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J. Biol. Chem., Vol. 282, Issue 6, 3755-3765, February 9, 2007

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The Eukaryotic Initiation Factor-2 Kinase Pathway Facilitates Differential GADD45a Expression in Response to Environmental Stress^*

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

Phosphorylation of eukaryotic initiation factor-2 (eIF2) regulates general and gene-specific translation in response to diverse environmental stresses. Central to gene expression induced by eIF2 phosphorylation is the preferential translation of ATF4, a basic zipper transcription activator. Phosphorylation of eIF2 and its attendant induction of ATF4 can lead to different patterns of gene expression depending on the environmental stress. This is of fundamental importance because eIF2 kinases can induce the expression of genes involved in survival as well as in apoptosis. In this report, we explore the molecular basis for why there can be differential expression of GADD45a, a stress-responsive protein that regulates genome stability, apoptosis, and immune responses. We find that whereas ATF4 is required for GADD45a transcription during many different environmental stresses, GADD45a protein accumulates only during a limited number of stress arrangements. The basis for this difference between measurable GADD45a mRNA and protein lies in the observation that GADD45a protein is labile. Those stress agents that enhance ATF4-directed GADD45a transcription and impede the turnover of GADD45a protein by blocking ubiquitin/proteasome-mediated degradation elevate GADD45a protein levels. By comparison, those stress arrangements that trigger ATF4 levels and GADD45a transcription, but do not perturb the proteasome pathway, only elevate GADD45a mRNA levels. This study highlights the molecular mechanisms by which environmental stresses can differentially control central regulatory proteins targeted by the eIF2 kinase pathway.

Received for publication, July 7, 2006 , and in revised form, December 14, 2006.

^* This study was supported in part by grants from the National Institutes of Health (to R. C. W.) and the American Heart Association (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.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indiana University School of Medicine, Indianapolis, IN 46202. Tel.: 317-274-0549; Fax: 317-274-4686; E-mail: rwek{at}iupui.edu.

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