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Clarification of the mechanism for p53-dependent apoptosis and its application for the development of cancer therapies

Research Project

Project/Area Number 15390110
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionNational Cancer Center Research Institute

Principal Investigator

ARAKAWA Hirofumi  National Cancer Center Research Institute, Cancer Medicine and Biophysics Division, Chief, 生物物理部, 部長 (70313088)

Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 2004: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2003: ¥4,000,000 (Direct Cost: ¥4,000,000)
Keywordstumor suppressor gene / p53 / apoptosis / cancer therapy / gene therapy / がん抑制遺伝子 / アデノウイルス / がん治療 / ネトリン / 軸索誘導 / 転写因子 / 標的遺伝子
Research Abstract

To clarify the mechanism for p53-dependent apoptosis, we have tried to identify new p53-target genes involved in apoptosis, and we have carried out their functional analyses for these two years. Eventually, we have published five papers in 2004 and 2005 in order to report the results. We have identified two new p53-target genes, STAG1 and ALDH4. STAG1 was initially isolated as a specific target of p53-121F, an activated form of p53, and it was also shown to mediate p53-dependent apoptosis. ALDH4 is also a p53-target gene encoding a mitochondrial protein, but it negatively mediates p53-dependent apoptosis through the regulation of a proline metabolism, implying its role in cell survival. In addition, we evaluated the tumor suppressive activity of p53AIP1 in vivo, which was previously identified a p53-target gene that mediates p53-dependent apoptosis. In our experiments adenovirus-mediated p53AIP1 gene transfer into tumors remarkably induced growth suppression of tumors in vivo. This result suggests that apoptotic p53-target genes would become promising tools for cancer therapies instead of p53. Moreover, we have discovered that axon-guidance molecules including p53RDL1/UNC5B and netrin-1 are involved in p53-regulated apoptosis. That is, in the absence of netrin-1,p53RDL1/UNC5B induces apoptosis, whereas it blocks p53-induced apoptosis in the presence of netrin-1,based on which we proposed a new model for p53-regulated apoptosis. Taken together, our findings in this project greatly contributed to our understanding of the mechanism for p53-dependent apoptosis, and in addition they provided a possibility for the development of new cancer therapies.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (21 results)

All 2005 2004 Other

All Journal Article (15 results) Publications (6 results)

  • [Journal Article] p53,apoptosis and axon-guidance molecules2005

    • Author(s)
      Arakawa H
    • Journal Title

      Cell Death and Differentiation (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] p53,apoptosis and axon-guidance molecules2005

    • Author(s)
      Arakawa H.
    • Journal Title

      Cell Death and Differentiation (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Adenovirus-mediated p53AIP1 gene transfer as a new strategy for treatment of p53-resistant tumors2004

    • Author(s)
      Yoshida K
    • Journal Title

      Cancer Science 95

      Pages: 91-97

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses2004

    • Author(s)
      Yoon KA
    • Journal Title

      Journal of Human Genetics 49

      Pages: 134-140

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of STAG1 as a key mediator of a p53-dependent apoptotic pathway2004

    • Author(s)
      Anazawa Y
    • Journal Title

      Oncogene 23

      Pages: 7621-7627

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Netrin-1 and its receptors in tumorigenesis2004

    • Author(s)
      Arakawa H
    • Journal Title

      Nature Reviews Cancer 4

      Pages: 978-987

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Adenovirus-mediated p53AIP1 gene transfer as a new strategy for treatment of p53-resistant tumors2004

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

      Cancer Science 95

      Pages: 91-97

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses2004

    • Author(s)
      Yoon KA et al.
    • Journal Title

      Journal of Human Genetics 49

      Pages: 134-140

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of STAG1 as a key mediator of a p53-dependent apoptotic pathway2004

    • Author(s)
      Anazawa Y et al.
    • Journal Title

      Oncogene 23

      Pages: 7621-7627

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Netrin-1 and its receptors in tumorigenesis2004

    • Author(s)
      Arakawa H.
    • Journal Title

      Nature Reviews Cancer 4

      Pages: 978-987

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Adenovirus-mediated p53AIP1 gene tansfer as a new strategy for treatment of p53-resistant tumors2004

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

      Cancer Science 95・1

      Pages: 91-97

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses2004

    • Author(s)
      Yoon, K.A.et al.
    • Journal Title

      Journal of Human Genetics 49・3

      Pages: 134-140

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Identification of STAG1 as a key mediator of p53-dependent apoptotic pathway2004

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

      Oncogene 23・46

      Pages: 7621-7627

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Netrin-1 and its receptors in tumorigenesis2004

    • Author(s)
      Arakawa, H.
    • Journal Title

      Nature Reviews Cancer 4・12

      Pages: 978-987

    • Related Report
      2004 Annual Research Report
  • [Journal Article] p53, apoptosis and axon-guidance molecules

    • Author(s)
      Arakawa, H.
    • Journal Title

      Cell Death and Differentiation (In press)

    • Related Report
      2004 Annual Research Report
  • [Publications] Anazawa, Y. et al.: "Identification of STAG1 as a key mediator of p53-dependent apoptotic pathway."Oncogene. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida, K. et al.: "Adenovirus-mediated p53AIP1 gene transfer as a new strategy for treatment of p53-resistant tumors."Cancer Science. 95・1. 91-97 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kimura, T, et al.: "Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools."Nature Genetics. 34・4. 440-445 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ng, C.C.et al.: "p53RFP, a p53-inducible RING-finger protein, regulates the stability of p21(WAF1)."Oncogene. 22・28. 4449-4458 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kimura, T. et al.: "hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53."Cancer Science. 94・5. 431-436 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanikawa, C. et al.: "p53RDL1 regulates p53-dependent apoptotis."Nature Cell Biology. 5・3. 216-223 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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