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Initiation Factor eIF2α Phosphorylation in Stress Responses and Apoptosis

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Part of the book series: Progress in Molecular and Subcellular Biology ((PMSB,volume 27))

Abstract

Protein synthesis in eukaryotes is a complex process which can be regulated at many points in the pathway. In recent years it has become clear that both the overall rate of translation and the relative rates of synthesis of individual proteins can be controlled post-transcriptionally through changes in the activities or levels of a small number of key components, and that such regulation usually takes place at the level of polypeptide chain initiation. A large body of evidence indicates that the essential polypeptide chain initiation factor eIF2 is a frequent target for regulation, and that its activity is often rate-limiting for protein synthesis. The phosphorylation of the smallest (α) subunit of eIF2 is a widely used mechanism of translational control in many organisms, and there are numerous physiologically important situations where eIF2α kinases are activated or inhibited. This chapter provides a review of our knowledge concerning the mechanisms by which eIF2 is controlled by reversible protein phosphorylation.

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References

  • Abastado J-P, Miller PF, Jackson BM, Hinnebusch AG (1991) Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control. Mol Cell Biol 11:486–496

    PubMed  CAS  Google Scholar 

  • Abraham N, Stojdl DF, Duncan PI, Méthot N, Ishii T, Dubé M, Vanderhyden BC, Atkins HL, Gray DA, McBurney MW, Koromilas AE, Brown EG, Sonenberg N, Bell JC (1999) Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR. J Biol Chem 274:5953–5962

    Article  PubMed  CAS  Google Scholar 

  • Aktas H, Flückiger R, Acosta JA, Savage JM, Palakurthi SS, Halperin JA (1998) Depletion of intracellular Ca2+ stores, phosphorylation of eIF2α, and sustained inhibition of translation initiation mediate the anticancer effects of clotrimazole. Proc Natl Acad Sci USA 95:8280–8285

    Article  PubMed  CAS  Google Scholar 

  • Altmann M, Trachsel H (1993) Regulation of translation initiation and modulation of cellular physiology. Trends Biochem Sci 18:429–432

    Article  PubMed  CAS  Google Scholar 

  • Asano K, Krishnamoorthy T, Phan L, Pavitt GD, Hinnebusch AG (1999) Conserved bipartite motifs in yeast eIF5 and eIF2Bî, GTPase-activating and GDP-GTP exchange factors in translation initiation, mediate binding to their common substrate eIF2. EMBO J 18:1673–1688

    Article  PubMed  CAS  Google Scholar 

  • Aulak KS, Mishra R, Zhou LY, Hyatt SL, De Jonge W, Lamers W, Snider M, Hatzoglou M (1999) Post-transcriptional regulation of the arginine transporter Cat-1 by amino acid availability. J Biol Chem 274:30424–30432

    Article  PubMed  CAS  Google Scholar 

  • Balachandran S, Kim CN, Yeh WC, Mak TW, Bhalla K, Barber GN (1998) Activation of the dsRNAdependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. EMBO J 17:6888–6902

    Article  PubMed  CAS  Google Scholar 

  • Balachandran S, Roberts PC, Kipperman T, Bhalla KN, Compans RW, Archer DR, Barber GN (2000) Alpha/beta interferons potentiate virus-induced apoptosis through activation of the FADD/Caspase-8 death signaling pathway. J Virol 74:1513–1523

    Article  PubMed  CAS  Google Scholar 

  • Barber GN, Wambach M, Wong M-L, Dever TE, Hinnebusch AG, Katze MG (1993) Translational regulation by the interferon-induced double-stranded-RNA-activated 68-kDa protein kinase. Proc Natl Acad Sci USA 90:4621–4625

    Article  PubMed  CAS  Google Scholar 

  • Barbet NC, Schneider U, Helliwell SB, Stansfield I, Tuite MF, Hall MN (1996) TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell 7:25–42

    PubMed  CAS  Google Scholar 

  • Berlanga JJ, Herrero S, De Haro C (1998) Characterization of the hemin-sensitive eukaryotic initiation factor 2a kinase from mouse nonerythroid cells. J Biol Chem 273:32340–32346

    Article  PubMed  CAS  Google Scholar 

  • Berlanga JJ, Santoyo J, De Haro C (1999) Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2α kinase. Eur J Biochem 265:754–762

    Article  PubMed  CAS  Google Scholar 

  • Berset C, Trachsel H, Altmann M (1998) The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci USA 95:4264–4269

    Article  PubMed  CAS  Google Scholar 

  • Brostrom CO, Brostrom MA (1990) Calcium-dependent regulation of protein synthesis in intact mammalian cells. Annu Rev Physiol 52:577–590

    Article  PubMed  CAS  Google Scholar 

  • Brostrom CO, Brostrom MA (1998) Regulation of translation initiation during cellular responses to stress. Prog Nucleic Acid Res Mol Biol 58:79–125

    Article  PubMed  CAS  Google Scholar 

  • Brostrom MA, Cade C, Prostko CR, Gmitter-Yellen D, Brostrom CO (1990) Accommodation of protein synthesis to chronic deprivation of intracellular sequestered calcium. A putative role for GRP78. J Biol Chem 265:20539–20546

    PubMed  CAS  Google Scholar 

  • Brostrom MA, Prostko CR, Gmitter D, Brostrom CO (1995) Independent signaling of grp78 gene transcription and phosphorylation of eukaryotic initiation factor 2α by the stressed endoplasmic reticulum. J Biol Chem 270:4127–4132

    Article  PubMed  CAS  Google Scholar 

  • Brostrom CO, Prostko CR, Kaufmann RJ, Brostrom MA (1996) Inhibition of translational initiation by activators of the glucose-regulated stress protein and heat shock protein stress response systems — role of the interferon-inducible double-stranded RNA-activated eukaryotic initiation factor 2α kinase. J Biol Chem 271:24995–25002

    Article  PubMed  CAS  Google Scholar 

  • Brown CY, Mize GJ, Pineda M, George DL, Morris DR (1999) Role of two upstream open reading frames in the translational control of oncogene mdm2. Oncogene 18:5631–5637

    Article  PubMed  CAS  Google Scholar 

  • Bruhat A, Jousse C, Wang XZ, Ron D, Ferrara M, Fafournoux P (1997) Amino acid limitation induces expression of CHOP, a CCAAT/enhancer binding protein-related gene, at both transcriptional and post-transcriptional levels. J Biol Chem 272:17588–17593

    Article  PubMed  CAS  Google Scholar 

  • Burda J, Martín ME, García A, Alcázar A, Fando JL, Salinas M (1994) Phosphorylation of the a subunit of initiation factor 2 correlates with the inhibition of translation following transient cerebral ischaemia in the rat. Biochem J 302:335–338

    PubMed  CAS  Google Scholar 

  • Bushell M, McKendrick L, Jänicke RU, Clemens MJ, Morley SJ (1999) Caspase-3 is necessary and sufficient for cleavage of protein synthesis eukaryotic initiation factor 4G during apoptosis. FEBS Lett 451:332–336

    Article  PubMed  CAS  Google Scholar 

  • Bushell M, Poncet D, Marissen WE, Flotow H, Lloyd RE, Clemens MJ, Morley SJ (2000a) Cleavage of polypeptide chain initiation factor eIF4GI during apoptosis: Characterisation of an internal fragment generated by caspase-3-mediated cleavage. Cell Death Differ 7:628–636

    Article  PubMed  CAS  Google Scholar 

  • Bushell M, Wood W, Clemens MJ, Morley SJ (2000b) Changes in integrity and association of eukaryotic protein synthesis initiation factors during apoptosis. Eur J Biochem 267:1083–1091

    Article  PubMed  CAS  Google Scholar 

  • Chang GC, Liu R, Panniers R, Li GC (1994) Rat fibroblasts transfected with the human 70-kDa heat shock gene exhibit altered translation and eukaryotic initiation factor 2 alpha phosphorylation following heat shock. Int J Hypertherm 10:325–337

    Article  CAS  Google Scholar 

  • Chatterjee M, Chatterjee N, Datta R, Datta B, Gupta NK (1998) Expression and activity of p67 are induced during heat shock. Biochem Biophys Res Commun 249:113–117

    Article  PubMed  CAS  Google Scholar 

  • Chen JJ, Yang JM, Petryshyn R, Kosower N, London IM (1989) Disulfide bond formation in the regulation of eIF-2a kinase by heme. J Biol Chem 264:9559–9564

    PubMed  CAS  Google Scholar 

  • Chen JJ, Throop MS, Gehrke L, Kuo I, Pal JK, Brodsky M, London IM (1991) Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2a (eIF-2α) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2a kinase. Proc Natl Acad Sci USA 88:7729–7733

    Article  PubMed  CAS  Google Scholar 

  • Chen JJ, Crosby JS, London IM (1994) Regulation of heme-regulated eIF-2a kinase and its expression in erythroid cells. Biochimie 76:761–769

    Article  PubMed  CAS  Google Scholar 

  • Cheshire JL, Williams BRG, Baldwin AS Jr (1999) Involvement of double-stranded RNA-activated protein kinase in the synergistic activation of nuclear factor-kappaB by tumor necrosis factora and gamma-interferon in preneuronal cells. J Biol Chem 274:4801–4806

    Article  PubMed  CAS  Google Scholar 

  • Child SJ, Miller MK, Geballe AP (1999) Translational control by an upstream open reading frame in the HER-2/neu transcript. J Biol Chem 274:24335–24341

    Article  PubMed  CAS  Google Scholar 

  • Chinchar VG, Dholakia JN (1989) Frog virus 3-induced translational shut-off: Activation of an eIF-2 kinase in virus-infected cells. Virus Res 14:207–224

    Article  PubMed  CAS  Google Scholar 

  • Choi S-Y, Scherer BJ, Schnier J, Davies MV, Kaufman RJ, Hershey JWB (1992) Stimulation of protein synthesis in COS cells transfected with variants of the a-subunit of initiation factor eIF-2. J Biol Chem 267:286–293

    PubMed  CAS  Google Scholar 

  • Chong KL, Feng L, Schappert K, Meurs E, Donahue TF, Friesen JD, Hovanessian AG, Williams BRG (1992) Human p68 kinase exhibits growth suppression in yeast and homology to the translational regulator GCN2. EMBO J 11:1553–1562

    PubMed  CAS  Google Scholar 

  • Chu WM, Ballard R, Carpick BW, Williams BRG, Schmid CW (1998) Potential Alu function: Regulation of the activity of double-stranded RNA-activated kinase PKR. Mol Cell Biol 18:58–68

    PubMed  CAS  Google Scholar 

  • Circle DA, Neel OD, Robertson HD, Clarke PA, Mathews MB (1997) Surprising specificity of PKR binding to delta agent genomic RNA. RNA Publ RNA Soc 3:438–448

    CAS  Google Scholar 

  • Clemens MJ (1996) Protein kinases that phosphorylate eIF2 and eIF2B, and their role in eukaryotic cell translational control. In: Hershey JWB, Mathews MB, Sonenberg N (eds) Translational control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 139–172

    Google Scholar 

  • Clemens MJ (1997) PKR — a protein kinase regulated by double-stranded RNA. Int J Biochem Cell Biol 29:945–949

    Article  PubMed  CAS  Google Scholar 

  • Clemens MJ, Bommer UA (1999) Translational control: the cancer connection. Int J Biochem Cell Biol 31:1–23

    Article  PubMed  CAS  Google Scholar 

  • Clemens MJ, Elia A (1997) The double-stranded RNA-dependent protein kinase PKR: structure and function. J Interferon Cytokine Res 17:503–524

    Article  PubMed  CAS  Google Scholar 

  • Clemens MJ, Galpine A, Austin SA, Panniers R, Henshaw EC, Duncan R, Hershey JWB, Pollard JW (1987) Regulation of polypeptide chain initiation in Chinese hamster ovary cells with a temperature-sensitive leucyl-tRNA synthetase. J Biol Chem 262:767–771

    PubMed  CAS  Google Scholar 

  • Clemens MJ, Laing K, Jeffrey IW, Schofield A, Sharp TV, Elia A, Matys V, James MC, Tilleray VJ (1994) Regulation of the interferon-inducible eIF-2a protein kinase by small RNAs. Biochimie 76:770–778

    Article  PubMed  CAS  Google Scholar 

  • Clemens MJ, Bushell M, Morley SJ (1998) Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines. Oncogene 17:2921–2931

    Article  PubMed  CAS  Google Scholar 

  • Clemens MJ, Bushell M, Jeffrey IW, Pain VM, Morley SJ (2000) Translation initiation factor modifications and the regulation of protein synthesis in apoptotic cells. Cell Death Differ 7:603–615

    Article  PubMed  CAS  Google Scholar 

  • Coolidge CJ, Patton JG (2000) A new double-stranded RNA-binding protein that interacts with PKR. Nucleic Acids Res 28:1407–1417

    Article  PubMed  CAS  Google Scholar 

  • Craig AWB, Cosentino GP, Donzé O, Sonenberg N(1996) The kinase insert domain of interferoninduced protein kinase PKR is required for activity but not for interaction with the pseudosubstrate K3L. J Biol Chem 271:24526–24533

    Article  PubMed  CAS  Google Scholar 

  • Crosby JS, Lee K, London IM, Chen J-J (1994) Erythroid expression of the heme-regulated eIF2α kinase. Mol Cell Biol 14:3906–3914

    PubMed  CAS  Google Scholar 

  • Cuddihy AR, Li SY, Tam NWN, Wong AHT, Taya Y, Abraham N, Bell JC, Koromilas AE (1999a) Double-stranded-RNA-activated protein kinase PKR enhances transcriptional activation by tumor suppressor p53. Mol Cell Biol 19:2475–2484

    PubMed  CAS  Google Scholar 

  • Cuddihy AR, Wong AHT, Tam NWN, Li SY, Koromilas AE (1999b) The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. Oncogene 18:2690–2702

    Article  PubMed  CAS  Google Scholar 

  • Datta B, Datta R (1999) Induction of apoptosis due to lowering the level of eukaryotic initiation factor 2-associated protein, p67, from mammalian cells by antisense approach. Exp Cell Res 246:376–383

    Article  PubMed  CAS  Google Scholar 

  • Datta B, Datta R, Mukherjee S, Zhang ZL (1999) Increased phosphorylation of eukaryotic initiation factor 2a at the G2/M boundary in human osteosarcoma cells correlates with deglycosylation of p67 and a decreased rate of protein synthesis. Exp Cell Res 250:223–230

    Article  PubMed  CAS  Google Scholar 

  • Davies MV, Furtado M, Hershey JWB, Thimmappaya B, Kaufman RJ (1989) Complementation of adenovirus virus-associated RNA I gene deletion by expression of a mutant eukaryotic translation initiation factor. Proc Natl Acad Sci USA 86:9163–9167

    Article  PubMed  CAS  Google Scholar 

  • De Haro C, Méndez R, Santoyo J (1996) The eIF-2α kinases and the control of protein synthesis. FASEB J 10:1378–1387

    PubMed  Google Scholar 

  • DeGracia DJ, Neumar RW, White BC, Krause GS (1996) Global brain ischemia and reperfusion: Modifications in eukaryotic initiation factors associated with inhibition of translation initiation. J Neurochem 67:2005–2012

    Article  PubMed  CAS  Google Scholar 

  • DeGracia DJ, Sullivan JM, Neumar RW, Alousi SS, Hikade KR, Pittman JE, White BC, Rafols JA, Krause GS (1997) Effect of brain ischemia and reperfusion on the localization of phosphorylated eukaryotic initiation factor 2α. J Cereb Blood Flow Metab 17:1291–1302

    Article  PubMed  CAS  Google Scholar 

  • DeGracia DJ, Adamczyk S, Folbe AJ, Konkoly LL, Pittman JE, Neumar RW, Sullivan JM, Scheuner D, Kaufman RJ, White BC, Krause GS (1999) Eukaryotic initiation factor 2α kinase and phosphatase activity during postischemic brain reperfusion. Exp Neurol 155:221–227

    Article  PubMed  CAS  Google Scholar 

  • Demarchi F, Gutierrez MI, Giacca M (1999) Human immunodeficiency virus type 1 Tat protein activates transcription factor NF-kappaB through the cellular interferon-inducible, doublestranded RNA-dependent protein kinase, PKR. J Virol 73:7080–7086

    CAS  Google Scholar 

  • Der SD, Yang YL, Weissmann C, Williams BRG (1997) A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc Natl Acad Sci USA 94:3279–3283

    Article  PubMed  CAS  Google Scholar 

  • DeStefano J, Olmsted E, Panniers R, Lucas-Lenard J (1990) The α subunit of eucaryotic initiation factor 2 is phosphorylated in mengovirus-infected mouse L cells. J Virol 64:4445–4453

    PubMed  CAS  Google Scholar 

  • Dever TE, Feng L, Wek RC, Cigan AM, Donahue TF, Hinnebusch AG (1992) Phosphorylation of initiation factor 2α by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell 68:585–596

    Article  PubMed  CAS  Google Scholar 

  • Donzé O, Picard D (1999) Hsp90 binds and regulates the ligand-inducible α subunit of eukaryotic translation initiation factor kinase Gcn2. Mol Cell Biol 19:8422–8432

    PubMed  Google Scholar 

  • Donzé O, Jagus R, Koromilas AE, Hershey JWB, Sonenberg N (1995) Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J 14:3828–3834

    PubMed  Google Scholar 

  • Donzé O, Dostie J, Sonenberg N (1999) Regulatable expression of the interferon-induced doublestranded RNA dependent protein kinase PKR induces apoptosis and Fas receptor expression. Virology 256:322–329

    Article  PubMed  Google Scholar 

  • Duncan RF, Hershey JWB (1989) Protein synthesis and protein phosphorylation during heat stress, recovery and adaptation. J Cell Biol 109:1467–1481

    Article  PubMed  CAS  Google Scholar 

  • Farrell PJ, Balkow K, Hunt T, Jackson RJ, Trachsel H (1977) Phosphorylation of initiation factor eIF-2 and control of reticulocyte protein synthesis. Cell 11:187–200

    Article  PubMed  CAS  Google Scholar 

  • Fox HL, Pham PT, Kimball SR, Jefferson LS, Lynch CJ (1998) Amino acid effects on translational repressor 4 E-BP 1 are mediated primarily by L-leucine in isolated adipocytes. Am J Physiol Cell Physiol 275:C1232-C1238

    Google Scholar 

  • Fraser CS, Pain VM, Morley SJ (1999) Cellular stress in Xenopus kidney cells enhances the phosphorylation of eukaryotic translation initiation factor (elF)4 E and the association of e1F4F with poly(A)-binding protein. Biochem J 342:519–526

    Article  PubMed  CAS  Google Scholar 

  • Gale M Jr, Tan SL, Wambach M, Katze MG (1996) Interaction of the interferon-induced PKR protein kinase with inhibitory proteins p58IPK and vaccinia virus K3L is mediated by unique domains: implications for kinase regulation. Mol Cell Biol 16:4172–4181

    PubMed  CAS  Google Scholar 

  • Gatignol A, Buckler C, Jeang K-T (1993) Relatedness of an RNA-binding motif in human immunodeficiency virus type 1 TAR RNA-binding protein TRBP to human P1/dsI kinase and Drosophila Staufen. Mol Cell Biol 13:2193–2202

    PubMed  CAS  Google Scholar 

  • Gil J, Alcamí J, Esteban M (1999) Induction of apoptosis by double-stranded-RNA-dependent protein kinase (PKR) involves the alpha subunit of eukaryotic translation initiation factor 2 and NF-kappaB. Mol Cell Biol 19:4653–4663

    PubMed  CAS  Google Scholar 

  • Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N (1999) Regulation of 4 E-BP 1 phosphorylation: a novel two-step mechanism. Genes Dev 13:1422–1437

    Article  PubMed  CAS  Google Scholar 

  • Gross M, Olin A, Hessefort S, Bender S (1994) Control of protein synthesis by hemin. Purification of a rabbit reticulocyte hsp 70 and characterization of its regulation of the activation of the hemin-controlled eIF-2(α) kinase. J Biol Chem 269:22738–22748

    PubMed  CAS  Google Scholar 

  • Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J (1998) Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4 E BP 1 through a common effector mechanism. J Biol Chem 273:14484–14494

    Article  PubMed  CAS  Google Scholar 

  • Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274

    Article  PubMed  CAS  Google Scholar 

  • Henry GL, McCormack SJ, Thomis DC, Samuel CE (1994) Mechanism of interferon action. Translational control and the RNA-dependent protein kinase (PKR): Antagonists of PKR enhance the translational activity of mRNAs that include a 161 nucleotide region from reovirus 51 mRNA. J Biol Regul Homeost Agents 8:15–24

    PubMed  CAS  Google Scholar 

  • Hinnebusch AG (1990) Involvement of an initiation factor and protein phosphorylation in translational control of GCN4 mRNA. Trends Biochem Sci 15:148–152

    Article  PubMed  CAS  Google Scholar 

  • Hinnebusch AG (1996) Translational control of GCN4: gene-specific regulation by phosphorylation of eIF2. In: Hershey JWB, Mathews MB, Sonenberg N (eds) Translational control. Cold Spring Harbor Laboratory Press, Plainsview, NY, pp 199–244

    Google Scholar 

  • Hu BR, Wieloch T (1993) Stress-induced inhibition of protein synthesis initiation: Modulation of initiation factor 2 and guanine nucleotide exchange factor activities following transient cerebral ischemia in the rat. J Neurosci 13:1830–1838

    PubMed  CAS  Google Scholar 

  • Hu B-R, Yang Y-BO, Wieloch T (1993) Heat-shock inhibits protein synthesis and eIF-2 activity in cultured cortical neurons. Neurochem Res 18:1003–1007

    Article  PubMed  CAS  Google Scholar 

  • Huang J, Schneider RJ (1990) Adenovirus inhibition of cellular protein synthesis is prevented by the drug 2-aminopurine. Proc Natl Acad Sci USA 87:7115–7119

    Article  PubMed  CAS  Google Scholar 

  • Icely PL, Gros P, Bergeron JJM, Devault A, Afar DEH, Bell JC (1991) TIK, a novel serine/threonine kinase, is recognized by antibodies directed against phosphotyrosine. J Biol Chem 266: 16073–16077

    PubMed  CAS  Google Scholar 

  • Ito T, Jagus R, May WS (1994) Interleukin 3 stimulates protein synthesis by regulating doublestranded RNA-dependent protein kinase. Proc Natl Acad Sci USA 91:7455–7459

    Article  PubMed  CAS  Google Scholar 

  • Ito T, Warnken SP, May WS (1999a) Protein synthesis inhibition by flavonoids: Roles of eukaryotic initiation factor 2a kinases. Biochem Biophys Res Commun 265:589–594

    Article  PubMed  CAS  Google Scholar 

  • Ito T, Yang ML, May WS (1999b) RAX, a cellular activator for double-stranded RNA-dependent protein kinase during stress signaling. J Biol Chem 274:15427–15432

    Article  PubMed  CAS  Google Scholar 

  • Jackson RJ, Hunt SL, Reynolds JE, Kaminski A (1995) Cap-dependent and cap-independent translation — Operational distinctions and mechanistic interpretations. Curr Topics Microbiol Immunol 203:1–29

    Article  CAS  Google Scholar 

  • Jagus R, Joshi B, Barber GN (1999) PKR, apoptosis and cancer. Int J Biochem Cell Biol 31:123–138

    Article  PubMed  CAS  Google Scholar 

  • Jefferies HBJ, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G (1997) Rapamycin suppresses 5’TOP mRNA translation through inhibition of p70S6k. EMBO J 16:3693–3704

    Article  PubMed  CAS  Google Scholar 

  • Jeffrey IW, Kadereit S, Meurs EF, Metzger T, Bachmann M, Schwemmle M, Hovanessian AG, Clemens MJ (1995) Nuclear localization of the interferon-inducible protein kinase PKR in human cells and transfected mouse cells. Exp Cell Res 218:17–27

    Article  PubMed  CAS  Google Scholar 

  • Jiménez-García LF, Green SR, Mathews MB, Spector DL (1993) Organization of the doublestranded RNA-activated protein kinase DAI and virus-associated VA RNA1 in adenovirus- 2infected HeLa cells. J Cell Sci 106:11–22

    PubMed  Google Scholar 

  • Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233

    Article  PubMed  CAS  Google Scholar 

  • Kaufman RJ, Murtha P(1987) Translational control mediated by eucaryotic initiation factor-2 is restricted to specific mRNAs in transfected cells. Mol Cell Biol 7:1568–1571

    PubMed  CAS  Google Scholar 

  • Kaufman RJ, Davies MV, Pathak VK, Hershey JWB (1989) The phosphorylation state of eucaryotic initiation factor 2 alters translational efficiency of specific mRNAs. Mol Cell Biol 9:946–958

    PubMed  CAS  Google Scholar 

  • Kawakubo K, Kuhen KL, Vessey JW, George CX, Samuel CE (1999) Alternative splice variants of the human PKR protein kinase possessing different 5’-untranslated regions: Expression in untreated and interferon-treated cells and translational activity. Virology 264:106–114

    Article  PubMed  CAS  Google Scholar 

  • Kedersha NL, Gupta M, Li W, Miller I, Anderson P (1999) RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2α to the assembly of mammalian stress granules. J Cell Biol 147:1431–1441

    Article  PubMed  CAS  Google Scholar 

  • Kimball SR (1999) Eukaryotic initiation factor eIF2. Int J Biochem Cell Biol 31:25–29

    Article  PubMed  CAS  Google Scholar 

  • Kimball SR, Jefferson LS (1992) Regulation of protein synthesis by modulation of intracellular calcium in rat liver. Am J Physiol Endocrinol Metab 263:E958–E964

    Google Scholar 

  • Kimball SR, Karinch AM, Feldhoff RC, Mellor H, Jefferson LS (1994) Purification and characterization of eukaryotic translational initiation factor eIF-2B from liver. Biochim Biophys Acta Gen Subj 1201:473–481

    Article  Google Scholar 

  • Kimball SR, Fabian JR, Pavitt GD, Hinnebusch AG, Jefferson LS (1998a) Regulation of guanine nucleotide exchange through phosphorylation of eukaryotic initiation factor eIF2a. J Biol Chem 273:12841–12845

    Article  PubMed  CAS  Google Scholar 

  • Kimball SR, Heinzinger NK, Horetsky RL, Jefferson LS (1998b) Identification of interprotein interactions between the subunits of eukaryotic initiation factors eIF2 and eIF2B. J Biol Chem 273:3039–3044

    Article  PubMed  CAS  Google Scholar 

  • Kimball SR, Horetsky RL, Jefferson LS (1998c) Implication of eIF2B rather than eIF4E in the regulation of global protein synthesis by amino acids in L6 myoblasts. J Biol Chem 273:30945–30953

    Article  PubMed  CAS  Google Scholar 

  • Kimball SR, Shantz LM, Horetsky RL, Jefferson LS (1999) Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J Biol Chem 274:11647–11652

    Article  PubMed  CAS  Google Scholar 

  • Kirchhoff S, Koromilas AE, Schaper F, Grashoff M, Sonenberg N, Hauser H (1995) IRF-1 induced cell growth inhibition and interferon induction requires the activity of the protein kinase PKR. Oncogene 11:439–445

    PubMed  CAS  Google Scholar 

  • Kleijn M, Scheper GC, Voorma HO, Thomas AAM (1998) Regulation of translation initiation factors by signal transduction. Eur J Biochem 253:531–544

    Article  PubMed  CAS  Google Scholar 

  • Koromilas AE, Lazaris-Karatzas A, Sonenberg N (1992a) mRNAs containing extensive secondary structure in their 5’ non-coding region translate efficiently in cells overexpressing initiation factor eIF-4 E. EMBO J 11:4153–4158

    PubMed  CAS  Google Scholar 

  • Koromilas AE, Roy S, Barber GN, Katze MG, Sonenberg N (1992b) Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase. Science 257:1685–1689

    Article  PubMed  CAS  Google Scholar 

  • Kozak M (1999) Initiation of translation in prokaryotes and eukaryotes. Gene 234:187–208

    Article  PubMed  CAS  Google Scholar 

  • Kronfeld-Kinar Y, Vilchik S, Hyman T, Leibkowicz F, Salzberg S (1999) Involvement of PKR in the regulation of myogenesis. Cell Growth Differ 10:201–212

    PubMed  CAS  Google Scholar 

  • Kumar A, Yang YL, Flati V, Der S, Kadereit S, Deb A, Haque J, Reis L, Weissmann C, Williams BRG (1997) Deficient cytokine signaling in mouse embryo fibroblasts with a targeted deletion in the PKR gene: Role of IRF-1 and NF-kappaB. EMBO J 16:406–416

    Article  PubMed  CAS  Google Scholar 

  • Kumar KU, Srivastava SP, Kaufman RJ (1999) Double-stranded RNA-activated protein kinase (PKR) is negatively regulated by 60 S ribosomal subunit protein L18. Mol Cell Biol 19:1116–1125

    PubMed  CAS  Google Scholar 

  • Laitusis AL, Brostrom MA, Brostrom CO (1999) The dynamic role of GRP78/BiP in the coordination of mRNA translation with protein processing. J Biol Chem 274:486–493

    Article  PubMed  CAS  Google Scholar 

  • Lang CH, Wu DQ, Frost RA, Jefferson LS, Vary TC, Kimball SR (1999) Chronic alcohol feeding impairs hepatic translation initiation by modulating eIF2 and eIF4E. Am J Physiol Endocrinol Metab 277:E805–E814

    Google Scholar 

  • Langland JO, Kao PN, Jacobs BL (1999) Nuclear factor-90 of activated T-cells: a double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR. Biochemistry 38:6361–6368

    Article  PubMed  CAS  Google Scholar 

  • Lee SB, Esteban M (1993) The interferon-induced double-stranded RNA-activated human p68 protein kinase inhibits the replication of vaccinia virus. Virology 193:1037–1041

    Article  PubMed  CAS  Google Scholar 

  • Lee SB, Melkova Z, Yan W, Williams BRG, Hovanessian AG, Esteban M (1993) The interferoninduced double-stranded RNA-activated human p68 protein kinase potently inhibits protein synthesis in cultured cells. Virology 192:380–385

    Article  PubMed  CAS  Google Scholar 

  • Lee SB, Rodríguez D, Rodriguez JR, Esteban M (1997) The apoptosis pathway triggered by the interferon-induced protein kinase PKR requires the third basic domain, initiates upstream of Bc1–2, and involves ICE-like proteases. Virology 231:81–88

    Article  PubMed  CAS  Google Scholar 

  • Lee TG, Tang N, Thompson S, Miller J, Katze MG (1994) The 58,000-Dalton cellular inhibitor of the interferon-induced double-stranded RNA-activated protein kinase (PKR) is a member of the tetratricopeptide repeat family of proteins. Mol Cell Biol 14:2331–2342

    Article  PubMed  CAS  Google Scholar 

  • Leroux A, London IM (1982) Regulation of protein synthesis by phosphorylation of eukaryotic initiation factor 2a in intact reticulocytes and reticulocyte lyStates. Proc Natl Acad Sci USA 79:2147–2151

    Article  PubMed  CAS  Google Scholar 

  • Lu JF, O’Hara EB, Trieselmann BA, Romano PR, Dever TE (1999) The interferon-induced doublestranded RNA-activated protein kinase PKR will phosphorylate serine, threonine, or tyrosine at residue 51 in eukaryotic initiation factor 2a. J Biol Chem 274:32198–32203

    Article  PubMed  CAS  Google Scholar 

  • Marissen WE, Lloyd RE (1998) Eukaryotic translation initiation factor 4G is targeted for proteolytic cleavage by caspase 3 during inhibition of translation in apoptotic cells. Mol Cell Biol 18:7565–7574

    PubMed  CAS  Google Scholar 

  • Marissen WE, Guo Y, Thomas AA, Matts RL, Lloyd RE (2000) Identification of caspase 3mediated cleavage and functional alteration of eukaryotic initiation factor 2alpha in apoptosis. J Biol Chem 275:9314–9323

    Article  PubMed  CAS  Google Scholar 

  • Martin SJ, Green DR (1995) Protease activation during apoptosis: death by a thousand cuts? Cell 82:349–352

    Article  PubMed  CAS  Google Scholar 

  • Marton MJ, De Aldana CRV, Qiu HF, Chakraburtty K, Hinnebusch AG (1997) Evidence that GCN1 and GCN20, translational regulators of GCN4, function on elongating ribosomes in activation of eIF2α kinase GCN2. Mol Cell Biol 17:4474–4489

    PubMed  CAS  Google Scholar 

  • Mathews MB, Shenk T (1991) Adenovirus virus-associated RNA and translation control. J Virol 65:5657–5662

    PubMed  CAS  Google Scholar 

  • Matts RL, Hurst R (1992) The relationship between protein synthesis and heat shock proteins levels in rabbit reticulocyte lyStates. J Biol Chem 267:18168–18174

    PubMed  CAS  Google Scholar 

  • Matts RL, Schatz JR, Hurst R, Kagen R (1991) Toxic heavy metal ions activate the heme-regulated eukaryotic initiation factor-2a kinase by inhibiting the capacity of hemin-supplemented reticulocyte lyStates to reduce disulfide bonds. J Biol Chem 266:12695–12702

    PubMed  CAS  Google Scholar 

  • Matts RL, Xu Z, Pal JK, Chen J-J (1992) Interactions of the heme-regulated eIF-2a kinase with heat shock proteins in rabbit reticulocyte lyStates. J Biol Chem 267:18160–18167

    PubMed  CAS  Google Scholar 

  • Matts RL, Hurst R, Xu Z (1993) Denatured proteins inhibit translation in hemin-supplemented rabbit reticulocyte lyState by inducing the activation of the heme-regulated eIF-2a kinase. Biochemistry 32:7323–7328

    Article  PubMed  CAS  Google Scholar 

  • Mellor H, Flowers KM, Kimball SR, Jefferson LS (1994) Cloning and characterization of cDNA encoding rat hemin-sensitive initiation factor-2α (eIF-2a) kinase. Evidence for multitissue expression. J Biol Chem 269:10201–10204

    PubMed  CAS  Google Scholar 

  • Melville MW, Hansen WJ, Freeman BC, Welch WJ, Katze MG (1997) The molecular chaperone hsp40 regulates the activity of p58IPK the cellular inhibitor of PKR. Proc Natl Acad Sci USA 94:97–102

    Article  PubMed  CAS  Google Scholar 

  • Melville MW, Tan SL, Wambach M, Song J, Morimoto RI, Katze MG (1999) The cellular inhibitor of the PKR protein kinase, p58IPK, is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity. J Biol Chem 274:3797–3803

    Article  PubMed  CAS  Google Scholar 

  • Meurs E, Chong K, Galabru J, Thomas NSB, Kerr IM, Williams BRG, Hovanessian AG (1990) Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62:379–390

    Article  PubMed  CAS  Google Scholar 

  • Meurs EF, Watanabe Y, Kadereit S, Barber GN, Katze MG, Chong K, Williams BRG, Hovanessian AG (1992) Constitutive expression of human double-stranded RNA-activated p68 kinase in murine cells mediates phosphorylation of eukaryotic initiation factor 2 and partial resistance to encephalomyocarditis virus growth. J Virol 66:5805–5814

    PubMed  CAS  Google Scholar 

  • Meurs EF, Galabru J, Barber GN, Katze MG, Hovanessian AG (1993) Tumor suppressor function of the interferon-induced double-stranded RNA-activated protein kinase. Proc Natl Acad Sci USA 90:232–236

    Article  PubMed  CAS  Google Scholar 

  • Méndez R, De Haro C (1994) Casein kinase II is implicated in the regulation of heme-controlled translational inhibitor of reticulocyte lyStates. J Biol Chem 269:6170–6176

    PubMed  Google Scholar 

  • Méndez R, Moreno A, De Haro C (1992) Regulation of heme-controlled eukaryotic polypeptide chain initiation factor 2 a-subunit kinase of reticulocyte lyStates. J Biol Chem 267:11500–11507

    PubMed  Google Scholar 

  • Montine KS, Henshaw EC (1989) Serum growth factors cause rapid stimulation of protein synthesis and dephosphorylation of eIF-2 in serum deprived Ehrlich cells. Biochim Biophys Acta 1014:282–288

    Article  PubMed  CAS  Google Scholar 

  • Morley SJ, McKendrick L, Bushell M (1998) Cleavage of translation initiation factor 4G (eIF4G) during anti-Fas IgM-induced apoptosis does not require signalling through the p38 mitogenactivated protein (MAP) kinase. FEBS Lett 438:41–48

    Article  PubMed  CAS  Google Scholar 

  • Morley SJ, Jeffrey IW, Bushell M, Pain VM, Clemens MJ (2000) Differential requirements for caspase-8 activity in the mechanism of phosphorylation of eIF2α, cleavage of eIF4GI and signaling events associated with the inhibition of protein synthesis in apoptotic Jurkat T cells. FEBS Lett 477:229–236

    Article  PubMed  CAS  Google Scholar 

  • Mundschau LJ, Faller DV (1991) BALB/c-3T3 fibroblasts resistant to growth inhibition by beta interferon exhibit aberrant platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor signal transduction. Mol Cell Biol 11:3148–3154

    PubMed  CAS  Google Scholar 

  • Mundschau LJ, Faller DV (1995) Platelet-derived growth factor signal transduction through the interferon-inducible kinase PKR. Immediate early gene induction. J Biol Chem 270:3100–3106

    Article  PubMed  CAS  Google Scholar 

  • Murtha-Riel P, Davies MV, Scherer BJ, Choi S-Y, Hershey JWB, Kaufman RJ (1993) Expression of a phosphorylation-resistant eukaryotic initiation factor 2 a-subunit mitigates heat shock inhibition of protein synthesis. J Biol Chem 268:12946–12951

    PubMed  CAS  Google Scholar 

  • Nanduri S, Carpick BW, Yang YW, Williams BRG, Qin J (1998) Structure of the double-stranded RNA-binding domain of the protein kinase PKR reveals the molecular basis of its dsRNAmediated activation. EMBO J 17:5458–5465

    Article  PubMed  CAS  Google Scholar 

  • Oldfield S, Jones BL, Tanton D, Proud CG (1994) Use of monoclonal antibodies to study the structure and function of eukaryotic protein synthesis initiation factor eIF-2B. Eur J Biochem 221:399–410

    Article  PubMed  CAS  Google Scholar 

  • Osman F, Jarrous N, Ben-Asouli Y, Kaempfer R (1999) A cis-acting element in the 3’-untranslated region of human TNF-α mRNA renders splicing dependent on the activation of protein kinase PKR. Genes Dev 13:3280–3293

    Article  PubMed  CAS  Google Scholar 

  • Pain VM (1994) Translational control during amino acid starvation. Biochimie 76:718–728

    Article  PubMed  CAS  Google Scholar 

  • Pain VM (1996) Initiation of protein synthesis in eukaryotic cells. Eur J Biochem 236:747–771

    Article  PubMed  CAS  Google Scholar 

  • Palfrey HC, Nairn AC (1995) Calcium-dependent regulation of protein synthesis. Adv Second Messenger Phosphoprotein Res 30:191–223

    Article  PubMed  CAS  Google Scholar 

  • Park H, Davies MV, Langland JO, Chang H-W, Nam YS, Tartaglia J, Paoletti E, Jacobs BL, Kaufman RJ, Venkatesan S (1994) TAR RNA-binding protein is an inhibitor of the interferon-induced protein kinase PKR. Proc Natl Acad Sci USA 91:4713–4717

    Article  PubMed  CAS  Google Scholar 

  • Patel RC, Sen GC (1998a) Requirement of PKR dimerization mediated by specific hydrophobic residues for its activation by double-stranded RNA and its antigrowth effects in yeast. Mol Cell Biol 18:7009–7019

    PubMed  CAS  Google Scholar 

  • Patel RC, Sen GC (1998b) PACT, a protein activator of the interferon-induced protein kinase, PKR. EMBO J 17:4379–4390

    Article  PubMed  CAS  Google Scholar 

  • Patel RC, Stanton P, Sen GC (1994) Role of the amino-terminal residues of the interferon-induced protein kinase in its activation by double-stranded RNA and heparin. J Biol Chem 269:18593–18598

    PubMed  CAS  Google Scholar 

  • Patel RC, Vestal DJ, Xu Z, Bandyopadhyay S, Guo WD, Erme SM, Williams BRG, Sen GC (1999) DRBP76, a double-stranded RNA-binding nuclear protein, is phosphorylated by the interferon-induced protein kinase, PKR. J Biol Chem 274:20432–20437

    Article  PubMed  CAS  Google Scholar 

  • Pavitt GD, Yang WM, Hinnebusch AG (1997) Homologous segments in three subunits of the guanine nucleotide exchange factor eIF2B mediate translational regulation by phosphorylation of eIF2. Mol Cell Biol 17:1298–1313

    PubMed  CAS  Google Scholar 

  • Pavitt GD, Ramaiah KVA, Kimball SR, Hinnebusch AG (1998) eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange. Genes Dev 12:514–526

    Article  PubMed  CAS  Google Scholar 

  • Petryshyn R, Chen J-J, London IM (1984) Growth-related expression of a double-stranded RNAdependent protein kinase in 3T3 cells. J Biol Chem 259:14736–14742

    PubMed  CAS  Google Scholar 

  • Petryshyn R, Chen J-J, London IM (1988) Detection of activated double-stranded RNAdependent protein kinase in 3T3-F442 A cells. Proc Natl Acad Sci USA 85:1427–1431

    Article  PubMed  CAS  Google Scholar 

  • Pollard JW, Galpine AR, Clemens MJ (1989) A novel role for aminoacyl-tRNA synthetases in the regulation of polypeptide chain initiation. Eur J Biochem 182:1–9

    Article  PubMed  CAS  Google Scholar 

  • Polunovsky VA, Rosenwald IB, Tan AT, White J, Chiang L, Sonenberg N, Bitterman PB (1996) Translational control of programmed cell death: Eukaryotic translation initiation factor 4 E blocks apoptosis in growth-factor-restricted fibroblasts with physiologically expressed or deregulated Myc. Mol Cell Biol 16:6573–6581

    PubMed  CAS  Google Scholar 

  • Preiss T, Hentze MW (1999) From factors to mechanisms: translation and translational control in eukaryotes. Curr Opin Genet Dev 9:515–521

    Article  PubMed  CAS  Google Scholar 

  • Prostko CR, Brostrom MA, Malara EM, Brostrom CO (1992) Phosphorylation of eukaryotic initiation factor (eIF) 2α and inhibition of eIF-2B in GH3 pituitary cells by perturbants of early protein processing that induce GRP78. J Biol Chem 267:16751–16754

    PubMed  CAS  Google Scholar 

  • Prostko CR, Brostrom MA, Brostrom CO (1993) Reversible phosphorylation of eukaryotic initiation factor 2a in response to endoplasmic reticular signaling. Mol Cell Biochem 127128:255–265

    Article  Google Scholar 

  • Prostko CR, Dholakia JN, Brostrom MA, Brostrom CO (1995) Activation of the double-stranded RNA-regulated protein kinase by depletion of endoplasmic reticular calcium stores. J Biol Chem 270:6211–6215

    Article  PubMed  CAS  Google Scholar 

  • Qu S, Cavener DR (1994) Isolation and characterization of the Drosophila melanogaster eIF-2α gene encoding the alpha subunit of translation initiation factor eIF-2. Gene 140:239–242

    Article  PubMed  CAS  Google Scholar 

  • Raine DA, Jeffrey IW, Clemens MJ (1998) Inhibition of the double-stranded RNA-dependent protein kinase PKR by mammalian ribosomes. FEBS Lett 436:343–348

    Article  PubMed  CAS  Google Scholar 

  • Ramaiah KVA, Davies MV, Chen J-J, Kaufman RJ (1994) Expression of mutant eukaryotic initiation factor 2 α subunit (eIF-2a) reduces inhibition of guanine nucleotide exchange activity of eIF-2B mediated by eIF-2a phosphorylation. Mol Cell Biol 14:4546–4553

    PubMed  CAS  Google Scholar 

  • Ramirez M, Wek RC, Hinnebusch AG (1991) Ribosome association of GCN2 protein kinase, a translational activator of the GCN4 gene of Saccharomyces cerevisiae. Mol Cell Biol 11:3027–3036

    PubMed  CAS  Google Scholar 

  • Ramirez M, Wek RC, Vazquez de Aldana CR, Jackson BM, Freeman B, Hinnebusch AG (1992) Mutations activating the yeast eIF-2a kinase GCN2: Isolation of alleles altering the domain related to histidyl-tRNA synthetases. Mol Cell Biol 12:5801–5815

    PubMed  CAS  Google Scholar 

  • Rau M, Ohlmann T, Morley SJ, Pain VM (1996) A reevaluation of the cap-binding protein, eIF4E, as a rate-limiting factor for initiation of translation in reticulocyte lyState. J Biol Chem 271:8983–8990

    Article  PubMed  CAS  Google Scholar 

  • Ray MK, Datta B, Chakraborty A, Chattopadhyay A, Meza-Keuthen S, Gupta NK (1992) The eukaryotic initiation factor 2-associated 67-kDa polypeptide (p67) plays a critical role in regulation of protein synthesis initiation in animal cells. Proc Natl Acad Sci USA 89:539–543

    Article  PubMed  CAS  Google Scholar 

  • Ray MK, Chakraborty A, Datta B, Chattopadhyay A, Saha D, Bose A, Kinzy TG, Wu S, Hileman RE, Merrick WC, Gupta NK (1993) Characteristics of the eukaryotic initiation factor 2 associated 67-kDa polypeptide. Biochemistry 32:5151–5159

    Article  PubMed  CAS  Google Scholar 

  • Rhoads RE (1999) Signal transduction pathways that regulate eukaryotic protein synthesis. J Biol Chem 274:30337–30340

    Article  PubMed  CAS  Google Scholar 

  • Rivas C, Gil J, Esteban M (1999) Identification of functional domains of the interferon-induced enzyme PKR in cells lacking endogenous PKR. J Interferon Cytokine Res 19:1229–1236

    Article  PubMed  CAS  Google Scholar 

  • Robertson HD, Manche L, Mathews MB (1996) Paradoxical interactions between human delta hepatitis agent RNA and the cellular protein kinase PKR. J Virol 70:5611–5617

    PubMed  CAS  Google Scholar 

  • Romano PR, Green SR, Barber GN, Mathews MB, Hinnebusch AG (1995) Structural requirements for double-stranded RNA binding, dimerization, and activation of the human eIF-2a kinase DAI in Saccharomyces cerevisiae. Mol Cell Biol 15:365–378

    PubMed  CAS  Google Scholar 

  • Romano PR, Garcia-Barrio MT, Zhang XL, Wang QZ, Taylor DR, Zhang F, Herring C, Mathews MB, Qin J, Hinnebusch AG (1998) Autophosphorylation in the activation loop is required for full kinase activity in vivo of human and yeast eukaryotic initiation factor 2a kinases PKR and GCN2. Mol Cell Biol 18:2282–2297

    PubMed  CAS  Google Scholar 

  • Rowlands AG, Montine KS, Henshaw EC, Panniers R (1988a) Physiological stresses inhibit guanine-nucleotide-exchange factor in Ehrlich cells. Eur J Biochem 175:93–99

    Article  PubMed  CAS  Google Scholar 

  • Rowlands AG, Panniers R, Henshaw EC (1988b) The catalytic mechanism of guanine nucleotide exchange factor action and competitive inhibition by phosphorylated eucaryotic initiation factor 2. J Biol Chem 263:5526–5533

    PubMed  CAS  Google Scholar 

  • Satoh S, Hijikata M, Handa H, Shimotohno K (1999) Caspase-mediated cleavage of eukaryotic translation initiation factor subunit 2a. Biochem J 342:65–70

    Article  PubMed  CAS  Google Scholar 

  • Scorsone KA, Panniers R, Rowlands AG, Henshaw EC (1987) Phosphorylation of eukaryotic initiation factor 2 during physiological stresses which affect protein synthesis. J Biol Chem 262:14538–14543

    PubMed  CAS  Google Scholar 

  • Shah OJ, Antonetti DA, Kimball SR, Jefferson LS (1999) Leucine, glutamine, and tyrosine reciprocally modulate the translation initiation factors eIF4F and eIF2B in perfused rat liver. J Biol Chem 274:36168–36175

    Article  PubMed  CAS  Google Scholar 

  • Shantz LM, Pegg AE (1994) Overproduction of ornithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res 54:2313–2316

    PubMed  CAS  Google Scholar 

  • Sharp TV, Schwemmle M, Jeffrey I, Laing K, Mellor H, Proud CG, Hilse K, Clemens MJ (1993) Comparative analysis of the regulation of the interferon-inducible protein kinase PKR by Epstein-Barr virus RNAs EBER-1 and EBER-2 and adenovirus VA1 RNA. Nucleic Acids Res 21:4483–4490

    Article  PubMed  CAS  Google Scholar 

  • Sharp TV, Xiao Q, Justesen J, Gewert DR, Clemens MJ (1995) Regulation of the interferoninducible protein kinase PKR and (2’-5’) oligo(adenylate) synthetase by a catalytically inactive PKR mutant through competition for double-stranded RNA binding. Eur J Biochem 230: 97–103

    Article  PubMed  CAS  Google Scholar 

  • Sharp TV, Witzel JE, Jagus R (1997) Homologous regions of the α subunit of eukaryotic translational initiation factor 2 (eIF2α) and the vaccinia virus K3L gene product interact with the same domain within the dsRNA-activated protein kinase (PKR). Eur J Biochem 250:85–91

    Article  PubMed  CAS  Google Scholar 

  • Sharp TV, Moonan F, Romashko A, Joshi B, Barber GN, Jagus R (1998) The vaccinia virus E3L gene product interacts with both the regulatory and the substrate binding regions of PKR: Implications for PKR autoregulation. Virology 250:302–315

    Article  PubMed  CAS  Google Scholar 

  • Sheikh MS, Fornace AJ Jr (1999) Regulation of translation initiation following stress. Oncogene 18:6121–6128

    Article  PubMed  CAS  Google Scholar 

  • Shi YG, Vattem KM, Sood R, An J, Liang JD, Stramm L, Wek RC (1998) Identification and characterization of pancreatic eukaryotic initiation factor 2 α-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18:7499–7509

    PubMed  CAS  Google Scholar 

  • Shi YG, An J, Liang JD, Hayes SE, Sandusky GE, Stramm LE, Yang NN (1999) Characterization of a mutant pancreatic eIF-2a kinase, PEK, and co-localization with somatostatin in islet delta cells. J Biol Chem 274:5723–5730

    Article  PubMed  CAS  Google Scholar 

  • Sonenberg N, Gingras AC (1998) The mRNA 5’ cap-binding protein eIF4E and control of cell growth. Curr Opin Cell Biol 10:268–275

    Article  PubMed  CAS  Google Scholar 

  • Srivastava SP, Davies MV, Kaufman RJ (1995) Calcium depletion from the endoplasmic reticulum activates the double-stranded RNA-dependent protein kinase (PKR) to inhibit protein synthesis. J Biol Chem 270:16619–16624

    Article  PubMed  CAS  Google Scholar 

  • Srivastava SP, Kumar KU, Kaufman RJ (1998) Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNAdependent protein kinase. J Biol Chem 273:2416–2423

    Article  PubMed  CAS  Google Scholar 

  • St Johnston D, Brown NH, Gall JG, Jantsch M (1992) A conserved double-stranded RNA-binding domain. Proc Natl Acad Sci USA 89:10979–10983

    Article  Google Scholar 

  • Stark GR, Kerr IM, Williams BRG, Silverman RH, Schreiber RD (1998) How cells respond to interferons. Annu Rev Biochem 67:227–264

    Article  PubMed  CAS  Google Scholar 

  • Sudhakar A, Krishnamoorthy T, Jain A, Chatterjee U, Hasnain SE, Kaufman RJ, Ramaiah KVA (1999) Serine 48 in initiation factor 2a (eIF2α) is required for high-affinity interaction between eIF2α(P) and eIF2B. Biochemistry 38:15398–15405

    Article  PubMed  CAS  Google Scholar 

  • Sullivan JM, Alousi SS, Hikade KR, Bahu NJ, Rafols JA, Krause GS, White BC (1999) Insulin induces dephosphorylation of eukaryotic initiation factor 2α and restores protein synthesis in vulnerable hippocampal neurons after transient brain ischemia. J Cerebral Blood Flow Metab 19:1010–1019

    Article  CAS  Google Scholar 

  • Takizawa T, Tatematsu C, Nakanishi Y (1999) Double-stranded RNA-activated protein kinase (PKR) fused to green fluorescent protein induces apoptosis of human embryonic kidney cells: possible role in the Fas signaling pathway. J Biochem (Tokyo) 125:391–398

    Article  CAS  Google Scholar 

  • Tam NWN, Ishii T, Li SY, Wong AHT, Cuddihy AR, Koromilas AE (1999) Upregulation of STAT1 protein in cells lacking or expressing mutants of the double-stranded RNA-dependent protein kinase PKR. Eur J Biochem 262:149–154

    Article  PubMed  CAS  Google Scholar 

  • Tan SL, Katze MG (1998) Using genetic means to dissect homologous and heterologous proteinprotein interactions of PKR, the interferon-induced protein kinase. Methods 15:207–223

    Article  PubMed  CAS  Google Scholar 

  • Tan SL, Katze MG (1999) The emerging role of the interferon-induced PKR protein kinase as an apoptotic effector: a new face of death. J Interferon Cytokine Res 19:543–554

    Article  PubMed  CAS  Google Scholar 

  • Tang NM, Korth MJ, Gale M Jr, Wambach M, Der SD, Bandyopadhyay SK, Williams BRG, Katze MG (1999) Inhibition of double-stranded RNA- and tumor necrosis factor alpha-mediated apoptosis by tetratricopeptide repeat protein and cochaperone p581PK. Mol Cell Biol 19:4757–4765

    PubMed  CAS  Google Scholar 

  • Taylor DR, Lee SB, Romano PR, Marshak DR, Hinnebusch AG, Esteban M, Mathews MB (1996) Autophosphorylation sites participate in the activation of the double-stranded-RNA-activated protein kinase PKR. Mol Cell Biol 16:6295–6302

    PubMed  CAS  Google Scholar 

  • Tee AR, Proud CG (2000) DNA-damaging agents cause inactivation of translational regulators linked to mTOR signalling. Oncogene 19:3021–3031

    Article  PubMed  CAS  Google Scholar 

  • Terenzi F, DeVeer MJ, Ying H, Restifo NP, Williams BRG, Silverman RH (1999) The antiviral enzymes PKR and RNase L suppress gene expression from viral and non-viral based vectors. Nucleic Acids Res 27:4369–4375

    Article  PubMed  CAS  Google Scholar 

  • Thomas D, Kim HY, Morgan R, Hanley MR (1998) Double-stranded-RNA-activated protein kinase (PKR) regulates Ca2+ stores in Xenopus oocytes. Biochem J 330:599–603

    PubMed  CAS  Google Scholar 

  • Thomis DC, Samuel CE (1992) Mechanism of interferon action: Autoregulation of RNAdependent P1/eIF-2a protein kinase (PKR) expression in transfected mammalian cells. Proc Natl Acad Sci USA 89:10837–10841

    Article  PubMed  CAS  Google Scholar 

  • Thomas G, Hall MN (1997) TOR signalling and control of cell growth. Curr Opin Cell Biol 9:782–787

    Article  PubMed  CAS  Google Scholar 

  • Tian B, White RJ, Xia T, Welle S, Turner DH, Mathews MB, Thornton CA (2000) Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR. RNA 6:79–87

    Article  PubMed  CAS  Google Scholar 

  • Uma S, Thulasiraman V, Matts RL (1999) Dual role for Hsc70 in the biogenesis and regulation of the heme-regulated kinase of the a subunit of eukaryotic translation initiation factor 2. Mol Cell Biol 19:5861–5871

    PubMed  CAS  Google Scholar 

  • Vazquez de Aldana CR, Dever TE, Hinnebusch AG (1993) Mutations in the a subunit of eukaryotic translation initiation factor 2 (eIF-2a) that overcome the inhibitory effect of eIF-2α phosphorylation on translation initiation. Proc Natl Acad Sci USA 90:7215–7219

    Article  Google Scholar 

  • Vries RGJ, Flynn A, Patel JC, Wang XM, Denton RM, Proud CG (1997) Heat shock increases the association of binding protein- 1 with initiation factor 4 E. J Biol Chem 272:32779–32784

    Article  CAS  Google Scholar 

  • Wang ST, Rosenwald IB, Hutzler MJ, Pihan GA, Savas L, Chen JJ, Woda BA (1999) Expression of the eukaryotic translation initiation factors 4 E and 2α in non-Hodgkin’s lymphomas. Am J Pathol 155:247–255

    Article  PubMed  CAS  Google Scholar 

  • Wang XM, Campbell LE, Miller CM, Proud CG (1998) Amino acid availability regulates p70 S6 kinase and multiple translation factors. Biochem J 334:261–267

    PubMed  CAS  Google Scholar 

  • Webb BLJ, Proud CG (1997) Eukaryotic initiation factor 2B (eIF2B). Int J Biochem Cell Biol 29:1127–1131

    Article  PubMed  CAS  Google Scholar 

  • Wek RC, Jackson BM, Hinnebusch AG (1989) Juxtaposition of domains homologous to protein kinases and histidyl-tRNA synthetases in GCN2 protein suggests a mechanism for coupling GCN4 expression to amino acid availability. Proc Natl Acad Sci USA 86:4579–4583

    Article  PubMed  CAS  Google Scholar 

  • Welsh GI, Proud CG (1993) Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J 294:625–629

    PubMed  CAS  Google Scholar 

  • Welsh GI, Miller CM, Loughlin AJ, Price NT, Proud CG (1998) Regulation of eukaryotic initiation factor eIF2B: glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Lett 421:125–130

    Article  PubMed  CAS  Google Scholar 

  • Williams BRG (1999) PKR; a sentinel kinase for cellular stress. Oncogene 18:6112–6120

    Article  PubMed  CAS  Google Scholar 

  • Wong AHT, Tam NWN, Yang YL, Cuddihy AR, Li SY, Kirchhoff S, Hauser H, Decker T, Koromilas AE (1997) Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways. EMBO J 16:1291–1304

    Article  PubMed  CAS  Google Scholar 

  • Wu SY, Rehemtulla A, Gupta NK, Kaufman RJ (1996) A eukaryotic translation initiation factor 2associated 67 kDa glycoprotein partially reverses protein synthesis inhibition by activated double-stranded RNA-dependent protein kinase in intact cells. Biochemistry 35:8275–8280

    Article  PubMed  CAS  Google Scholar 

  • Xu G, Kwon G, Marshall CA, Lin TA, Lawrence JC Jr, McDaniel ML (1998) Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic ß-cells — a possible role in protein translation and mitogenic signaling. J Biol Chem 273:28178–28184

    Article  PubMed  CAS  Google Scholar 

  • Yang YL, Reis LFL, Pavlovic J, Aguzzi A, Schäfer R, Kumar A, Williams BRG, Aguet M, Weissmann C (1995) Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J 14:6095–6106

    PubMed  CAS  Google Scholar 

  • Yeung MC, Lau AS (1998) Tumor suppressor p53 as a component of the tumor necrosis factorinduced, protein kinase PKR-mediated apoptotic pathway in human promonocytic U937 cells. J Biol Chem 273:25198–25202

    Article  PubMed  CAS  Google Scholar 

  • Yeung MC, Liu J, Lau AS (1996) An essential role for the interferon-inducible, double-stranded RNA-activated protein kinase PKR in the tumor necrosis factor-induced apoptosis in U937 cells. Proc Natl Acad Sci USA 93:12451–12455

    Article  PubMed  CAS  Google Scholar 

  • Zamanian-Daryoush M, Der SD, Williams BRG (1999) Cell cycle regulation of the double stranded RNA activated protein kinase, PKR. Oncogene 18:315–326

    Article  PubMed  CAS  Google Scholar 

  • Zamanian-Daryoush M, Mogensen TH, DiDonato JA, Williams BRG (2000) NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is mediated through NF-kappaBinducing kinase and IkappaB kinase. Mol Cell Biol 20:1278–1290

    Article  PubMed  CAS  Google Scholar 

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© 2001 Springer-Verlag Berlin Heidelberg

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Clemens, M.J. (2001). Initiation Factor eIF2α Phosphorylation in Stress Responses and Apoptosis. In: Rhoads, R.E. (eds) Signaling Pathways for Translation. Progress in Molecular and Subcellular Biology, vol 27. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-09889-9_3

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  • DOI: https://doi.org/10.1007/978-3-662-09889-9_3

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-07505-6

  • Online ISBN: 978-3-662-09889-9

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