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2005 Fiscal Year Final Research Report Summary

Molecular mechanism of CHOP dependent cell death induced by extracellular stresses

Research Project

Project/Area Number 16590057
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionNagoya City University

Principal Investigator

HAYASHI Hidetoshi  Nagoya City Univ., Grad.Sch.Pharm.Sci., Assoc.Prof., 大学院・薬学研究科, 助教授 (80198853)

Co-Investigator(Kenkyū-buntansha) ONOZAKI Kikuo  Nagoya City Univ., Grad.Sch.Pharm.Sci., Professor, 大学院・薬学研究科, 教授 (20101313)
Project Period (FY) 2004 – 2005
KeywordsTRB3 / CHOP / ATF4 / p300 / endoplasmic reticulum stress / apoptosis / diabetes / neurodegenerative diseases
Research Abstract

The endoplasmic reticulum(ER) stress is induced by the accumulation of misfolding or malfolding proteins in ER caused by genetic mutation or abnormal modification of proteins. Recently, it is clarified that the ER stress-induced apoptosis cause the neurodegenerative diseases and the diabetes. Applicants are advancing the study of analysis on transcription factor CHOP to which are induced at the ER stress, and are related of apoptosis. Here we have shown that the TRB3, one of the human homologs of a Drosophila kinase like molecule Tribbles, is induced by ER stress and its promoter is activated via ER stress-induced transcription factors, CHOP and ATF4. TRB3 proteins suppress the transcriptional activities of CHOP and ATF4, suggesting CHOP(probably also ATF4)signaling is strictly regulated by TRB3 via a negative feedback mechanism.
In addition, overexpression of TRB3 enhances the ER stress-induced cell death, while the knockdown of TRB3 by a siRNA method decreased the cell death. We have … More also observed the association between TRB3 and CHOP by the immunoprecipitaion-Western blot methods. Inhibitory effect of TRB3 on the transcriptional activity of CHOP is Independent of protein degradation. Moreover, the expression of TRB3 did not influence the dimer formation and DNA binding activities of CHOP. However, TRB3 associated with CHOP through its transcriptional domain and this domain is overlapped with a p300 binding domain. Overexpression of TRB3 remarkably inhibited the formation of p300-CHOP complex. These results suggest that TRB3 may function as an antagonist to replace the p300 from CHOP, and control its transcriptional effect. Moreover, transactivational activity of ATF4 is also suppressed by TRB3 probably by the decrease in its stability and by the dissociation of p300 from ATF4.
It is well known that some products necessary for cell survival are the downstream targets of ATF4, suggesting that the downregulation of ATF4 by TRB3 may greatly contribute the apoptosis according to the ER stress. Less

  • Research Products

    (12 results)

All 2006 2005 2004

All Journal Article (12 results)

  • [Journal Article] CCAAT/enhancer-binding protein homologous protein (CHOP) reulates osteoblast differentiation.2006

    • Author(s)
      Ken Shirakawa et al.
    • Journal Title

      Molecular and Cellular Biology (in press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] 小胞体ストレスによる新たな細胞死の経路2006

    • Author(s)
      林 秀敏
    • Journal Title

      生化学 (in press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] CCAAT/enhancer-binding protein homologous protein(CHOP) regulates osteoblast differentiation.2006

    • Author(s)
      Ken Shirakawa et al.
    • Journal Title

      Molecular and Cellular Biology (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Contribution of the constitutive and inducible degradation of Smad3 by ubiquitin-proteasome pathway to TGF-β signaling.2006

    • Author(s)
      Yasumichi Inoue et al.
    • Journal Title

      Journal of Interferon and Cytokine Research (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Novel pathway for endoplasmic reticulum stress-induced cell death.2006

    • Author(s)
      Hidetoshi Hayashi et al.
    • Journal Title

      SEIKAGAKU (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] TRB3, a novel sensor molecule for endoplasmic reticulum stress.2006

    • Author(s)
      Hidetoshi Hayashi et al.
    • Journal Title

      KAGAKU TO SEIBUTSU (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and involved in cell death.2005

    • Author(s)
      Nobumichi Ohoka et al.
    • Journal Title

      EMBO Journal 24(6)

      Pages: 1243-1255

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta.2005

    • Author(s)
      Naro Ohashi et al.
    • Journal Title

      FEBS Letters 579(12)

      Pages: 2557-2563

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta.2005

    • Author(s)
      Naro Ohashi et al.
    • Journal Title

      FEBS letters 579(12)

      Pages: 2557-2563

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] TGF-beta down-regulates IL-1-alpha-induced TLR2 expression in murine hepatocytes.2004

    • Author(s)
      Takayuki Matsumura et al.
    • Journal Title

      Journal of Leukocyte Biology 75(6)

      Pages: 1056-1061

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Contribution of the constitutive and inducible degradation of Smad3 by ubiquitin-proteasome pathway to TGF-β signaling.2004

    • Author(s)
      Yasumichi Inoue et al.
    • Journal Title

      Journal of Interferon and Cytokine Research 24(1)

      Pages: 43-54

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] TGF-beta down-regulates IL-1-alpha-induced TLR2 expression in murine hepatocytes.2004

    • Author(s)
      Takayuki Matsumura et al.
    • Journal Title

      Journal of Leukocyre Biology 24(1)

      Pages: 1056-1061

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

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Published: 2007-12-13  

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