PMID- 16709838
OWN - NLM
STAT- MEDLINE
DCOM- 20060713
LR  - 20191210
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 176
IP  - 11
DP  - 2006 Jun 1
TI  - Phosphatidylinositol 3-kinase/Akt positively regulates Fas (CD95)-mediated 
      apoptosis in epidermal Cl41 cells.
PG  - 6785-93
AB  - 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.
FAU - Lu, Bin
AU  - Lu B
AD  - Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV 
      26506, USA.
FAU - Wang, Liying
AU  - Wang L
FAU - Stehlik, Christian
AU  - Stehlik C
FAU - Medan, Djordje
AU  - Medan D
FAU - Huang, Chuanshu
AU  - Huang C
FAU - Hu, Shuiying
AU  - Hu S
FAU - Chen, Fei
AU  - Chen F
FAU - Shi, Xianglin
AU  - Shi X
FAU - Rojanasakul, Yon
AU  - Rojanasakul Y
LA  - eng
GR  - HL071545/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Androstadienes)
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (CFLAR protein, human)
RN  - 0 (Chromones)
RN  - 0 (FASLG protein, human)
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Tumor Necrosis Factor Inhibitors)
RN  - 0 (Tumor Necrosis Factors)
RN  - 0 (fas Receptor)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Apoptosis/drug effects/*immunology
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein
MH  - Cell Line
MH  - Chromones/pharmacology
MH  - Enzyme Activation/drug effects/immunology
MH  - Epidermal Cells
MH  - Epidermis/*enzymology/*immunology/metabolism
MH  - Fas Ligand Protein
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Membrane Glycoproteins/antagonists & inhibitors/metabolism/physiology
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism/*physiology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-akt/antagonists & 
      inhibitors/genetics/metabolism/*physiology
MH  - RNA, Messenger/antagonists & inhibitors/biosynthesis
MH  - Reactive Oxygen Species/pharmacology
MH  - Signal Transduction/drug effects/immunology
MH  - Tumor Necrosis Factor Inhibitors
MH  - Tumor Necrosis Factors/metabolism/physiology
MH  - Wortmannin
MH  - fas Receptor/biosynthesis/*metabolism/physiology
EDAT- 2006/05/20 09:00
MHDA- 2006/07/14 09:00
CRDT- 2006/05/20 09:00
PHST- 2006/05/20 09:00 [pubmed]
PHST- 2006/07/14 09:00 [medline]
PHST- 2006/05/20 09:00 [entrez]
AID - 176/11/6785 [pii]
AID - 10.4049/jimmunol.176.11.6785 [doi]
PST - ppublish
SO  - J Immunol. 2006 Jun 1;176(11):6785-93. doi: 10.4049/jimmunol.176.11.6785.