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J. Biol. Chem., Vol. 280, Issue 14, 14189-14202, April 8, 2005

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Phosphorylation of the -Subunit of the Eukaryotic Initiation Factor-2 (eIF2) Reduces Protein Synthesis and Enhances Apoptosis in Response to Proteasome Inhibition^*

Hao-Yuan Jiang and Ronald C. Wek

From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202

Protein ubiquitination and subsequent degradation by the proteasome are important mechanisms regulating cell cycle, growth and differentiation, and apoptosis. Recent studies in cancer therapy suggest that drugs that disrupt the ubiquitin/proteasome pathway induce apoptosis and sensitize malignant cells and tumors to conventional chemotherapy. In this study we addressed the role of phosphorylation of the -subunit eukaryotic initiation factor-2 (eIF2), and its attendant regulation of gene expression, in the cellular stress response to proteasome inhibition. Phosphorylation of eIF2 in mouse embryo fibroblast (MEF) cells subjected to proteasome inhibition leads to a significant reduction in protein synthesis, concomitant with induced expression of the bZIP transcription regulator, ATF4, and its target gene CHOP/GADD153. The primary eIF2 kinase activated by exposure of these fibroblast cells to proteasome inhibition is GCN2 (EIF2AK4), which has a central role in the recognition of cytoplasmic stress signals. Endoplasmic reticulum (ER) stress is not effectively induced in MEF cells subjected to proteasome inhibition, with minimal activation of the ER stress sensory proteins, eIF2 kinase PEK (PERK/EIF2AK3), IRE1 protein kinase and the transcription regulator ATF6 following up to 6 h of proteasome inhibitor treatment. Loss of eIF2 phosphorylation thwarts caspase activation and delays apoptosis. Central to this pro-apoptotic function of eIF2 kinases during proteasome inhibition is the transcriptional regulator CHOP, as deletion of CHOP in MEF cells impedes apoptosis. We conclude that eIF2 kinases are integral to cellular stress pathways induced by proteasome inhibitors, and may be central to the efficacy of anticancer drugs that target the ubiquitin/proteasome pathway.

Received for publication, December 3, 2004 , and in revised form, January 28, 2005.

^* This study was supported in part by Grants RO1GM49164 and R01GM64350 (to R. C. W.) from the National Institutes of Health, and by a Biomedicine Research Grant from Indiana University School of Medicine (to H. Y. J.). 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.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, 635 Barnhill Drive, IN University School of Medicine, Indianapolis, IN 46202. Tel.: 317-274-0914; Fax: 317-274-4686; E-mail: hjiang{at}iupui.edu.

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