| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506;
Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV 26505; and
Nelson Institute of Environmental Medicine, New York University, Tuxedo, NY 10987
Fas (CD95)-mediated apoptosis is an essential mechanism for the maintenance of homeostasis, and disruption of this death pathway contributes to many human diseases. The cell survival protein kinase Akt/protein kinase B (PKB) is a known regulator of apoptosis, but its role in Fas-mediated cell death and its regulatory mechanisms are unclear. In this study, we show that stimulation of the Fas receptor by its ligand (FasL) induces rapid phosphorylation of Akt/PKB and a parallel increase in cell apoptosis in epidermal Cl41 cells. Inhibition of PI3K/Akt by dominant-negative overexpression of PI3K (
p85) and Akt (Akt-T308A/S473A) protects the cells from apoptosis, indicating an unexpected proapoptotic role of PI3K/Akt in the Fas signaling process. Treatment of the cells with pharmacological inhibitors of PI3K, wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-1 (LY294002), similarly inhibits FasL-induced apoptosis and Akt/PKB phosphorylation, indicating that PI3K is an upstream mediator of Akt/PKB and is involved in Fas-mediated cell death. Electron spin resonance studies show that FasL treatment induces rapid generation of reactive oxygen species, and inhibition of ROS by antioxidants effectively inhibits Akt/PKB signaling, suggesting that FasL activation of Akt/PKB is redox sensitive. In cells transfected with dominant-negative PI3K/Akt, Fas expression is down-regulated, but FLIP expression is unaffected. Reporter gene and mRNA expression assays show that FasL activates fas transcriptional activity and this effect is inhibited by PI3K/Akt suppression. Together, our results indicate that the PI3K/Akt, in addition to its normal prosurvival role, also plays an apoptotic role in Fas-mediated cell death through a mechanism that involves transcriptional activation of Fas receptor.
This article has been cited by other articles:
|
|
 |
|
  S. Maddika, S. R. Ande, E. Wiechec, L. L. Hansen, S. Wesselborg, and M. Los Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis J. Cell Sci., April 1, 2008; 121(7): 979 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-W. Park, H. P. Kim, S.-J. Lee, X. Wang, Y. Wang, E. Ifedigbo, S. C. Watkins, M. Ohba, S. W. Ryter, Y. M. Vyas, et al. Protein Kinase C{alpha} and {zeta} Differentially Regulate Death-Inducing Signaling Complex Formation in Cigarette Smoke Extract-Induced Apoptosis J. Immunol., April 1, 2008; 180(7): 4668 - 4678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Guo, T. Zhu, Z.-X. J. Xiao, and C.-Y. Chen Modulation of Intracellular Signaling Pathways to Induce Apoptosis in Prostate Cancer Cells J. Biol. Chem., August 17, 2007; 282(33): 24364 - 24372. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
