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2003 Fiscal Year Final Research Report Summary

Regulation of nitric oxide (NO) synthesis and NO-induced apoptosis

Research Project

Project/Area Number 14370047
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionKumamoto University

Principal Investigator

MORI Masataka  Kumamoto University, Grad.Sch.Med.Sci., Professor, 大学院・医学薬学研究部, 教授 (40009650)

Co-Investigator(Kenkyū-buntansha) GOTOH Tomomi  Kumamoto University, Grad.Sch.Med.Sci., Lecture, 大学院・医学薬学研究部, 講師 (20264286)
TERADA Kazutoyo  Kumamoto University, Grad.Sch.Med.Sci., Associate Professor, 大学院・医学薬学研究部, 助教授 (00253724)
Project Period (FY) 2002 – 2003
Keywordsnitric oxide / ER stress / apoptosis / CHOP / diabetes
Research Abstract

Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Purturbations of ER homrostasis affect protein folding and cause ER stress. Nitric oxide (NO) is a messenger molecule functioning in vascular regulation, immunity, neurotransmission and others, and has been implicated in many diseases. NO is synthesized from arginine by NO synthase (NOS), and the availability of arginine has been shown to be a rate-limiting factor in NO production. Citrulline formed as a by-product of the NOS reaction can be recycled to arginine by argininosuccinate synthetase and argininosuccinate lyase, forming the "citrulline-NO cycle". On the other hand, arginase isoforms have been shown to downregulate NO production by depleting arginine. Excessive NO leads to apoptosis in various cells. When macrophages were immunostimulated or treated with NO, apoptosis occurred. Under these conditions, p53 accumulation was not observed, indicating that DNA damage is not the main trigger of NO-mediated apoptosis. Furthermore, apoptosis was induced in p53-deficient microglial cells by NO. We found that CHOP/GADD153, a C/EBP family transcription factor which is involved in ER stress-mediated apoptosis, is induced. The induction of CHOP was followed by the mitochondrial apoptotic pathway involving cytochrome c release and activation of caspase cascade. Excessive NO production in cytokine-activated β-cells has been implicated in β-cell distruption in type 1 diabetes. NO depleted ER Ca^<2+>, and overexpression of calreticulin, a major Ca^<2+> binding protein in ER, increased ER Ca^<2+> and protected cells against NO-mediated apoptosis. Furthermore, pancreatic islets from CHOP-deficient mice showed resistance to NO. We conclude that NO depletes ER Ca^<2+>, causes ER stress, and leads to apoptosis.

  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Oyadomari, S. et al.: "Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes"J.Clin.Invest.. 109. 525-532 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Gotoh, T.et al.: "Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP"J.Biol.Chem.. 277. 12343-12350 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oyadomari, S. et al.: "Endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cells"Apoptosis. 7. 335-345 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mori, M.: "Arginases"Wiley Encyclopedia of Molecular Medicine. 5. 247-250 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Koga, T. et al.: "Coinduction of nitric oxide synthase and arginine metabolic enzymes in endotoxin-induced uveitis rats"Exp.Eye Res.. 75. 659-667 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Endo, M. et al.: "Induction of arginase I and II in bleomycin-induced fibrosis of mouse lung"Am.J.Physiol.. 285. L313->321 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Koga, T. et al.: "Induction of citrulline-nitric oxide (NO) cycle enzymes and NO production in immunostimulated rat RPE-J cells"Exp.Eye Res.. 76. 15-21 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Gotoh, T. et al.: "Hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by translocation of Bax to mitochondria"Cell Death Differ.. 11. 390-402 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tajiri, S. et al.: "Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP"Cell Death Differ.. 11. 403-415 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oyadomari, S., Mori, M.: "Roles of CHOP/GADD153 in endoplasmic reticulum stress"Cell Death Differ.. 11. 381-389 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oyadomari, S. et al.: "Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes"J.Clin.Invest.. 109. 525-532 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Gotoh, T. et al.: "Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP"J.Biol.Chem.. 277. 12343-12350 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oyadomari, S. et al.: "Endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cells"Apoptosis. 7(Invited review). 335-345 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koga, T. et al.: "Coinduction of nitric oxide synthase and arginine metabolic enzymes in endotoxin-induced uveitis rats"Exp.Eye Res.. 75. 659-667 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koga, T. et al.: "Induction of citrulline-nitric oxide (NO) cycle enzymes and NO production in immunostimulated rat RPE-J cells"Exp.Eye Res.. 76. 15-21 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Endo, M. et al.: "Induction of arginase I and II in bleomycin-induced fibrosis of mouse lung"Am.J.Physiol.. L313-L321 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Gotoh, T. et al.: "Hsp70-DnaJ chaperone pair prevents nitric oxide-and CHOP-induced apoptosis by translocation of Bax to mitochondria"Cell Death Differ.. 11. 390-402 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tajiri, S. et al.: "Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP"Cell Death Differ.. 11. 403-415 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oyadomari, S., Mori, M.: "Cell Death Differ 11, 403-415 (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress"Cell Death Differ.. 11(Invited review). 381-389 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mori, M.: "Arginases, Wiley Encyclopedia of Molecular Medicine, Vol. 5"John Wiley & Sons. 247-250 (2002)

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

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Published: 2005-04-19  

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