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J. Biol. Chem., Vol. 283, Issue 25, 17020-17029, June 20, 2008

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Endoplasmic Reticulum (ER) Chaperone Regulation and Survival of Cells Compensating for Deficiency in the ER Stress Response Kinase, PERK^*

Yukihiro Yamaguchi, Dennis Larkin, Roberto Lara-Lemus, Jose Ramos-Castañeda, Ming Liu, and Peter Arvan¹

From the Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109 and the Centro de Investigaciones sobre Enfermedades Infecciosas, 62580 Cuernavaca Morelos, Mexico

The activity of PERK, an endoplasmic reticulum (ER) transmembrane protein kinase, assists in an ER stress response designed to inhibit general protein synthesis while allowing upregulated synthesis of selective proteins such as the ATF4 transcription factor. PERK null mice exhibit phenotypes that especially affect secretory cell types. Although embryonic fibroblasts from these mice are difficult to transfect with high efficiency, we have generated 293 cells stably expressing the PERK-K618A dominant negative mutant. 293/PERK-K618A cells, in response to ER stress: (a) do not properly inhibit general protein synthesis, (b) exhibit defective/delayed induction of ATF4 and BiP, and (c) exhibit exuberant splice activation of XBP1 and robust cleavage activation of ATF6, with abnormal regulation of calreticulin levels. The data suggest compensatory mechanisms allowing for cell survival in the absence of functional PERK. Interestingly, although induction of CHOP (a transcription factor implicated in apoptosis) is notably delayed after onset of ER stress, 293/PERK-K618A cells eventually produce CHOP at normal or even supranormal levels and exhibit increased apoptosis either in response to general ER stress or, more importantly, to specific misfolded secretory proteins.

Received for publication, March 31, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 DK40344 and DK48280. 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: Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, 5560 MSRB2, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0678. Tel.: 734-936-5505; Fax: 718-936-6684; E-mail: parvan{at}umich.edu.

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