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

Hao Yuan Jiang, Sheree A. Wek, Barbara C. McGrath, Dan Lu, Tsonwin Hai, Heather P. Harding, Xiaozhong Wang, David Ron, Douglas R. Cavener, Ronald Wek

Research output: Contribution to journalArticle

330 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1365-1377
Number of pages13
JournalMolecular and Cellular Biology
Volume24
Issue number3
DOIs
StatePublished - Feb 2004

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Activating Transcription Factor 3
Eukaryotic Initiation Factor-2
Phosphotransferases
Leucine Zippers
Endoplasmic Reticulum Stress
Starvation
Gene Expression
Amino Acids
Phosphoprotein Phosphatases
Protein Kinases
Genes
Proteins
Embryonic Structures
Fibroblasts
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response. / Jiang, Hao Yuan; Wek, Sheree A.; McGrath, Barbara C.; Lu, Dan; Hai, Tsonwin; Harding, Heather P.; Wang, Xiaozhong; Ron, David; Cavener, Douglas R.; Wek, Ronald.

In: Molecular and Cellular Biology, Vol. 24, No. 3, 02.2004, p. 1365-1377.

Research output: Contribution to journalArticle

Jiang, HY, Wek, SA, McGrath, BC, Lu, D, Hai, T, Harding, HP, Wang, X, Ron, D, Cavener, DR & Wek, R 2004, 'Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response', Molecular and Cellular Biology, vol. 24, no. 3, pp. 1365-1377. https://doi.org/10.1128/MCB.24.3.1365-1377.2004
Jiang, Hao Yuan ; Wek, Sheree A. ; McGrath, Barbara C. ; Lu, Dan ; Hai, Tsonwin ; Harding, Heather P. ; Wang, Xiaozhong ; Ron, David ; Cavener, Douglas R. ; Wek, Ronald. / Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response. In: Molecular and Cellular Biology. 2004 ; Vol. 24, No. 3. pp. 1365-1377.
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