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The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation.

Authors
Wang-LY; Azad-N; Kongkaneramit-L; Chen-F; Lu-YJ; Jiang-BH; Rojanasakul-Y
Source
J Immunol 2008 Mar; 180(5):3072-3080
NIOSHTIC No.
20034080
Abstract
Fas-mediated apoptosis plays an important role in normal tissue homeostasis, and disruption of this death pathway contributes to many human diseases. Induction of apoptosis via Fas activation has been associated with reactive oxygen species (ROS) generation and down-regulation of FLICE inhibitory protein (FLIP); however, the relationship between these two events and their role in Fas-mediated apoptosis are unclear. We show herein that ROS are required for FLIP down-regulation and apoptosis induction by Fas ligand (FasL) in primary lung epithelial cells. ROS mediate the down-regulation of FLIP by ubiquitination and subsequent degradation by proteasome. Inhibition of ROS by antioxidants or by ectopic expression of ROS-scavenging enzymes glutathione peroxidase and superoxide dismutase effectively inhibited FLIP down-regulation and apoptosis induction by FasL. Hydrogen peroxide is a primary oxidative species responsible for FLIP down-regulation, whereas superoxide serves as a source of peroxide and a scavenger of NO, which positively regulates FLIP via S-nitrosylation. NADPH oxidase is a key source of ROS generation induced by FasL, and its inhibition by dominant-negative Rac1 expression or by chemical inhibitor decreased the cell death response to FasL. Taken together, our results indicate a novel pathway of FLIP regulation by an interactive network of reactive oxygen and nitrogen species that provides a key mechanism of apoptosis regulation in Fas-induced cell death and related apoptosis disorders.
Keywords
Cell-biology; Cell-function; Cell-metabolism; Cell-transformation; Cell-damage; Chemical-composition; Chemical-inhibition; Chemical-properties; Chemical-synthesis; Enzyme-activity
Contact
Dr. Yon Rojanasakul, West Virginia University, Department of Pharmaceutical Sciences, P.O. Box 9530, Morgantown, WV 26506
CODEN
JOIMA3
Publication Date
20080301
Document Type
Journal Article
Email Address
yrojan@hse.wvu.edu
Fiscal Year
2008
NTIS Accession No.
NTIS Price
Issue of Publication
5
ISSN
0022-1767
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
The Journal of Immunology
State
WV
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