Epidermal Growth Factor Protects Epithelial Cells against Fas-induced Apoptosis
REQUIREMENT FOR Akt ACTIVATION*
- From the ‡Program in Molecular Signal Transduction, Division of Basic Sciences, National Jewish Medical and Research Center and the Departments of ¶Pathology and ‖Pharmacology, University of Colorado Medical School, Denver, Colorado 80206
Abstract
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.
Footnotes
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↵* Supported by National Institutes of Health Grants DK 48845, DK 37871, GM 30324, and CA 58157.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ A Leukemia Society Fellow. To whom correspondence should be addressed: Program in Molecular Signal Transduction, Division of Basic Sciences, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1772; Fax: 303-398-1225; E-mail:johnsonlab{at}njc.org.
- Abbreviations:
- EGF
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epidermal growth factor
- ERK
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extracellular signal-regulated kinase
- HEK
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human embryonic kidney epithelial cells
- MEK
-
mitogen-activated protein kinase kinase
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- Received January 21, 1999.
- Revision received March 15, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
