Apaf-1 deficiency confers resistance to ultraviolet-induced apoptosis in mouse embryonic fibroblasts by disrupting reactive oxygen species amplification production and mitochondrial pathway

Details

• Personal Author:
  Castranova, Vincent ; Feng R ; Han J ; Yang M ; Ziegler J
• Description:
  Apoptosis requires tightly regulated cell death pathways. The signaling pathways that trigger a cell to undergo apoptosis after UV radiation are cell type specific and are currently being defined. Here, we have used pharmacological and genetic tools to demonstrate the decisive part of the mitochondrial pathway in UVC-induced apoptosis in mouse embryo fibroblasts (MEFs). UVC-induced apoptosis proceeded independent of the activation of death receptor components. In contrast, soon after UV radiation, MAPK activation and generation of reactive oxygen species (ROS) increased, followed by a decline in mitochondrial membrane potential (MMP) and cytochrome c release, as well as activation of caspase-9 and -3 and the upregulation of p47-phox. Deficiency of apaf-1, a critical member of the apoptosome, dramatically abolished all the UV-induced signal deterioration and cell death. In parallel, UVC-induced apoptosis was largely attenuated by either DN-caspase-9 or Bcl-X(L) overexpression. Pretreatment of cells with N-acetylcysteine or catalase but not Tempol decreased UVC-induced MAPK activation and apoptosis. Inhibition of JNK and caspase attenuated p47-phox upregulation. Altogether, we have for the first time demonstrated the critical role of Apaf-1 in the regulation of MAPK, ROS, and MMP in UVC-radiated MEFs and propose that the amplification feedback loop among mitochondrial signal molecules culminates in the demise of the cell. [Description provided by NIOSH]
• Subjects:
  Cytology Free Radicals Genetics Laboratories Occupational Health Pathology Radiation Safety Ultraviolet Rays
• Keywords:
  Apaf-1 Apoptosis Author Keywords: UVC Radiation Cell-alteration Cell-biology Cell-damage Cell-morphology Cellular-reactions Cytopathology Free-radicals Free Radicals Laboratory-animals Laboratory-testing Mitochondria Molecular-biology Mouse Embryo Fibroblast Pharmacology Radiation-exposure Reactive Oxygen Species Amplification Loop Ultraviolet-radiation

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• ISSN:
  0891-5849
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  52
• Issue:
  5
• NIOSHTIC Number:
  nn:20040230
• Citation:
  Free Radic Biol Med 2012 Mar; 52(5):889-897
• Contact Point Address:
  Rentian Feng, Department of Pathology, Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
• Email:
  ref19@pitt.edu
• Federal Fiscal Year:
  2012
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Free Radical Biology and Medicine
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:73ed7f1e98d41738d9cd89cbe526d17d7d5d8d82986d834138e129b5005d9c0074a49238eef55b05d02a23401d1cd22bfef78f169bba311f5a84f34b2ba0e1ba
• Download URL:
  https://stacks.cdc.gov/view/cdc/193172/cdc_193172_DS1.pdf
• File Type:
  [PDF - 1.00 MB ]