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J. Biol. Chem., Vol. 281, Issue 30, 21458-21468, July 28, 2006

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Double-stranded RNA-dependent Protein Kinase Phosphorylation of the -Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis^*

Donalyn Scheuner, Rupali Patel, Feng Wang, Kuei Lee, Kotlo Kumar¹, Jun Wu, Anders Nilsson, Michael Karin, and Randal J. Kaufman^¶2

From the Departments of Biological Chemistry and ^¶Internal Medicine, Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109-0650, and the Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636

As the molecular processes of complex cell stress signaling pathways are defined, the subsequent challenge is to elucidate how each individual event influences the final biological outcome. Phosphorylation of the translation initiation factor 2 (eIF2)atSer⁵¹ is a molecular signal that inhibits translation in response to activation of any of four diverse eIF2 stress kinases. We used gene targeting to replace the wild-type Ser⁵¹ allele with an Ala in the eIF2 gene to test the hypothesis that translational control through eIF2 phosphorylation is a central death stimulus in eukaryotic cells. Homozygous eIF2 mutant mouse embryo fibroblasts were resistant to the apoptotic effects of dsRNA, tumor necrosis factor-, and serum deprivation. TNF treatment induced eIF2 phosphorylation and activation of caspase 3 primarily through the dsRNA-activated eIF2 kinase PKR. In addition, expression of a phospho-mimetic Ser⁵¹ to Asp mutant eIF2-activated caspase 3, indicating that eIF2 phosphorylation is sufficient to induce apoptosis. The proapoptotic effects of PKR-mediated eIF2 phosphorylation contrast with the anti-apoptotic response upon activation of the PKR-related endoplasmic reticulum eIF2 kinase, PERK. Therefore, divergent fates of death and survival can be mediated through phosphorylation at the same site within eIF2. We propose that eIF2 phosphorylation is fundamentally a death signal, yet it may promote either death or survival, depending upon coincident signaling events.

Received for publication, April 20, 2006 , and in revised form, May 22, 2006.

^* This work was supported in part by National Institutes of Health Grants ES04151 (to M. K.) and DK42394 and HL52173 (to R. J. K.). 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 Figs. S1 and S2.

¹ VA Chicago Health Care System, West Side Division, Chicago, IL.

² To whom correspondence should be addressed. Tel.: 734-763-9037; Fax: 734-763-9323; E-mail: kaufmanr{at}umich.edu.

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