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2002 Fiscal Year Final Research Report Summary

Regulation of NO-induced apoptosis by molecular chaperones

Research Project

Project/Area Number 13670124
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

GOTOH Tomomi  Kumamoto University School of Medicine, Department of Molecular Genetics, Lecturer, 医学部, 講師 (20264286)

Project Period (FY) 2001 – 2002
KeywordsNitric Oxide / apoptosis / ERstress / CHOP / ATF6 / RAW264.7 cell / macrophage / pancreatic β cell
Research Abstract

Nitric oxide (NO) is a multifunctional biomolecule involved in a variety of physiological and pathological processes. In pathological conditions, NO functions as a bactericidal or tumoricidal agent. Excess NO induces apoptosis in some cell types including pancreatic β cells and macrophages, however, the cascade of NO-mediated apoptosis is not fully understood. We investigated the initial steps of NO-mediated apoptosis, and found that the ER stress pathway is involved in NO-mediated apoptosis.
No induces apoptosis in pancreatic β cells and mouse macrophage-like RAW 264.7 cells. Under these conditions, p53 accumulation was not observed, indicating that DNA damage is not the main trigger of NO-mediated apoptosis. In fact, NO induced apoptosis in microglia from p53 knockout mice. On the other hand, CHOP, a transcription factor known to be induced by endoplasmic reticulum (ER) stress, was induced. RAW 264.7 cells and COS-7 cells transfected with an expression plasmid for CHOP, underwent apoptotic cell death. Pancreatic β cells and peritoneal macrophages from CHOP knockout mice showed resistance to NO-induced apoptosis. Then we analyzed the upstream of the CHOP induction. In NO-mediated apoptosis, p90ATF6, an ER membrane-bound transcription factor involved in ER stress response, was cleaved to its active soluble form p50ATF6. The latter was transported to nucleus and bound to the ER-stress-response element (ERSE) of the CHOP gene. The induction of CHOP was preceded by ATF6 activation. When cells were transfected with a p50ATF6 plasmid, apoptosis occurred. This apoptosis induced by p50ATF6 was prevented by a CHOP dominant negative form as well as by an ATF6 dominant negative form. Therefore, CHOP induction is mediated by activation of ATF6. All these results indicate that the ER stress pathway involving ATF6 and CHOP plays a key role in NO-mediated apoptosis. We also found that hsp70/DnaJ (hsp40) chaperone pairs prevent CHOP-induced apoptosis.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Gotoh, T. et al.: "hsp70-DnaJ chaperone pairs prevent nitric oxide-mediated apoptosis in RAW 264.7 macrophages"Cell Death Differ.. 8. 357-366 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oyadomari, S. et al.: "Nitric oxide-induced apoptosis in pancreatic β cells is mediated by the endoplasmic reticulum stress pathway"Proc.Natl.Acad.Sci.USA. 98. 10845-10850 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oyadomari, S. et al.: "Coinduction of endothelial nitric oxide synthase and arginine recycling enzymes in aorta of diabetic rats"Nitric Oxide. 5. 252-260 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kawahara, K. et al.: "Induction of CHOP and apoptosis by nitric oxide in p53-deficient microglial cells"FEBS Lett.. 506. 135-139 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oyadomari, S., et al.: "A targeted disruption of the CHOP gene protects mice against ER stress-induced 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] Gotoh, T. et al.: "hsp70-DnaJ chaperone pairs prevent nitric oxide-mediated apoptosis in RAW 264.7 macrophages"Cell Death Differ.. 8. 357-366 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oyadomari, S. et al.: "Nitric oxide-induced apoptosis in pancreatic β cells is mediated by the endoplasmic reticulum stress pathway"Proc. Natl. Acad. Sci. USA. 98. 10845-10850 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oyadomari, S. et al.: "Coinduction of endothelial nitric oxide synthase and arginine recycling enzymes in aorta of diabetic rats"Nitric Oxide. 5. 252-260 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kawahara, K. et al.: "Induction of CHOP and apoptosis by nitric oxide in p53-deficient microglial cells"FEBS Lett.. 506. 135-139 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oyadomari, S. et al.: "A targeted disruption of the CHOP gene protects mice against ER stress-induced 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

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Published: 2004-04-14  

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