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Degradation of the CDK inhibitor p27^<Kip1> by a novel ubiquitin ligase.

Research Project

Project/Area Number 17590243
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionHamamatsu University School of Medicine

Principal Investigator

UCHIDA Chiharu  Hamamatu University, School of Medicine, Research Associate, 医学部, 助手 (60223567)

Co-Investigator(Kenkyū-buntansha) KITAGAWA Masatoshi  Hamamatu University, School of Medicine, Professor, 医学部, 教授 (50294971)
HATTORI Takayuki  Hamamatu University, School of Medicine, Post doctoral fellow (COE), 医学部, COE研究員 (50377751)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordsp27kip1 / Ubiquitin / Proteasome / Degradation / Cell cycle / p27<kip1>
Research Abstract

Cell cycle progression is controlled by cyclin-dependent kinases (CDKs). The CDK activities are negatively regulated by CDK inhibitor proteins (CKIs). In the quiescent and early G1 phase, p27^<Kip1>, one of the Cip/Kip-type CKIs, exists in abundance in the cell nucleus to suppress cell cycle progression. p27^<Kip1> is degraded in late G1 phase by the ubiquitin-proteasome pathway, allowing cells to enter S phase. In this study, we identified p27NBP1 as a p27^<Kip1>-interacting protein. p27NBP1 physically interacted with p27^<Kip1> and directly ubiquitinated p27^<Kip1> in an intact RING finger domain-dependent manner. Since we isolated p27NBP1 as a protein that interacts with the amino-terminal portion of p27^<Kip1> containing Ser10, we next examined whether interaction between these two proteins was affected by Ser10 phosphorylation status. In spite of the substitution of Ser10, p27^<Kip1> mutants associated with p27NBP1 to an extent similar to that of wild-type p27^<Kip1>. This result suggested that p27NBP1 interacts with p27^<Kip1> regardless of the status of Ser10 phosphorylation. Ablation of endogenous p27NBP1 by small interfering RNA increased the steady-state level of p27^<Kip1> and decelerated p27^<Kip1> turnover. p27^<Kip1> was decreased in synchronization with accumulation of p27NBP1 in late G1 phase. Furthermore, depletion of p27NBP1 resulted in inhibition of cell cycle progression from G1 to S phase in a p53-independent manner. Overall, the results indicate that p27NBP1 acts as a negative regulator of p27^<Kip1> function by promoting ubiquitin-dependent proteasomal degradation.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (22 results)

All 2006 2005 Other

All Journal Article (22 results)

  • [Journal Article] Up-regulation of GPR48 induced by down-regulation of p27^<Kip1> enhances carcinoma cell invasiveness and metastasis.2006

    • Author(s)
      Gao, Y., e al.
    • Journal Title

      Cancer Res. 66

      Pages: 11623-11631

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Degradation of Tob1 Mediated by SCF^<Skp2>-Dependent Ubiquitination.2006

    • Author(s)
      Hiramatsu, Y., et al.
    • Journal Title

      Cancer Res. 66

      Pages: 8477-8483

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia.2006

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

      Neuromolecular Med. 8

      Pages: 361-374

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury.2006

    • Author(s)
      Fukasawa, H., et al.
    • Journal Title

      Kidney Int. 69

      Pages: 1733-1740

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Generation of a constitutively active mutant of human GPR48/LGR4, a G-protein-coupled receptor.2006

    • Author(s)
      Gao, Y., et al.
    • Journal Title

      H.J. Med. Sci(北海道医誌). 81

      Pages: 101-109

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Immunohistochemical and genetic features of gastric and metastatic liver gastrointestinal stromal tumors : Sequential analyses.2006

    • Author(s)
      Kikuchi, H., et al.
    • Journal Title

      Cancer Sci. 97

      Pages: 127-132

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Effects of MdmX on Mdm2-mediated downregulation of pRB.2006

    • Author(s)
      Uchida, C., et al.
    • Journal Title

      FEBS letters. 580

      Pages: 1753-1758

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Ubiquitin-dependent degradation of adenovirus EIA protein is inhibited by BS69.2006

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

      Biochem Biophys Res Commun. 339

      Pages: 367-374

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner.2006

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

      Biochem Biophys Res Commun. 340

      Pages: 54-61

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Up-regulation of GPR48 induced by down-regulation of p27^<Kip1> enhances carcinoma cell invasiveness and metastasis.2006

    • Author(s)
      Gao, Y., et al.
    • Journal Title

      Cancer Res. 66

      Pages: 11623-11631

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Degradation of Tob1 Mediated by SCF^<Kip2>-Dependent Ubiquitination.2006

    • Author(s)
      Hiramatsu, Y., et al.
    • Journal Title

      Cancer Res. 66

      Pages: 8477-8483

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Generation of a constitutively active mutant of human GPR48/LGR4, a G-protein-coupled receptor.2006

    • Author(s)
      Gao, Y., et al.
    • Journal Title

      H. J. Med. Sci. 81

      Pages: 101-109

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69.2006

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

      Biochem Biophys Res Commun. 339

      Pages: 367-374

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury..2006

    • Author(s)
      Fukasawa, H., et al.
    • Journal Title

      Kidney Int. 69

      Pages: 1733-1740

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Effects of MdmX on Mdm2-mediated downregulation of pRB2006

    • Author(s)
      Uchida, C., et al.
    • Journal Title

      FEBS letters. 580

      Pages: 1753-1758

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury.2006

    • Author(s)
      Fukasawa, H., et al.
    • Journal Title

      Kidney Int. (In press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation.2005

    • Author(s)
      Uchida, C., et al.
    • Journal Title

      EMBO J. 24

      Pages: 160-169

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Transcriptional induction of Smurf2 ubiquitin ligase by TGF-β.2005

    • Author(s)
      Ohashi, N., et al.
    • Journal Title

      FEBS Letters 579

      Pages: 2557-2563

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Preferences for phosphorylation sites in the retinoblastoma protein of D-Type cyclin-dependent kinases, Cdk4 and Cdk6 in vitro.2005

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

      J. Biochem. 137

      Pages: 381-386

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The FWD1/β-TrCP-mediated degradation pathway establishes a turning off switch of a Cdc42 guanine nucleotide exchange factor, FGD1.2005

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

      Genes to Cells 10

      Pages: 241-251

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] TGF-beta signaling by Smads and its roles in tissue fibrosis. (review article).

    • Author(s)
      Fukasawa, H., et al.
    • Journal Title

      Current signal transduction therapy (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] TGF-beta signaling by Smads and its roles in tissue fibrosis. (review article).

    • Author(s)
      Fukasawa, H., et al.
    • Journal Title

      Current signal transduction therapy (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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