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Analysis of hepatocarcinogenesis via the complex between the E3 ubiquitin ligase MDM2 and gankyrin

Research Project

Project/Area Number 18590732
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionKyoto University

Principal Investigator

HIGASHITSUJI Hiroaki  Kyoto University, Graduate School of Medicine, assistant professor (60281094)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsubiquitin / E3 ubiquitin ligase / MDM2 / oncoprotein gankyrin / hepatocellular carcinoma / hepatocarcinogenesis / 肝発癌 / ユビキチンリガーゼ / p53 / pRb / トランスジェニックマウス / proteomics / pRB / gene expression profile
Research Abstract

Hepatocellular carcinoma is one of the most common cancers in Asia and Africa, where hepatitis virus infection and exposure to specific liver carcinogens are prevalent Gankyrin is overexpressed in most hepatocellular carcinomas. Gankyrin interacts with the S6 proteasomal ATPase and accelerates the degradation of the tumor suppressor pRb. Gankyrin is an anti-apoptofic oncoprotein and increases the degradation of another tumor suppressor p53. Gankyrin binds to Mdm2, an E3 ubiquitin ligase for p53, and potentiates the ubiquitylating activity. Thus, gankyrin is a cofactor that increases the activities of Mdm2 on p53 and probably targets polyubiquitylated p53 into the 26S proteasome. Gankyrin interacts with multiple proteins and forms the high-molecular-weight complex. In another complex, gankyrin binds to NF-kB and suppresses its activity at the transcriptional level by modulating acetylation via SIRT1, a class III histone deacetylase. Gankyrin plays an oncogenic role mainly at the early stages of human hepatocarcinogenesis, and IGFBP-5 inducible by gankyrin overexpression may be involved in it Gankyrin overexpression increases tumor growth, cell motility, invasiveness in vitro and tumor formation in vivo. Gankyrin overexpression is associated with poor prognosis in human esophageal squamous cell carcinoma.

Report

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

    (23 results)

All 2008 2007 2006

All Journal Article (18 results) (of which Peer Reviewed: 9 results) Presentation (5 results)

  • [Journal Article] Association of gankyrin protein expression with early clinical stages and IGFBP-5 expression in human hepatocellular2008

    • Author(s)
      Atsushi Umemura, et. al.
    • Journal Title

      Hepatology 47

      Pages: 493-502

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gankyrin oncoprotein overexpression as a critical factor for tumour growth in human esophageal squamous carcinoma and its clinical2008

    • Author(s)
      Ortiz, CM, et. al.
    • Journal Title

      Int J Cancer 122

      Pages: 325-332

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The oncoprotein gankyrin interacts with RelA and suppresses NF-kBactivity.2007

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

      Biochem. Biophys. Res. Common. 363

      Pages: 879-884

    • 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] Enhanced deacetylation of p53 by the anti-apoptotic protein HSCO in association with HDAC1.2007

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

      J. Biol. Chem. 282

      Pages: 13716-13725

    • 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] Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma.2007

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

      Hepatology 47

      Pages: 493-502

    • 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] Gankyrin oncoprotein overegpression as a critical factor for tumor growth in human esophageal squamous cell carcinoma and its clinical significance.2007

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

      Int. J. Cancer. 122

      Pages: 325-332

    • 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] The oncoprotein gankyrin interacts with RelA and suppreses NF-kB activity2007

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

      Biochem. Biophys. Res. Commun 363

      Pages: 879-884

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Enhanced deacetylation of p53 by the anti-apoptotic protein HSCO in association with HDAC12007

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

      J. Biol. Chem 282

      Pages: 13716-13725

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Association of gankyrin protein expression With early clinical stages and insulin-like growth factor-binding Protein 5 expression in human hepatocellular carcinoma2007

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

      Hepatology 47

      Pages: 493-502

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Gankyrin oncoprotein overexpression as a critical Factor for tumor growth in human esophageal squamous cell Carcinoma and its clinical significance2007

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

      Int J Cancer 122

      Pages: 325-332

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] The oncoprotein gankyrin interacts with RelA and suppresses NFkappaB activity.2007

    • Author(s)
      Hiroaki Higashitsuji, et. al.
    • Journal Title

      Biochem Biophys Res Commun 363

      Pages: 879-884

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enhanced deacetylation of p53 by the anti-apoptotic protein hsco in association with histone deacetylase 1.2007

    • Author(s)
      Hisako Higashitsuji
    • Journal Title

      J Biol Chem (On line publication)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Gankyrin: a new oncoprotein and regulator of pRb and p53.2006

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

      Trellds Cell Biol. 16

      Pages: 229-233

    • 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] Cirp protects against tumor necrosis factor-alpha-induced apoptosis viaactivation of extracellular signal-regulated kinase.2006

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

      Biochim. Biophys. Acta-Mol. Cell. Res. 1763

      Pages: 290-295

    • 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] Gankyrin : a new oncoprotein and regulator of pRb and p532006

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

      Trends Cell Biol 16

      Pages: 229-233

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Cirp protects against tumor necrosis factor-alpha-Induced apoptosis via activation of extracellular signal-regulated Kinase2006

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

      Biochim. Biophys. Acta-Mol. Cell. Res 1763

      Pages: 290-295

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Gankyrin : a new oncoprotei and regulator of pRb and p53.2006

    • Author(s)
      Simon Dawson
    • Journal Title

      Trends Cell Biol. 16

      Pages: 229-233

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Cirp protects against tumor necrosis factor-alpha-induced apoptosis via activation of extracellular signal-regulated kinase.2006

    • Author(s)
      Toshikazu Sakurai
    • Journal Title

      Biochim Biophys Acta. 1763

      Pages: 290-295

    • Related Report
      2006 Annual Research Report
  • [Presentation] HSCOはHDAC1と複合体を形成し、p53の脱アセチル化を亢進することにより、腫瘍細胞に化学療法耐性を賦与する。2007

    • Author(s)
      東辻宏明
    • Organizer
      第66回日本癌学会学術総会
    • Place of Presentation
      横浜市
    • Year and Date
      2007-10-04
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Enhanced deacetylation of p53 by the anti-apoptotic protein HSCO in association with HDAC12007

    • Author(s)
      Higashitsuji, Hiroaki
    • Organizer
      66th annual meeting of the Japanese Cancer Association
    • Place of Presentation
      Yokohama city
    • Year and Date
      2007-10-04
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Enhanced deacetylation of p53 by the anti-apoptotic protein HSCO in association with histone deacetylase12007

    • Author(s)
      Hiroaki Higashitsuji
    • Organizer
      66th Annual Meeting of the Japanese Cancer Association
    • Place of Presentation
      Pacifico Yokohama, Yokohama
    • Year and Date
      2007-10-04
    • Related Report
      2007 Annual Research Report
  • [Presentation] がん遺伝子ガンキリンによるがん抑制遺伝子p53のユビキチンプロテアソームでの分解促進。2006

    • Author(s)
      東辻宏明
    • Organizer
      第42回日本肝臓学会総会
    • Place of Presentation
      京都市
    • Year and Date
      2006-05-25
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p532006

    • Author(s)
      Higashitsuji, Hiroaki
    • Organizer
      42nd annual meeting of the Japan Society of Hepatology
    • Place of Presentation
      Kyoto city
    • Year and Date
      2006-05-25
    • 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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