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Studies on the irreversibility of cellular senescence and its role in vivo

Research Project

Project/Area Number 18370080
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Cell biology
Research InstitutionThe University of Tokushima

Principal Investigator

HARA Eiji  The University of Tokushima, The Institute for Genome Research, Professor (80263268)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥17,970,000 (Direct Cost: ¥15,300,000、Indirect Cost: ¥2,670,000)
Fiscal Year 2007: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
Fiscal Year 2006: ¥6,400,000 (Direct Cost: ¥6,400,000)
KeywordsCellular Senescence / p16 / pRB / p53 / ROS / PKCδ / Cytokinesis / Tumor suppression / PI3キナーゼ / 不死化
Research Abstract

Cellular senescence is a state of permanent cell cycle arrest that can be induced by a variety of potentially oncogenic stresses. It is therefore proposed as a fail-safe mechanism that protects normal cells from losing control of cell division and forming tumors. Although molecular mechanism inducing cellular senescence has been well studied in tissue culture cells, very little is known about how senescent cell cycle arrest is stably maintained in vivo. To gain further insight into the roles and mechanisms of cellular senescence in vivo, we attempted to elucidate molecular mechanisms underlying irreversibility of senescent cell cycle arrest. Towards this end, we utilized a conditionally immortalized cell line that express temperature-sensitive SV4- large T antigen. Using this cell line, we uncovered that p 16^<INK4a> tumor suppressor blocks not only DNA replication but also cytokinesis through activating reactive oxygen species (ROS) -PKCδsignalling in senescent human cells. Importantly, once activated by ROS, PKCδ promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS-PKCδsignalling. Sustained activation of ROS-PKCδ signalling irreversibly blocks cytokinesis, at least partly through blocking the function of LATS1/WARTS, a mitotic exit network kinase required for cytokinesis. We also established the transgenic mice lines expressing the firefly luciferase under the control of the senescence-associated gene promoter. In conjunction with a noninvasive bioluminescence imaging technique, these transgenic mice lines enabled us to monitor the senescence-associated gene expression in vivo. Using this system, we were able to unveil the dynamics of senescence signaling throughout entire lifespan in vivo. We hope that these studies will provide new insights into the development of cancer and open up new possibilities for its control.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (11 results)

All 2007 2006

All Journal Article (8 results) (of which Peer Reviewed: 5 results) Presentation (3 results)

  • [Journal Article] Visualizing the dynamics of p21^<Wafl/Cipl> cyclin-dependent kinase inhibitor expression in living animals.2007

    • Author(s)
      Naoko Ohtani
    • Journal Title

      Proceedings of the National Academy of Sciences of the United States of America 104

      Pages: 15034-15039

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Irreversibility of cellular senescence: dual roles of p16^<INK4a>/Rb-pathway in cell cycle control.2007

    • Author(s)
      Akiko Takahashi
    • Journal Title

      Cell Division 7

      Pages: 2-10

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Visualizing the dynamics of p21^<Wafl/cipl>yclin dependent kinase inhibitor expression in living animals2007

    • Author(s)
      Naoko, Ohtani
    • Journal Title

      Proceedings of the National Academy of Sciences of the United States of America 104

      Pages: 15034-15039

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Irreversibility of cellular senescence : dual roles of p16^<INK4a>/Rb-pathway in cell cycle control2007

    • Author(s)
      Akiko, Takahashi
    • Journal Title

      Cell Division 7

      Pages: 2-10

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Visualizing the dynamics of p21^<wafl/Cipl> cyclin-dependent kinase inhibitor expression in living animals2007

    • Author(s)
      Naoko Ohtani
    • Journal Title

      Proceedings of the National Academy of Sciences of the United States of America 104

      Pages: 15034-15039

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Irreversibility of cellular senescence:dual roles of p16^<INK4a>/Rb-pathway in cell cycle control2007

    • Author(s)
      Akiko Takahashi
    • Journal Title

      Cell Division 7

      Pages: 2-10

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mitogenic signalling and the p16^<INK4a>/Rb pathway cooperate to enforce irreversible cellular senescence2006

    • Author(s)
      Akiko Takahashi
    • Journal Title

      Nature Cell Biology 8

      Pages: 1291-1297

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary 2006 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mitogenic signalling and the p16^<INK4a>/Rb pathway cooperate to enforce irreversible cellular senescence2006

    • Author(s)
      Akiko, Takahashi
    • Journal Title

      Nature Cell Biology 8

      Pages: 1291-1297

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] The role of p16 CDK inhibitor in cell cycle control and senescence.2007

    • Author(s)
      Eiji Hara
    • Organizer
      Genes&Cancer 24th Meeting
    • Place of Presentation
      イギリス・Warwick市
    • Year and Date
      2007-12-12
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] The role of p16 CDK inhibitor in cell cycle control and senescence2007

    • Author(s)
      Eiji Hara
    • Organizer
      Genes&Cancer 24^<th> Meeting
    • Place of Presentation
      イギリス・Warwick市
    • Year and Date
      2007-12-12
    • Related Report
      2007 Annual Research Report
  • [Presentation] The role of p16 CDK inhibitor in cell cycle control and senescence2007

    • Author(s)
      Eiji, Hara
    • Organizer
      Genes & Cancer 24th Meeting, December 12th
    • Place of Presentation
      Warwick, UK
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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