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J. Biol. Chem., Vol. 282, Issue 31, 22551-22562, August 3, 2007

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Translational Repression of MCL-1 Couples Stress-induced eIF2 Phosphorylation to Mitochondrial Apoptosis Initiation^*

From the Department of Medicine 2, Technical University of Munich, 81675 Munich, Germany

The integrated stress response (ISR) integrates a broad range of environmental and endogenous stress signals to the phosphorylation of the -subunit of eukaryotic translation initiation factor 2 (eIF2). Although intense or prolonged activation of this pathway is known to induce apoptosis, the molecular mechanisms coupling stress-induced eIF2 phosphorylation to the cell death machinery have remained incompletely understood. In this study, we characterized apoptosis initiation in response to classical activators of the ISR (tunicamycin, UVC, elevated osmotic pressure, arsenite). We found that all applied stress stimuli activated a mitochondrial pathway of apoptosis initiation. Rapid and selective down-regulation of the anti-apoptotic BCL-2 family protein MCL-1 preceded the activation of BAX, BAK, and caspases. Stabilization of MCL-1 blocked apoptosis initiation, while cells with reduced MCL-1 protein content were strongly sensitized to stress-induced apoptosis. Stress-induced elimination of MCL-1 occurred with unchanged protein turnover and independently of MCL-1 mRNA levels. In contrast, stress-induced phosphorylation of eIF2 at Ser⁵¹ was both essential and sufficient for the down-regulation of MCL-1 protein in stressed cells. These findings indicate that stress-induced phosphorylation of eIF2 is directly coupled to mitochondrial apoptosis regulation via translational repression of MCL-1. Down-regulation of MCL-1 enables but not enforces apoptosis initiation in stressed cells.

Received for publication, March 28, 2007 , and in revised form, May 16, 2007.

^* This work was supported in part by Technical University of Munich (KKF 8733166, to R. F.) and Deutsche Forschungsgemeinschaft (SFB 456, to G. S. and R. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Technical University of Munich, Klinikum rechts der Isar, Dept. of Medicine 2, Ismaninger Strasse 22, 81675 Munich, Germany. Tel.: 49-89-41402250; Fax: 49-89-41404871; E-mail: roland.schmid{at}lrz.tum.de.

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