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Molecular and Cellular Biology, February 2004, p. 1365-1377, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1365-1377.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response

Hao-Yuan Jiang,1 Sheree A. Wek,1 Barbara C. McGrath,2 Dan Lu,3 Tsonwin Hai,3 Heather P. Harding,4 Xiaozhong Wang,5 David Ron,5 Douglas R. Cavener,2 and Ronald C. Wek1*

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202,1 Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802,2 Department of Molecular and Cellular Biochemistry and Center for Molecular Neurobiology, Ohio State University, Columbus, Ohio 43210,3 Department of Pharmacology,4 Skirball Institute, New York University School of Medicine, New York, New York 100165

Received 23 June 2003/ Returned for modification 28 July 2003/ Accepted 5 November 2003

In response to environmental stress, cells induce a program of gene expression designed to remedy cellular damage or, alternatively, induce apoptosis. In this report, we explore the role of a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) in coordinating stress gene responses. We find that expression of activating transcription factor 3 (ATF3), a member of the ATF/CREB subfamily of basic-region leucine zipper (bZIP) proteins, is induced in response to endoplasmic reticulum (ER) stress or amino acid starvation by a mechanism requiring eIF2 kinases PEK (Perk or EIF2AK3) and GCN2 (EIF2AK4), respectively. Increased expression of ATF3 protein occurs early in response to stress by a mechanism requiring the related bZIP transcriptional regulator ATF4. ATF3 contributes to induction of the CHOP transcriptional factor in response to amino acid starvation, and loss of ATF3 function significantly lowers stress-induced expression of GADD34, an eIF2 protein phosphatase regulatory subunit implicated in feedback control of the eIF2 kinase stress response. Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway. These results indicate that ATF3 has an integral role in the coordinate gene expression induced by eIF2 kinases. Given that ATF3 is induced by a very large number of environmental insults, this study supports involvement of eIF2 kinases in the coordination of gene expression in response to a more diverse set of stress conditions than previously proposed.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202. Phone: (317) 274-0549. Fax: (317) 274-4686. E-mail: rwek{at}iupui.edu.

Molecular and Cellular Biology, February 2004, p. 1365-1377, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.1365-1377.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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