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PMID: 14729979 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response.

Molecular and cellular biology ·Vol. 24 ·No. 3 ·2004-02-00 ·Pages 1365-77

Jiang HY, Wek SA, McGrath BC, Lu D, Hai T, Harding HP, Wang X, Ron D, Cavener DR, Wek RC

Abstract

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.

MeSH Terms
Activating Transcription Factor 3 Activating Transcription Factor 4 Animals CCAAT-Enhancer-Binding Proteins/metabolism Eukaryotic Initiation Factor-2/metabolism Mice Phosphorylation Phosphotransferases/metabolism Protein Kinases/metabolism Protein Serine-Threonine Kinases RNA, Messenger/metabolism Transcription Factor CHOP Transcription Factors/metabolism eIF-2 Kinase/metabolism
Chemicals
Activating Transcription Factor 3 CCAAT-Enhancer-Binding Proteins Ddit3 protein, mouse Eukaryotic Initiation Factor-2 RNA, Messenger Transcription Factors Activating Transcription Factor 4 Transcription Factor CHOP Phosphotransferases Protein Kinases Eif2ak4 protein, mouse Protein Serine-Threonine Kinases eIF-2 Kinase
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Jiang Hao-Yuan
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Wek Sheree A
McGrath Barbara C
Lu Dan
Hai Tsonwin
Harding Heather P
Wang Xiaozhong
Ron David
Cavener Douglas R
Wek Ronald C
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.3.1365-1377.2004
Published
2004-02-00
Pages
1365-77
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC321431
Subset
IM
Grants
NIDDK NIH HHS · R01 DK047119 · United States
NIGMS NIH HHS · R01 GM049164 · United States
NIGMS NIH HHS · R01 GM056957 · United States
NIEHS NIH HHS · R01 ES008681 · United States
NIEHS NIH HHS · ES08681 · United States
NIDDK NIH HHS · R01 DK059605 · United States
NIDDK NIH HHS · R37 DK047119 · United States
NIGMS NIH HHS · GM56957 · United States
NIGMS NIH HHS · R56 GM056957 · United States
NIDDK NIH HHS · DK59605 · United States
NIGMS NIH HHS · GM49164 · United States
NIDDK NIH HHS · DK47119 · United States
NIGMS NIH HHS · GM643540 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.3.1365-1377.2004 PMC Full Text View journal details
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