 5 promoters, the GAP promoters, the ADH promoter, etc. In the case of vesicles, SV40-derived promoters and retrovirus promoters can be used, respectively.
  • the gene it is also possible to express the gene as a fusion protein with another protein (eg, Dalphin thione S transferase, protein A, etc.).
  • the fused DERRP2 expressed in this manner can be excised using an appropriate protease (eg, thrombin or the like).
  • Hosts that can be used for expression of DERP 2 include various strains of cherichia il, a bacterium belonging to the genus Escherichia, various strains of Baci 1 lus subti 1 is, a bacterium belonging to the genus Bacillus, and various strains of Saccharomyces cerevi siae as yeast.
  • animal cells COS-7 cells, CHO cells and the like can be used.
  • a method for transforming a host cell using the above-described recombinant vector a conventional method or a transformation method generally used for each host cell can be applied.
  • a DNA that hybridizes with the sequence and encodes a protein having a function of regulating hair growth is also included in the scope of the present invention. It is.
  • the degree of the above-mentioned DNA mutation is within an allowable range as long as it has 90% or more homology with the DNA sequence of the gene derp2.
  • the degree of hybridization with the gene derp 2 was determined at 32 ° C when the probe was labeled under normal conditions (eg, DIG DNA Labeling kit, Bellinger's Mannheim Cat No. 1175033). Hybridize in DIG Easy Hyb solution (Behringer's Mannheim Cat No. 1603558) and remove membrane in 0.5 XSSC solution (containing 0.1% [w / V] SDS) at 50 ° C. Southern hybridization under washing conditions (1 XSSC is 0.15M NaC 0.015M sodium citrate) In this case, it is only necessary to hybridize to the gene derp2.
  • a protein encoded by a mutant gene having high homology to the gene derp2 as described above and having a function of regulating hair growth is also within the scope of the present invention.
  • the mutant has a function of regulating hair growth.
  • the mutant is within the scope of the present invention.
  • the side chains of amino acids that are constituents of the protein are different in hydrophobicity, charge, size, etc., but are substantially different in the entire protein.
  • the mutant protein is a mutant protein resulting from substitution, insertion, deletion, etc. in the amino acid sequence of the novel protein DERP 2 shown in SEQ ID NO: 1, the mutation is a mutation that is highly conserved in the three-dimensional structure of the DERP 2 protein. If the mutant protein has a function of regulating hair growth like DERP2, these can be said to be within the scope of the present invention.
  • the degree of mutation is within the acceptable range if the homology with the amino acid sequence shown in SEQ ID NO: 1 is 90% or more.
  • DERP 2 Since DERP 2 has a function of regulating hair growth, it is presumed that abnormal expression of the gene derP2 or abnormal expression of DERP 2 activity affects hair growth. Therefore, a substance that regulates the expression of the gene or a substance that regulates the function of DERP 2 can be expected as a hair-growing agent or a hair-restoring agent, and the gene derp 2 and the protein DERP 2 have such physiological activities.
  • the effect of a test substance on gene expression can be investigated by coexisting a test substance in the transcriptional expression system of gene derp 2 and detecting the expression level of gene derp 2 by an appropriate method such as PCR. it can. It is also possible to search for a bioactive protein that directly acts on DERP 2 and controls the function of DERP 2 to regulate hair growth.
  • Human hair papilla cells were isolated from the hair follicles of the hair growth part scalp of a healthy male (30 years old) according to the method of Messenger et al. (Br. J. Dermatol. 114, 425, 1986) and cultured. Remove the dermal papilla from the lower part of the hair follicle, place it in a Petri dish containing MEM medium supplemented with 12% fetal bovine serum (FBS), and add 5% C02Z 95% air, 37 ° C C ⁇ 2 ink. The cells were cultured overnight for 7 days. Outgrowth cells from the dermal papilla were collected using a 0.05% trypsin-0.53 mM EDTA solution. The separated hair papilla cells were subcultured in the same medium, and the cells at the fourth and fifth passages were used for the experiment.
  • a 3′-terminal cD ⁇ library was prepared according to the method of Okubo et al. (Okuboei al. Nature Genet., 1992, 2, ⁇ 3). 789 recombinants were randomly selected from the library, and the nucleotide sequence of the cDNA portion was determined.
  • DNA sequencing PRISM377, manufactured by ABI
  • a reaction kit manufactured by ABI were used.
  • oligonucleotide 12 in FIG. 1 which is a reverse complementary strand to a part of sequence-1 was synthesized using a DNA synthesizer (380B manufactured by ABI).
  • oligonucleotide 13 in FIG. 1 having a sequence in the vicinity of the cDNA insertion site of lambda phage cloning vector-1 (ADR2) was similarly synthesized.
  • Human Brain cerebral cortex 5'-STRETCH cDNA library (manufactured by Clontech Laboratories) using ⁇ DR 2 as a closing vector is designated as type II, and oligonucleotides of sequence 12 and sequence 13 are used as primers.
  • the following PCR procedures were performed using the evening PCR LA PCR Kit Ver.2 and PCR Thermocycla MP (both from Takara Shuzo).
  • PCR cycle After holding at 94 ° C for 2 minutes, react at 98 ° C for 20 seconds, cool to 68 ° C at a rate of 1 ° C for 2 seconds, and heat at 68 ° C for 3 minutes. The holding was further performed 30 times at 72 ° C. for 10 minutes.
  • the DNA fragment amplified in 3 was fractionated by agarose gel electrophoresis (gel concentration 1%). The gel was stained with ethidium bromide and irradiated with ultraviolet light to cut out the gel containing the target band. Extraction and purification of the DNA fragment from the agarose gel was performed using GENECLEAN II Kit (Bio101).
  • the extracted and purified DNA fragment was used as a base sequence determination vector pGEM-T (Promega (Fig. 3).
  • the ligation solution was used for evening color DNA Ligation Kit Ver.2 (Takara Shuzo) and reacted at 16 C for 1.5 hours with the following composition.
  • Escherichia coli K12 strain DH5 was transformed. Transformants were treated with ampicillin (Amp) 50 M g / r 1.5-Bromo-4-Chloro-3-indolyl ⁇ -D-galactose 40 g / m 1> Isopropyl— ⁇ -D-Thio It was plated on an LB agar medium containing -Ga1ac topyranosidel 100 ⁇ M and cultured at 37 ° C.
  • the colonies that appeared in the above plate were inoculated into 10 ml of an LB liquid medium containing 50 // g / m1 Amp, cultured at 37 ° C overnight, and the cells were collected by centrifugation. After that, the recombinant DNA was purified using QIAprep Spin Plasmid Miniprep Kit (Qiagen).
  • DNA sequencer PRISM377, manufactured by ABI
  • Oligonucleotides were synthesized based on the determined base sequences, and the entire base sequences of both strands were determined by the primer walking method (Fig. 4).
  • SEQ ID NO: 3 shows the entire nucleotide sequence of cDNA of the clone. Since the nucleotide sequence contained the upstream region of sequence 12 of sequence-2 and sequence-1, it was confirmed that the target gene clerp2 was cloned.
  • the cDNA comprises an ORF encoding a protein consisting of 345 residues (DERP2) (SEQ ID NO: 3). Since a stop codon appeared in the same reading frame in the upstream region of the methionine residue which is the start codon of the protein, the amino acid sequence of the protein encoded by the cDNA fragment was that shown in SEQ ID NO: 3. It was confirmed that it was the only one.
  • Test Example 1 Antibody staining of dermal papilla cells
  • the anti-peptide antibody is based on the Cell Engineering Separate Volume Anti-Peptide Antibody Experimental Protocol (Onami Shinobu, (Kunio Tsujimura, Shujunsha).
  • a peptide containing a part of the amino acid sequence of DERP2 (sequence 14 in Fig. 1) was synthesized using a peptide synthesizer (manufactured by ABI), and this was cross-linked to the carrier protein by molysin-mediated method with maleimide. And used as antigen.
  • 0.5 mg of this antigen was injected subcutaneously into the back of a egret (Kb1: JW, 10-year-old, female).
  • Hair papilla cells separated and cultured in Example 1 were seeded in an 8-well chamber slide (Nunc) at 1.5 104 ce 11 s / we 11 and a MEM medium supplemented with 12% FBS. In it, it was cultured. The medium was removed and the cells were fixed with 4% paraformaldehyde-0.25% Tween 20 for 15 minutes at room temperature. This was treated with 5 ⁇ g Zm1 of the anti-DERP2 peptide at ⁇ 4 ° C., reacted with a biotinylated anti-rabbit IgG antibody, and developed with an AEC staining kit (manufactured by Sigma). Was. The results are shown in FIG. The organelles around the nucleus of the dermal papilla cells (area of ER-Golgi) were strongly stained.
  • RNA was extracted by the method. After treating each total RNA l / g with 1 unit (U) of DNaseI (Gibco BRL), use 01 igo (dT) 12--18 Primer (GIBCO BRL) and Superscriptll (GIBCO BRU). CDNA was synthesized according to the protocol attached to Superscript II. The cDNA was converted into type I, and a derp2-specific primer synthesized using a DNA synthesizer (ABI 380B) (Fig. 1). The following PCR was carried out using the sequences 1 and 6) in a total amount of 40 ⁇ l. cDNA 40ng
  • the reaction mixture (6 il) was subjected to electrophoresis using a 12% polyacrylamide gel, and the gel was dried.
  • the radioactivity incorporated into the amplified derp 2 fragment was analyzed using BAS-2000II (Fujifilm). It was measured.
  • the amount of derp2 mRNA was expressed as a relative value to Libosomal protein S26 used as an internal standard after the measured radioactivity was corrected for the dCTP content in the amplified product.
  • Fig. 6 shows the results.
  • Hair papilla cells derived from bald areas of patients with androgenetic alopecia had higher expression of derp2mRNA than hair papilla cells derived from the hair growth region of healthy individuals.
  • Example 2 In the same manner as in Example 1, a male patient with alopecia (38 years old) was isolated and cultured for hair papilla cells derived from the hair growth part. The cells at the fifth passage were seeded to a 2 ⁇ 10 5 c e 11 s 6 cm scale and cultured until they reached confluence. Thereafter, the medium was replaced with a testosterone-supplemented medium (0, 10, 50, 250 nM), and the cells were further cultured for 24 to 72 hours. After removing the medium, the cells were washed with PBS (-) to extract total RNA. The following ⁇ CR was carried out using 40 ng of cDNA prepared in the same manner as in 5) of Example 1 and using primers of Sequence-5 and Sequence-16 in a total amount of 201.
  • the reaction solution was subjected to electrophoresis using a 2% agarose gel and stained with ethidium mouth. The results are shown in FIG. It was confirmed that the culture to which testosterone was added at 50 nM or more increased the expression level of the gene derp2 in the dermal papilla cells.
  • FIG. 1 shows nucleic acids or peptides used in the examples.
  • SEQ ID NO: 1 is the 3'-terminal cD obtained from human papillary cells by the method of Okubo et al.
  • Sequence-2 shows the sequence of the reverse complement of a part of Sequence-11.
  • SEQ ID NO: 13 shows the sequence of an oligonucleotide having a sequence near the cDNA insertion portion of the lambda phage cloning vector.
  • Sequence-4 is the DERP used to prepare the anti-DERP2 peptide antibody.
  • Sequence-5 is a subsequence for extending derp2 by PCR.
  • Sequence-6 is a partial sequence for amplifying .derp2 by PCR.
  • FIG. 2 shows the PCR for a cDNA library containing sequence-1.
  • FIG. 3 shows a scheme in which the gene derp2 is recombined into the cloning vector pGEMT.
  • FIG. 4 shows the outline of the primer-walking method.
  • FIG. 5 shows a diagram in which hair papilla cells separated and cultured are immunostained using an anti-DERP2 peptide antibody.
  • FIG. 6 shows a diagram comparing the expression levels of the gene derp2 in hair papilla cells derived from a normal male hair growth site and hair papilla cells derived from a bald patient with androgenetic alopecia.
  • FIG. 7 shows the expression of the gene derp2 in the presence of various concentrations of testosterone. Arrangement table

Abstract

L'invention concerne une nouvelle protéine DERP2 provenant des cellules de papilles dermiques humaines et ayant un effet régulateur sur la croissance des cheveux, ainsi qu'un gène derp2 codant pour cette protéine. Le gène derp2 codant pour la nouvelle protéine DERP2 possédant un effet régulateur sur la croissance des cheveux peut être obtenu par clonage à partir d'une bibliothèque d'ADNc provenant des cellules de papilles dermiques humaines. Grâce à son effet régulateur sur la croissance des cheveux, cette protéine peut être utilisée dans la conception d'agents favorisant la repousse des cheveux, etc.
PCT/JP1999/002813 1998-05-29 1999-05-28 Nouveau gene et proteine codee par ce gene WO1999063083A1 (fr)

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AU39550/99A AU3955099A (en) 1998-05-29 1999-05-28 Novel gene and protein encoded thereby

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JP10148579A JPH11332571A (ja) 1998-05-29 1998-05-29 新規遺伝子とそれにコードされる蛋白質
JP10/148579 1998-05-29

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Cited By (6)

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WO2000073454A1 (fr) * 1999-06-02 2000-12-07 Genentech, Inc. Polypeptides transmembranaires secretes et acides nucleiques codants pour ceux-ci
WO2004052927A1 (fr) * 2002-11-13 2004-06-24 Shanghai Institutes For Biological Sciences, Chinese Academy Of Sciences Gene associe a la calvitie et polypeptide code par ce gene, et utilisations correspondantes
US7119177B2 (en) 1997-06-16 2006-10-10 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
US7264801B2 (en) 1998-08-11 2007-09-04 Genentech, Inc. EG-VEGF nucleic acids and polypeptides and method of use
US7446168B2 (en) 1998-08-11 2008-11-04 Genentech, Inc. EG-VEGF nucleic acids and polypeptides and methods of use
US7547507B2 (en) 1998-08-18 2009-06-16 Genentech, Inc. Methods for the diagnosis of tumors

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WO1998042741A2 (fr) * 1997-03-25 1998-10-01 Genetics Institute, Inc. Proteines secretees et polynucleotides les codant

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7119177B2 (en) 1997-06-16 2006-10-10 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
US7189814B2 (en) 1997-06-16 2007-03-13 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
US7727536B2 (en) 1998-08-11 2010-06-01 Genentech, Inc. EG-VEGF nucleic acids and polypeptides and methods of use
US8557238B2 (en) 1998-08-11 2013-10-15 Genentech, Inc. EG-VEGF nucleic acids and polypeptides and methods of use
US7960531B2 (en) 1998-08-11 2011-06-14 Genetech, Inc. EG-VEGF nucleic acids and polypeptides and methods of use
US7264801B2 (en) 1998-08-11 2007-09-04 Genentech, Inc. EG-VEGF nucleic acids and polypeptides and method of use
US7446168B2 (en) 1998-08-11 2008-11-04 Genentech, Inc. EG-VEGF nucleic acids and polypeptides and methods of use
US7736645B2 (en) 1998-08-11 2010-06-15 Genentech, Inc. EG-VEGF nucleic acids and polypeptides and methods of use
US7691978B2 (en) 1998-08-18 2010-04-06 Genentech, Inc. Antibodies that bind TAT294
US7547507B2 (en) 1998-08-18 2009-06-16 Genentech, Inc. Methods for the diagnosis of tumors
US8097700B2 (en) 1998-08-18 2012-01-17 Genentech, Inc. TAT294 polypeptides
WO2000073454A1 (fr) * 1999-06-02 2000-12-07 Genentech, Inc. Polypeptides transmembranaires secretes et acides nucleiques codants pour ceux-ci
US7544485B2 (en) 2002-11-13 2009-06-09 Shanghai Institutes For Biological Sciences Cas Baldness related gene and the polypeptide encoded thereby, and uses
CN1303102C (zh) * 2002-11-13 2007-03-07 中国科学院上海生命科学研究院 利用人和鼠Rhor基因及其编码产物诊断和治疗秃发的方法
WO2004052927A1 (fr) * 2002-11-13 2004-06-24 Shanghai Institutes For Biological Sciences, Chinese Academy Of Sciences Gene associe a la calvitie et polypeptide code par ce gene, et utilisations correspondantes

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