Originally published In Press as doi:10.1074/jbc.M407700200 on August 31, 2004
J. Biol. Chem., Vol. 279, Issue 47, 49420-49429, November 19, 2004
Critical Role of Endogenous Akt/IAPs and MEK1/ERK Pathways in Counteracting Endoplasmic Reticulum Stress-induced Cell Death*
Ping Hu
,
Zhang Han¶,
Anthony D. Couvillon, and
John H. Exton||
From the
Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, and the ¶Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615
Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of many diseases and in cancer therapy. Although the unfolded protein response is known to alleviate ER stress by reducing the accumulation of misfolded proteins, the exact survival elements and their downstream signaling pathways that directly counteract ER stress-stimulated apoptotic signaling remain elusive. Here, we have shown that endogenous Akt and ERK are rapidly activated and act as downstream effectors of phosphatidylinositol 3-kinase in thapsigargin- or tunicamycin-induced ER stress. Introduction of either dominant-negative Akt or MEK1 or the inhibitors LY294002 and U0126 sensitized cells to ER stress-induced cell death in different cell types. Reverse transcription-PCR analysis of gene expression during ER stress revealed that cIAP-2 and XIAP, members of the IAP family of potent caspase suppressors, were strongly induced. Transcription of cIAP-2 and XIAP was up-regulated by the phosphatidylinositol 3-kinase/Akt pathway as shown by its reversal by dominant-negative Akt or LY294002. Ablation of these IAPs by RNA interference sensitized cells to ER stress-induced death, which was reversed by the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone. The protective role of IAPs in ER stress coincided with Smac release from mitochondria to the cytosol. Furthermore, it was shown that mTOR was not required for Akt-mediated survival. These results represent the first demonstration that activation of endogenous Akt/IAPs and MEK/ERK plays a critical role in controlling cell survival by resisting ER stress-induced cell death signaling.
Received for publication, July 8, 2004
, and in revised form, August 31, 2004.
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Both authors contributed equally to this work.
|| To whom correspondence should be addressed: Dept. of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 702 Light Hall, Nashville, TN 37232-0615. Tel.: 615-322-6494; Fax: 615-322-4381; E-mail: john.exton{at}vanderbilt.edu.
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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
