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.

[1]  M. Kilberg,et al.  Amino Acid Deprivation and Endoplasmic Reticulum Stress Induce Expression of Multiple Activating Transcription Factor-3 mRNA Species That, When Overexpressed in HepG2 Cells, Modulate Transcription by the Human Asparagine Synthetase Promoter* , 2003, Journal of Biological Chemistry.

[2]  L. Hendershot,et al.  Delineation of a Negative Feedback Regulatory Loop That Controls Protein Translation during Endoplasmic Reticulum Stress* , 2003, Journal of Biological Chemistry.

[3]  D. Scheuner,et al.  Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2 Is Required for Activation of NF-κB in Response to Diverse Cellular Stresses , 2003, Molecular and Cellular Biology.

[4]  D. Ron,et al.  Stress‐induced gene expression requires programmed recovery from translational repression , 2003, The EMBO journal.

[5]  R. Paules,et al.  An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. , 2003, Molecular cell.

[6]  A. Reimold,et al.  Differences in the Molecular Mechanisms Involved in the Transcriptional Activation of the CHOP and Asparagine Synthetase Genes in Response to Amino Acid Deprivation or Activation of the Unfolded Protein Response* , 2002, The Journal of Biological Chemistry.

[7]  A. Koromilas,et al.  Functional Characterization of pkr Gene Products Expressed in Cells from Mice with a Targeted Deletion of the N terminus or C terminus Domain of PKR* , 2002, The Journal of Biological Chemistry.

[8]  S. Kimball,et al.  The GCN2 eIF2α Kinase Is Required for Adaptation to Amino Acid Deprivation in Mice , 2002, Molecular and Cellular Biology.

[9]  C. Vinson,et al.  Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite. , 2002, Archives of biochemistry and biophysics.

[10]  K. Mori,et al.  Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response. , 2002, The Biochemical journal.

[11]  A. Gingras,et al.  Activation of GCN2 in UV-Irradiated Cells Inhibits Translation , 2002, Current Biology.

[12]  M. Kilberg,et al.  ATF4 Is a Mediator of the Nutrient-sensing Response Pathway That Activates the Human Asparagine Synthetase Gene* , 2002, The Journal of Biological Chemistry.

[13]  Peichuan Zhang,et al.  The PERK Eukaryotic Initiation Factor 2α Kinase Is Required for the Development of the Skeletal System, Postnatal Growth, and the Function and Viability of the Pancreas , 2002, Molecular and Cellular Biology.

[14]  Xiaohua Shen,et al.  The unfolded protein response in nutrient sensing and differentiation , 2002, Nature Reviews Molecular Cell Biology.

[15]  G. Sonenshein,et al.  RelB-p50 NF-κB Complexes Are Selectively Induced by Cytomegalovirus Immediate-Early Protein 1: Differential Regulation of Bcl-xL Promoter Activity by NF-κB Family Members , 2002, Journal of Virology.

[16]  Tsonwin Hai,et al.  The Roles of ATF3 in Liver Dysfunction and the Regulation of Phosphoenolpyruvate Carboxykinase Gene Expression* , 2002, The Journal of Biological Chemistry.

[17]  R. Wek,et al.  Dimerization and Release of Molecular Chaperone Inhibition Facilitate Activation of Eukaryotic Initiation Factor-2 Kinase in Response to Endoplasmic Reticulum Stress* , 2002, The Journal of Biological Chemistry.

[18]  L. Hendershot,et al.  Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. , 2002, Journal of molecular biology.

[19]  R. Kaufman,et al.  Ultraviolet Light Inhibits Translation through Activation of the Unfolded Protein Response Kinase PERK in the Lumen of the Endoplasmic Reticulum* , 2002, The Journal of Biological Chemistry.

[20]  Hiderou Yoshida,et al.  IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. , 2002, Genes & development.

[21]  Masataka Mori,et al.  Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. , 2002, The Journal of clinical investigation.

[22]  Krishnamurthy Natarajan,et al.  Gcn4p, a Master Regulator of Gene Expression, Is Controlled at Multiple Levels by Diverse Signals of Starvation and Stress , 2002, Eukaryotic Cell.

[23]  A. Koromilas,et al.  Regulation of Internal Ribosome Entry Site-mediated Translation by Eukaryotic Initiation Factor-2α Phosphorylation and Translation of a Small Upstream Open Reading Frame* , 2002, The Journal of Biological Chemistry.

[24]  Stevan R. Hubbard,et al.  IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA , 2002, Nature.

[25]  F. Urano,et al.  Transcriptional and translational control in the Mammalian unfolded protein response. , 2002, Annual review of cell and developmental biology.

[26]  K. Mori,et al.  XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor , 2001, Cell.

[27]  S. Shenolikar,et al.  Growth Arrest and DNA Damage-Inducible Protein GADD34 Assembles a Novel Signaling Complex Containing Protein Phosphatase 1 and Inhibitor 1 , 2001, Molecular and Cellular Biology.

[28]  P. Walter,et al.  Block of HAC1 mRNA Translation by Long-Range Base Pairing Is Released by Cytoplasmic Splicing upon Induction of the Unfolded Protein Response , 2001, Cell.

[29]  Tsonwin Hai,et al.  The Roles of ATF3 in Glucose Homeostasis , 2001, The Journal of Biological Chemistry.

[30]  Tsonwin Hai,et al.  The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. , 2001, Gene.

[31]  K. Ozato,et al.  Heterologous dimerization domains functionally substitute for the double‐stranded RNA binding domains of the kinase PKR , 2001, The EMBO journal.

[32]  R. Wek,et al.  Mechanism of activation of the double-stranded-RNA-dependent protein kinase, PKR: role of dimerization and cellular localization in the stimulation of PKR phosphorylation of eukaryotic initiation factor-2 (eIF2). , 2001, European journal of biochemistry.

[33]  M. Marton,et al.  Transcriptional Profiling Shows that Gcn4p Is a Master Regulator of Gene Expression during Amino Acid Starvation in Yeast , 2001, Molecular and Cellular Biology.

[34]  P. Walter,et al.  Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals. , 2001, Current opinion in cell biology.

[35]  E McEwen,et al.  Translational control is required for the unfolded protein response and in vivo glucose homeostasis. , 2001, Molecular cell.

[36]  D. Ron,et al.  Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. , 2001, Molecular cell.

[37]  D. Ron,et al.  Feedback Inhibition of the Unfolded Protein Response by GADD34-Mediated Dephosphorylation of eIF2α , 2001, The Journal of cell biology.

[38]  Tsonwin Hai,et al.  A TRANSGENIC MOUSE MODEL WITH LIVER DYSFUNCTION AND DEFECTS IN ENDOCRINE PANCREAS , 2001 .

[39]  J. W. Brewer,et al.  PERK mediates cell-cycle exit during the mammalian unfolded protein response. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Schapira,et al.  Regulated translation initiation controls stress-induced gene expression in mammalian cells. , 2000, Molecular cell.

[41]  Pierre Fafournoux,et al.  Amino Acids Control Mammalian Gene Transcription: Activating Transcription Factor 2 Is Essential for the Amino Acid Responsiveness of the CHOP Promoter , 2000, Molecular and Cellular Biology.

[42]  T. Aso,et al.  Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: activation of c-Jun NH(2)-terminal kinase and promoter response element. , 2000, Blood.

[43]  A. Leutz,et al.  Translational control of C/EBPalpha and C/EBPbeta isoform expression. , 2000, Genes & development.

[44]  A. Hinnebusch,et al.  Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. , 2000, Molecular cell.

[45]  G. Lathrop,et al.  EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome , 2000, Nature Genetics.

[46]  J. Robert,et al.  Wolcott-Rallison syndrome: a case with endocrine and exocrine pancreatic deficiency and pancreatic hypotrophy , 2000, European Journal of Pediatrics.

[47]  Anne Bertolotti,et al.  Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response , 2000, Nature Cell Biology.

[48]  D. Ron,et al.  Perk is essential for translational regulation and cell survival during the unfolded protein response. , 2000, Molecular cell.

[49]  R. Sood,et al.  Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. , 2000, The Biochemical journal.

[50]  R. Sood,et al.  A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha. , 2000, Genetics.

[51]  Jane-Jane Chen.  14 Heme-regulated eIF2α Kinase , 2000 .

[52]  D. Ron,et al.  15 PERK and Translational Control by Stress in the Endoplasmic Reticulum , 2000 .

[53]  J. Hershey,et al.  2 The Pathway and Mechanism of Initiation of Protein Synthesis , 2000 .

[54]  N. Sonenberg,et al.  Translational control of gene expression , 2000 .

[55]  A. Leutz,et al.  Translational control of C/EBP (cid:1) and C/EBP (cid:2) isoform expression , 2000 .

[56]  R. Sood,et al.  A Mammalian Homologue of GCN 2 Protein Kinase Important for Translational Control by Phosphorylation of Eukaryotic Initiation Factor-2 a , 2000 .

[57]  A. Bruhat,et al.  Amino acid regulation of gene expression. , 2000, Current opinion in clinical nutrition and metabolic care.

[58]  B. Williams,et al.  PKR; a sentinel kinase for cellular stress , 1999, Oncogene.

[59]  K. Mori,et al.  Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. , 1999, Molecular biology of the cell.

[60]  T. W. Fawcett,et al.  Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. , 1999, The Biochemical journal.

[61]  D. Ron,et al.  Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase , 1999, Nature.

[62]  Tsonwin Hai,et al.  ATF3 and stress responses. , 1999, Gene expression.

[63]  R. Sood,et al.  Translational Control -subunit Kinase, Pek, Involved in Α Pancreatic Eukaryotic Initiation Factor 2 Identification and Characterization Of , 1998 .

[64]  Xiaozhong Wang,et al.  CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. , 1998, Genes & development.

[65]  A. E. Rogers,et al.  Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. , 1997, The Journal of clinical investigation.

[66]  Peter Walter,et al.  The Transmembrane Kinase Ire1p Is a Site-Specific Endonuclease That Initiates mRNA Splicing in the Unfolded Protein Response , 1997, Cell.

[67]  A. Hinnebusch,et al.  Translational Regulation of Yeast GCN4 , 1997, The Journal of Biological Chemistry.

[68]  A. Fornace,et al.  Mammalian GADD34, an Apoptosis- and DNA Damage-inducible Gene* , 1997, The Journal of Biological Chemistry.

[69]  C. Thornton,et al.  Autopsy findings in the Wolcott-Rallison syndrome. , 1997, Pediatric pathology & laboratory medicine : journal of the Society for Pediatric Pathology, affiliated with the International Paediatric Pathology Association.

[70]  R. Wek,et al.  Histidyl-tRNA Synthetase-related Sequences in GCN2 Protein Kinase Regulate in Vitro Phosphorylation of eIF-2* , 1996, The Journal of Biological Chemistry.

[71]  G. Sonenshein,et al.  Maintenance of nuclear factor-kappa B/Rel and c-myc expression during CD40 ligand rescue of WEHI 231 early B cells from receptor-mediated apoptosis through modulation of I kappa B proteins. , 1996, Journal of immunology.

[72]  N. Holbrook,et al.  Physical and Functional Association between GADD153 and CCAAT/Enhancer-binding Protein β during Cellular Stress* , 1996, The Journal of Biological Chemistry.

[73]  C. Wolfgang,et al.  Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10 , 1996, Molecular and cellular biology.

[74]  M. Clemens.  5 Protein Kinases That Phosphorylate eIF2 and eIF2B, and Their Role in Eukaryotic Cell Translational Control , 1996 .

[75]  A. Aguzzi,et al.  Deficient signaling in mice devoid of double‐stranded RNA‐dependent protein kinase. , 1995, The EMBO journal.

[76]  R. Wek,et al.  The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids , 1995, Molecular and cellular biology.

[77]  N. Sonenberg,et al.  Translational control of gene expression , 2000 .

[78]  R. Wek.  eIF-2 kinases: regulators of general and gene-specific translation initiation. , 1994, Trends in biochemical sciences.

[79]  T. Willnow,et al.  Homologous recombination for gene replacement in mouse cell lines. , 1994, Methods in cell biology.

[80]  D. Ron,et al.  CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. , 1992, Genes & development.

[81]  B. M. Jackson,et al.  Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control , 1991, Molecular and cellular biology.

[82]  J. Fargnoli,et al.  Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents , 1989, Molecular and cellular biology.

[83]  D. Beier,et al.  Generation of murine stromal cell lines supporting hematopoietic stem cell proliferation by use of recombinant retrovirus vectors encoding simian virus 40 large T antigen , 1988, Molecular and cellular biology.