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2004 Fiscal Year Final Research Report Summary

Recognition of CDK inhibitor p21 by the Ubiquitin-proteasome pathway

Research Project

Project/Area Number 13672430
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Laboratory medicine
Research InstitutionShowa University

Principal Investigator

FUKUCHI Kunihiko  Showa University, School of Medicine, Department of Clinical Pathology, Associate professor, 医学部, 助教授 (70181287)

Co-Investigator(Kenkyū-buntansha) GOMI Kunihide  Showa University, School of Medicine, Department of Clinical Pathology, Professor, 医学部, 教授 (60053980)
Project Period (FY) 2001 – 2004
Keywordsp21 / ubiquitin / cyclin / DNA damage / apoptosis / caspase / CDK
Research Abstract

Cyclin kinase inhibitor p21 is a multifunctional protein which binds and inhibits cyclin kinases and PCNA, and also inhibits the process of apoptosis. Because the expression of p21 determines the fate of cells after DNA damage, the analysis of the regulatory mechanism for its expression and of its binding to cellular protein should be critical issue to be clarified. In this study, we analyzed three themes.
1. The regulatory region for the p21-degradation by the ubiquitin-proteasome was determined by analysis of its ubiquitination and stability of various deletion mutants. As a result, it became clear that C-terminal 148-157 as region is essential for the efficient ubiquitination.
2. The association of p21 and cyclinA after DNA damage was analyzed using various p21 mutants. CyclinA binding to p21 after DNA damage required neither cyclin binding motif at N-terminal nor cyclin binding motif at C-teminal. CDK2 binding region at 49-71 as were appeared to be essential region for CyclinA-p21 binding.
3. Effects of p21 on the regulation of apoptosis were analyzed. To define the apoptosis-regulatory function of p21, we constructed cells that stably express C-terminal deletion mutants of p21, 1-157, 1-147 or 1-128, and evaluated the apoptotic response of these cells. The AnnexinV positive cell fraction after y-irradiation did not increase in cells expressing 1-157. Consistently, an increase of caspase3 activity or the active form of caspase3 was not observed in cells expressing 1-157, but was prominent in cells expressing 1-128 and 1-147. Further, the activity of caspase9 was suppressed in y-irradiated cells expressing 1-157. Our data indicate that the 1-157 region of p21 inhibits apoptosis caused by y-irradiation by reducing the activity of caspase9 and caspase3, and the 148-157 region is critical for its inhibiting activity.

  • Research Products

    (8 results)

All 2004 2003 2002

All Journal Article (8 results)

  • [Journal Article] Identification of the region required for the antiapoptotic function of the cyclin kinase inhibitor, p212004

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

      Archives of Biochemistry and Biophysics 431

      Pages: 47-54

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Identification of the region required for the antiapoptotic function of the cyclin kinase inhibitor, p212004

    • Author(s)
      entarou Nakamura, Daisuke Arai, Kunihiko Fukuchi
    • Journal Title

      Archives of Biochemistry and Biophysics 431

      Pages: 47-54

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Developement of an in vitro ubiquitination system for the cyclin kinase inhibitor, p212003

    • Author(s)
      Fukuchi K, Gomi K et al.
    • Journal Title

      Showa University Journal of Medical Sciences 15

      Pages: 79-84

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The association of cyclin A and cyclin kinase inhibitior p21 in response to γ-irradiation requires the CDK2 binding region, but not the Cy motif2003

    • Author(s)
      Fukuchi K, Gomi K et al.
    • Journal Title

      Biochimica et Biophysica Acta 1642

      Pages: 163-171

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Development of an In vitro ubiquitination system for the cyclin kinase inhibitor p212003

    • Author(s)
      Kobayashi H, Fukuchi K, Takagi Y, Gomi K
    • Journal Title

      Showa University Journal of Medical Sciences 15

      Pages: 79-84

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The association of cyclin A and cyclin kinase inhibitor p21 in response to -irradiation requires the CDK2 binding region, but not the Cy motif2003

    • Author(s)
      Kunihiko Fukuchi, Kentarou Nakamura, Sachiko Ichimura, Kouichi Tatsumi, Kunihide Gomi
    • Journal Title

      Biochimica Biophysica Acta -Molecular Cell Research 1642

      Pages: 163-171

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Identification of the regulatory region required for ubiquitination of the cyclin kinase inhibitor, p212002

    • Author(s)
      Fukuchi K, Gomi K et al.
    • Journal Title

      Biochemical and Biophysical Research Communications 293

      Pages: 120-125

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Identification of the regulatory region required for ubiquitination of the cyclin kinase inhibitor, p212002

    • Author(s)
      Kunihiko Fukuchi, Tamio Hagiwara, Kentarou Nakamura, Sachiko Ichimura, Kouichi Tatsumi, Kunihide Gomi
    • Journal Title

      Biochemical and Biophysical Research Communications 293

      Pages: 120-125

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2006-07-11  

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