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* Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV 26505; and
Department of Pharmaceutical Sciences and
Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants HL071545 and HL763401.
2 Address correspondence and reprint requests to Dr. Yon Rojanasakul, West Virginia University, Department of Pharmaceutical Sciences, P.O. Box 9530, Morgantown, WV 26506. E-mail address: yrojan{at}hsc.wvu.edu
3 Abbreviations used in this paper: FasL, Fas ligand; AE2, alveolar epithelial type II; CAT, catalase; DAF-DA, 4,5-diaminofluorescein diacetate; DCF-DA, 2',7'-dichlorofluorescein diacetate; DHE, dihydroethidine; DPI, diphenylene iodonium; FADD, Fas-associated death domain; FLIP, FLICE inhibitory protein; GPx, glutathione peroxidase; H2O2, hydrogen peroxide; LAC, lactacystin; NAC, N-acetylcysteine; O2
, superoxide anion; OH·, hydroxyl radical; PTIO, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; Rac1N17, dominant-negative Rac1; ROS, reactive oxygen species; ROT, rotenone; SOD, superoxide dismutase.
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