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細胞周期の制御異常

Research Project

Project/Area Number 12215020
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe University of Tokyo

Principal Investigator

秋山 徹  東京大学, 分子細胞生物学研究所, 教授 (70150745)

Co-Investigator(Kenkyū-buntansha) 畑 裕  東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (80313237)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥309,100,000 (Direct Cost: ¥309,100,000)
Fiscal Year 2004: ¥63,000,000 (Direct Cost: ¥63,000,000)
Fiscal Year 2003: ¥63,000,000 (Direct Cost: ¥63,000,000)
Fiscal Year 2002: ¥63,100,000 (Direct Cost: ¥63,100,000)
Fiscal Year 2001: ¥65,000,000 (Direct Cost: ¥65,000,000)
Fiscal Year 2000: ¥55,000,000 (Direct Cost: ¥55,000,000)
Keywords細胞周期 / 癌抑制遺伝子 / APC / Asef / β-catenin / Wnt / 裏打ち蛋白 / 接着 / がん抑制遺伝子 / TGF-b / がん細胞 / 細胞運動 / ICAT / KAP3 / BAOP1 / MAG1 / PAPIN / 癌 / Wntシグナル / 細胞接着 / 細胞膜裏打ち蛋白質
Research Abstract

がん細胞における細胞周期制御異常の機構を明らかにすることを目的として研究を進め以下の事実を明らかにした。
1.APCによって活性化されるGEF分子Asefのファミリー分子を見出してAsef2と命名し、細胞の形態、接着、運動の制御に関与することを明らかにした。
2.AsefがJNKシグナルの活性化を引き起こすこと、APCがこの活性を促進することを見出した。
3.AsefおよびAsef2遺伝子欠損マウスを作製した。
4.β-catenin-cadherin複合体に結合しCdc42およびRacを標的とするGAP分子RICSの細胞内局在を明らかにし、結合分子2種類を同定した。
5.β-catenin-TCF複合体による転写活性化を促進し、細胞transformationを促進する作用をもつB9Lの遺伝子欠損マウスを作製し、血管、心臓に異常を起こし胎生致死となることを見出した。
6.β-catenin-TCFの標的遺伝子を検索し、機能未知の膜蛋白質およびzinc finger蛋白質が標的であることを見出した。
7.in silico promoter analysisによりTCFとcross talkしている可能性のあるいくつかの転写因子を同定した。
8.DLGと結合しているRap1特異的なGAP分子SPALのファミリー分子2種類を見出しその性質を明らかにした。
7.タイトジャンクションの裏打ち蛋白質MAGI-1に結合する候補分子Rassf1に類似する分子Rassf6の解析を行った。
8.接着分子JAM4とE3ユビキチンリガーゼLNX1の相互作用の解析を行った。
9.MAGI-1と遺伝性ネフローゼの原因遺伝子産物のひとつであるnephrinの相互作用の解析を行った。

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (56 results)

All 2004 Other

All Journal Article (6 results) Publications (50 results)

  • [Journal Article] Identification of BMP and Activin Membrane-bound Inhibitor (BAMBI)2004

    • Author(s)
      T.Sekiya et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 6840-6846

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Anteriorization of neural fate by ICAT, a negative regulator of Wnt signaling.2004

    • Author(s)
      K.Satoh et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 101

      Pages: 8017-8021

    • Related Report
      2004 Annual Research Report
  • [Journal Article] DKK1, a negative regulator of Wnt signaling, is a target of the β-catenin /TCF pathway.2004

    • Author(s)
      A.Niida et al.
    • Journal Title

      Oncogene 23

      Pages: 8520-8526

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of a BCL9-related β-catenin-binding protein, B9L, in tumorigenesis induced by aberrant activation of Wnt signaling.2004

    • Author(s)
      S.Adachi et al.
    • Journal Title

      Cancer Res. 64

      Pages: 8496-8501

    • Related Report
      2004 Annual Research Report
  • [Journal Article] DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites.2004

    • Author(s)
      T.Moriguchi et al.
    • Journal Title

      Genes Cells 9

      Pages: 549-560

    • Related Report
      2004 Annual Research Report
  • [Journal Article] JAM4 enhances hepatocyte growth factor-mediated branching and scattering of Madin-Darby canine kidney cells.2004

    • Author(s)
      H.Mori et al.
    • Journal Title

      Genes Cells 9

      Pages: 811-819

    • Related Report
      2004 Annual Research Report
  • [Publications] Y.Kawasaki: "Mutated APC and Asef are Involved in Migration of Colorectal Tumor Cells"Nature Cell Biology. 5・3. 211-215 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Okabe: "RICS, a novel GTPase-Activating Protein for Cdc42 and Rac1, is involved in the β-catenin-N-cadherin and NMDA receptor signaling.β"J.Biol.Chem.. 278. 9920-9927 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] S.Nada: "Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn"J.Biol.Chem.. 278. 47610-47621 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] H.Seo: "Incorporation of DUF/FACT into chromatin enhances the accessibility of nucleosomal DNA"Biochem.Biophys.Res.Commun.. 303. 8-13 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Sekiya: "Identification of BMP and Activin Membrane-bound Inhibitor (BAMBI), an Inhibitor of Transforming Growth β-Catenin Pathway in Colorectal Tumorβ Signaling"J Biol Chem.. 279. 6840-6846 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] N.Kakinuma: "Candidate Regions of Tumor Supressor Locus on Chromosome 9q31.1 in Gastric Cancer"Int.J.Cancer.. 109. 71-75 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] A.Hirata: "PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein augments the transforming activity in a rat fibroblast cell line"Virology. 318. 327-336 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] K.Haraguchi: "Activation of beta-catenin-TCF-mediated transcription by non-receptor tyrosine kinase v-Src"Biochem Biophys Res Commun.. 313. 841-844 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Moriguchi: "DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites"Gnes Cells. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Y.Hirabayashi: "The Wnt-β-catenin pathway directs neuronal differentiation of cortical neural precursor cells"Development. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] N.Kakinuma: "Improved In-Gel Competitive Reassociation technique can detect Epstein-Barr virus genome in gastric cancer"J.Electrophoresis. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Okabe: "RICS, a novel GTPase-Activating Protein for Cdc42 and Rac1, is involved in the b-catenin-N-cadherin and NMDA receptor signaling"J. Biol. Chem.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Y.Kawasaki: "Mutated APC and Asef are Involved in Migration of Colorectal Tumor Cells"Nature Cell Biology. 5(3). 211-215 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Jimbo: "Identification of link between the Tumor Suppressor APC and the Kinesin Superfamily of Proteins"Nature Cell Biol.. 4. 323-327 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Sekiya: "Overexpression of Icat Induces G2 Arrest and Cell Death in Tumor Cells Mutant for APC, β-catenin or Axin"Cancer Res.. 62. 3322-3326 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] B.C.Roy: "SPAL, a Rap-specific GTPase Activating Protein, is Present in the NMDA receptor-PSD-95 Complex in the Hippocampus"Genes Cells. 7. 607-617 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] K.Kohu: "The SH3, HOOK and Guanylate Kinase-like Domains of hDLG are Important for its Cytoplasmic Localization"Genes Cells. 7. 707-715 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kim M.: "Binding of the mammalian homolog of he Drosophila discs large tumor suppressor protein to the ribosome receptor"Biochem Biophys Res Commun.. 294. 1151-1154 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Koyama: "Mutation and expression of the β-catenin-interacting rotein ICAT in human colorectal tumors"Jpn. J. Clin. Oncol.. 358-362 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] F.Ogawa: "Binding of the Human Homolog of the Drosophila Discs Large Tumor Suppressor Protein to the Mitochondrial Ribosomal Protein MRP-S34"Biochem. Biophys. Res. Commun.. 294. 1151-1154 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takemura M.: "Phosphorylation-dependent migration of retinoblastoma protein into the nucleolus triggered by binding to nucleophosmin/B23"Exp. Cell Res.. 276. 233-241 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] H.Seo: "Incorporation of DUF/FACT into chromatin enhances the accessibility of nucleosomal DNA"Biochem. Biophys. Res. Commun.. (in press). (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohno H.: "Localization of p0071-interacting proteins, plakophilin-related armadillo-repeat protein-interacting protein and ERBIN, in epithelial cells"Oncogene. 21. 7042-7049 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yao I.: "Synaptic localization of SAPAP1, a synaptic membrane-associated protein"Genes Cells. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Hirabayashi S.: "C2PA is a nuclear protein implicated in heat shock response"J. Cell. Biochem. 87. 65-74 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yao I.: "Synaptic and nuclear localization of brain-enriched guanylate kinase-associated protein"J. Neurosci.. 22. 5354-5364 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iida J.: "Synaptic localization of membrane-associated guanylate kinase-interacting protein mediated by the pleckstrin homology domain"Eur. J. Neurosci.. 15. 1493-1498 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.jimbo: "Link between the Tumor Suppressor APC and the Kinesin Superfamily of Proteins"Nature Cell Biology. (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Kohu: "The SH3, HOOK and GuanylateKinase-like Domains of hDLG are Important for its Cytoplasmic Localization"Genes Cells. (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Sekiya: "Overexpression of ICAT Induces G2 Arrest and Cell Death in Tumor CellsMutant for APC, β-catenin or Axin"Cancer Research. (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] B.C.Roy: "SPAL, a Rap-specific GTPase Activating Protein, is Present in the NMDA receptor-PSD-95 Complex in the Hippocampus"Genes Cells. (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Takemura: "Stimulation of DNA polymerase aactivity by Cdk2-phosphorylated Rb protein. Biochem. Biophys."Res. Commun.. 282. 984-990 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] W.Nishimura: "Interaction of synaptic scaffolding molecule (S-SCAM) and β-catenin"J. Neurosci.. 22-3. 757-765 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] J.Iida: "Synaptic localization of membrane-associated guanylate kinase-interacting protein mediated by the pleckstrin homology domain"Eur. J. Neurosci.. (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Ishidate: "The APC-hDLG Complex Negatively Regulates Cell Cycle Progression from the G0/G1 to SPhase."Oncogene. 19. 365-372 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Nakagawa: "EB3, a novel member of the EB1 family preferentially expressed in the central nervous system, bins to a CNS-specific."Oncogene. 19. 210-216 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Nakagawa: "APCL, a central nervous system-specific homolog of adenomatous polysois coli tumor suppressor, binds to p53-binding protein 2 and translocates."Cancer Res.. 60. 101-105 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Kawahara.: "Downregulation of b-catenin by the Colorectal Tumor Suppressor APC Requires Association with Axin and β-catenin."J.Biol.Chem. 275. 8369-8374 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Akiyama: "Wht/β-catenin signaling."Cytokine & Growth Factor Reviews. 11. 273-282 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Yanai: "The Colorectal Tumor Suppressor APC is Present in the NMDA-receptor-PDS-95 Complex in the Brain."Genes Cells. 5. 815-822 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Kawasaki: "Asef, a Link between the Tumor Suppressor APC and G-protain Signaling."Science. 289. 1194-1197 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Haraguchi: "The hDLG-associated protein DAP interacts with dynein light chain and neuronal nitric oxide synthase."Gene Cells. 5. 905-911 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Dabashi: "APC protein is required for initiation of neuronal differentiation in rat pheochromocytoma PC12 cells."Biochem.Biopys.Res.Commun.. 279. 685-691 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Senda: "Expression of APC in the mouse kideney and its colocalization with A-canenin and hDLG."J.Histochem.Cytochem.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Kohu,K.: "Localization of the Novel GAP Family Protein SPAL in Epithelial Cells."Acta Histochem.Cytochem.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Kakinuma,N: "APC is Colocalized with β-catenin and hDLG in the Henle's Loop of the Mouse Kidney."Acta Histochem.Cytochem.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Tago,K.: "Inhibition of Wntsignaling by ICAT, a Novel β-catenin-interacting Protein."Gense Dev.. 14. 1741-1749 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nishimura,W: "Localization of BAP1/MAGI1 at adherens junctions in NRK cell : the polarized targeting mediated by the carboxyl-teminal PDZ domains."J.Cell.Physiol.. 185. 358-365 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Deguchi,M: "PAPIN : a novel multiple PDZ protein interacting with neural plakophilin-related armadillo-repeat protein/β-catenin and P0071"J.Biol.Chem.. 275. 29875-29880 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] yao,I.: "Association of membrane-associated guanylate kinase-interacting protein-1 with Raf-1."Biochem.Biophys.Res.Commun. 270. 538-542 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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