Phosphatidylinositol 3-Kinase/Akt Positively Regulates Fas (CD95)-Mediated Apoptosis in Epidermal Cl41 Cells

Details

• Personal Author:
  Chen F ; Hu S ; Huang C ; Lu B ; Medan D ; Rojanasakul Y ; Shi X ; Stehlik C ; Wang LY
• Description:
  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 (Deltap85) 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. [Description provided by NIOSH]
• Subjects:
  Cells, Cultured Immune System Occupational Health Safety
• Keywords:
  Cell-biology Cell-culture-techniques Cell-cultures Diseases Immunology
• ISSN:
  0022-1767
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  176
• Issue:
  11
• NIOSHTIC Number:
  nn:20030362
• Citation:
  J Immunol 2006 Jun; 176(11):6785-6793
• Federal Fiscal Year:
  2006
• NORA Priority Area:
  Research Tools and Approaches: Cancer Research Methods
• Peer Reviewed:
  True
• Source Full Name:
  The Journal of Immunology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:ae9d66c1687a68fa67f4aa6c7ab8a0a36ef84df12bf23ed41a03d57c1892fe0f0c6a0e5b517f253c619c6323084ee7974eb1e3b78a6aac15c244248e39a9101a
• Download URL:
  https://stacks.cdc.gov/view/cdc/191019/cdc_191019_DS1.pdf
• File Type:
  [PDF - 624.33 KB ]