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Differentially Regulate Death-Inducing Signaling Complex Formation in Cigarette Smoke Extract-Induced Apoptosis1
* Department of Pulmonary and Critical Care Medicine, Gachon Medical School, Gil Medical Center, Inchon, Republic of Korea;
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center,
Center for Biologic Imaging, Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh;
Division of Pediatric Hematology-Oncology, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213;
¶ Institute of Molecular Oncology, Showa University, Tokyo, Japan; and
|| Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Cigarette smoke, a major risk factor in emphysema, causes cell death by incompletely understood mechanisms. Death-inducing signaling complex (DISC) formation is an initial event in Fas-mediated apoptosis. We demonstrate that cigarette smoke extract (CSE) induces DISC formation in human lung fibroblasts (MRC-5) and promotes DISC trafficking from the Golgi complex to membrane lipid rafts. We demonstrate a novel role of protein kinase C (PKC) in the regulation of DISC formation and trafficking. The PKC isoforms, PKC
, 
, 
, and 
, were activated by CSE exposure. Overexpression of wild-type PKC inhibited, while PKC promoted, CSE-induced cell death. Dominant-negative (dn)PKC protected against CSE-induced cell death by suppressing DISC formation and caspase-3 activation, while dnPKC enhanced cell death by promoting these events. DISC formation was augmented by wortmannin, an inhibitor of PI3K. CSE-induced Akt phosphorylation was reduced by dnPKC, but it was increased by dnPKC. Expression of PKC in vivo inhibited DISC formation, caspase-3/8 activation, lung injury, and cell death after prolonged cigarette smoke exposure, whereas expression of PKC promoted caspase-3 activation. In conclusion, CSE-induced DISC formation is differentially regulated by PKC and PKC via the PI3K/Akt pathway. These results suggest that modulation of PKC may have therapeutic potential in the prevention of smoke-related lung injury.
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 in part by awards from the American Heart Association (0335035N to S.W.R and 0525552U to H.P.K.), National Institutes of Health Grant K08AI51402 and United States Immune Deficiency Network subcontract from National Institute of Allergy and Infectious Disease, National Institutes of Health (to Y.M.V.), and National Institutes of Health Grants R01HL60234, R01HL55330, R01HL079904, and P01HL70807 (to A.M.K.C.).
2 Address correspondence and reprint requests to Dr. Augustine M. K. Choi, Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. E-mail address: amchoi{at}rics.bwh.harvard.edu or Dr. Yatin M. Vyas, Division of Pediatric Hematology-Oncology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail address: yatin.vyas{at}chp.edu
3 Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; CS, cigarette smoke; CSE, cigarette smoke extract; DISC, death-inducing signaling complex; dn, dominant negative; FADD, Fas-associated protein with death domain; FasL, Fas ligand; LDH, lactate dehydrogenase; PKC, protein kinase C.
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