Epidermal growth factor protects epithelial cells against Fas-induced apoptosis. Requirement for Akt activation.
Chemotherapeutic drugs that damage DNA kill tumor cells, in part, by inducing the expression of a death receptor such as Fas or its ligand, FasL. Here, we demonstrate that epidermal growth factor (EGF) stimulation of T47D breast adenocarcinoma and embryonic kidney epithelial (HEK293) cells protects these cells from Fas-induced apoptosis. EGF stimulation of epithelial cells also inhibited Fas-induced caspase activation and the proteolysis of signaling proteins downstream of the EGF receptor, Cbl and Akt/protein kinase B (Akt). EGF stimulation of Akt kinase activity blocked Fas-induced apoptosis. Expression of activated Akt in MCF-7 breast adenocarcinoma cells was sufficient to block Fas-mediated apoptosis. Inhibition of EGF-stimulated extracellular signal-regulated kinase (ERK) activity did not affect EGF protection from Fas-mediated apoptosis. The findings indicate that EGF receptor stimulation of epithelial cells has a significant survival function against death receptor-induced apoptosis mediated by Akt.
Gibson
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S
Program in Molecular Signal Transduction, Division of Basic Sciences, National Jewish Medical and Research Center, University of Colorado Medical School, Denver, Colorado 80206, USA.
Tu
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Oyer
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R
Anderson
S M
SM
Johnson
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GL
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D019014:fas Receptor / Q000378:metabolism*
D000730:Androstadienes; D005419:Flavonoids; D011518:Proto-Oncogene Proteins; D019014:fas Receptor; D004815:Epidermal Growth Factor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020169:Caspases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin