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

Authors
Feng-R; Han-J; Ziegler-J; Yang-M; Castranova-V
Source
Free Radic Biol Med 2012 Mar; 52(5):889-897
NIOSHTIC No.
20040230
Abstract
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.
Keywords
Cell-biology; Cell-alteration; Cell-morphology; Cellular-reactions; Cell-damage; Free-radicals; Ultraviolet-radiation; Radiation; Radiation-exposure; Pharmacology; Genetics; Laboratory-animals; Laboratory-testing; Cytopathology; Pathology; Molecular-biology; Author Keywords: UVC radiation; Mouse embryo fibroblast; Apoptosis; Mitochondria; Reactive oxygen species amplification loop; Apaf-1; Free radicals
Contact
Rentian Feng, Department of Pathology, Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
CODEN
FRBMEH
Publication Date
20120301
Document Type
Journal Article
Email Address
ref19@pitt.edu
Fiscal Year
2012
NTIS Accession No.
NTIS Price
Issue of Publication
5
ISSN
0891-5849
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Free Radical Biology and Medicine
State
PA; WV
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