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2005 Fiscal Year Final Research Report Summary

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
KeywordsCell Cycle / Protein Degradation / Ubiquitin
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.

  • Research Products

    (4 results)

All 2005

All Journal Article (4 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
  • [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
  • [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
  • [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

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Published: 2007-12-13  

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