title: Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Hao-Yuan
authors.initials: HY
authors.lastname: Jiang
authors.forename: Sheree A
authors.initials: SA
authors.lastname: Wek
authors.forename: Barbara C
authors.initials: BC
authors.lastname: McGrath
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Tsonwin
authors.initials: T
authors.lastname: Hai
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Cavener
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
mesh_terms: D051700:Activating Transcription Factor 3; D051701:Activating Transcription Factor 4; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D051700:Activating Transcription Factor 3; D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D010770:Phosphotransferases; D011494:Protein Kinases; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase