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J Biol Chem, Vol. 275, Issue 19, 14624-14631, May 12, 2000
From the Cell Stress and Aging Section, Laboratory of Biological
Chemistry, NIA, National Institutes of Health,
Baltimore, Maryland 21224-6825 and The serine/threonine kinase Akt (also known as
protein kinase B) is activated in response to various stimuli by a
mechanism involving phosphoinositide 3-kinase (PI3-K). Akt provides a
survival signal that protects cells from apoptosis induced by growth
factor withdrawal, but its function in other forms of stress is less clear. Here we investigated the role of PI3-K/Akt during the cellular response to oxidant injury. H2O2
treatment elevated Akt activity in multiple cell types in a time-
(5-30 min) and dose (400 µM-2 mM)-dependent
manner. Expression of a dominant negative mutant of p85 (regulatory
component of PI3-K) and treatment with inhibitors of PI3-K (wortmannin
and LY294002) prevented H2O2-induced Akt activation. Akt activation by H2O2 also
depended on epidermal growth factor receptor (EGFR) signaling;
H2O2 treatment led to EGFR phosphorylation, and
inhibition of EGFR activation prevented Akt activation by
H2O2. As H2O2 causes
apoptosis of HeLa cells, we investigated whether alterations of
PI3-K/Akt signaling would affect this response. Wortmannin and LY294002
treatment significantly enhanced H2O2-induced
apoptosis, whereas expression of exogenous myristoylated Akt (an
activated form) inhibited cell death. Constitutive expression of v-Akt
likewise enhanced survival of H2O2-treated NIH3T3 cells. These results suggest that H2O2
activates Akt via an EGFR/PI3-K-dependent pathway and that
elevated Akt activity confers protection against oxidative
stress-induced apoptosis.
Epidermal Growth Factor Receptor-dependent Akt
Activation by Oxidative Stress Enhances Cell Survival*
, and Department of
Pharmacology, Columbia University, New York, New York 10032
*
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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