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Analysis of degradation of cell cycle regulators Kip family

Research Project

Project/Area Number 16390082
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionNagoya University (2005)
Kyushu University (2004)

Principal Investigator

KAMURA Takumi  Nagoya University, Graduate School of Science, Professor, 理学研究科, 教授 (40333455)

Co-Investigator(Kenkyū-buntansha) NAKAYAMA Keiichi  Kyushu University, Medical Institute of Bioregulation, Professor, 生体防御医学研究所, 教授 (80291508)
HATAKEYAMA Shigetsugu  Hokkaido University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (70294973)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2005: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2004: ¥7,700,000 (Direct Cost: ¥7,700,000)
KeywordsCell Cycle / Protein Degradation / Ubiquitin / p27 / KPC
Research Abstract

The cyclin-dependent kinase (CDK) inhibitor p27 is degraded at the G(0)-G(1) transition of the cell cycle by the ubiquitin-proteasome pathway in a Skp2-independent manner. We recently identified a novel ubiquitin ligase, KPC (Kip1 ubiquitylation-promoting complex), consisting of KPC1 and KPC2, which regulates the ubiquitin-dependent degradation of p27 at G(1) phase. We have now investigated the structural requirements for the interactions of KPC1 with KPC2 and p27. The NH(2)-terminal region of KPC1 was found to be responsible for binding to KPC2 and to p27. KPC1 mutants that lack this region failed to mediate polyubiquitylation of p27 in vitro and expression of one such mutant delayed p27 degradation in vivo. We also generated a series of deletion mutants of p27 and found that KPC failed to polyubiquitylate a p27 mutant that lacks the CDK inhibitory domain. Interestingly, the cyclin E.CDK2 complex prevented both the interaction of KPC with p27 as well as KPC-mediated polyubiquitylation of p27. A complex of cyclin E with a kinase-negative mutant of CDK2 also exhibited these inhibitory effects, suggesting that cyclin E.CDK2 competes with KPC1 for access to the CDK inhibitory domain of p27. These results suggest that free p27 is recognized by the NH(2)-terminal region of KPC1, which also associates with KPC2, and that p27 is then polyubiquitylated by the COOH-terminal RING-finger domain of KPC1.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (10 results)

All 2005 2004

All Journal Article (10 results)

  • [Journal Article] Role of the UBL-UBA protein KPC2 in degradation of p27 at G1 phase of the cell cycle.2005

    • Author(s)
      Hara, T, et al.
    • Journal Title

      Mol. Cell. Biol. 25

      Pages: 9292-9303

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Molecular dissection of the interaction between p27 and KPC, the ubiquitin ligase that regulates proteolysis of p27 in G1 phase.2005

    • Author(s)
      Kotoshiba, S, et al.
    • Journal Title

      J. Biol. Chem. 270

      Pages: 17694-17700

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of the UBL-UBA protein KPC2 in degradation of p27 at G1 phase of the cell cycle.2005

    • Author(s)
      Hara, T et al.
    • Journal Title

      Mol.Cell.Biol. 25

      Pages: 9292-9303

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Molecular dissection of the interaction between p27 and KPC, the ubiquitin ligase that regulates proteolysis of p27 in G1 phase.2005

    • Author(s)
      Kotoshiba, S et al.
    • Journal Title

      J.Biol.Chem. 270

      Pages: 17694-17700

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27Kip1 at G1 phase.2004

    • Author(s)
      Kamura, T et al.
    • Journal Title

      Nature Cell Biology 6

      Pages: 1229-1235

    • Related Report
      2004 Annual Research Report
  • [Journal Article] VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases.2004

    • Author(s)
      Kamura, T et al.
    • Journal Title

      Gened & Development 18

      Pages: 3055-3065

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Functional regulation of FEZ1 by the U-box-type ubiquitin ligase E4B contributes to neuritogenesis.2004

    • Author(s)
      Okumura, F et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 53533-53453

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Down-regulation of p27Kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4 : Evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation.2004

    • Author(s)
      Tamamori-Adachi, M et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 50429-50436

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Identification of elongin C and Skp1 sequences that determine cullin selection.2004

    • Author(s)
      Yan, Q et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 43019-43026

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Phosphorylation- dependent degradation of c-Myc is mediated by the F-box protein Fbw7.2004

    • Author(s)
      Yada, M et al.
    • Journal Title

      EMBO J. 23

      Pages: 2116-2125

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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