The eIF2α kinases: Their structures and functions

Cellular and Molecular Life Sciences

Volumn 70, Issue 19, 2013, Pages 3493-3511

  Donnelly, Neysan ^a,b   Gorman, Adrienne M ^a   Gupta, Sanjeev ^a   Samali, Afshin ^a  

^a NATIONAL UNIVERSITY OF IRELAND   (Ireland)

^b MAX PLANCK INSTITUTE OF BIOCHEMISTRY   (Germany)

Author keywords

Activating transcription factor 4 (ATF4); Cell stress; eIF2 kinases; General control non derepressible 2 (GCN2); Heme regulated inhibitor (HRI); PKR like ER kinase (PERK); Protein kinase double stranded RNA dependent (PKR)

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR 4; CYCLIN D1; GROWTH ARREST AND DNA DAMAGE INDUCIBLE PROTEIN 153; HEAT SHOCK PROTEIN 90; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INITIATION FACTOR; INITIATION FACTOR 2ALPHA; NITRIC OXIDE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN GCN2; PROTEIN HRI; PROTEIN KINASE R; PROTEIN P53; PROTEIN PERK; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG;

APOPTOSIS; AUTOPHOSPHORYLATION; BINDING AFFINITY; BINDING SITE; CANCER CELL; CANCER GROWTH; CELL PROLIFERATION; CELL SURVIVAL; CELL VIABILITY; CELLULAR DISTRIBUTION; DIMERIZATION; ENDOPLASMIC RETICULUM STRESS; G2 PHASE CELL CYCLE CHECKPOINT; GROWTH INHIBITION; HUMAN; NITROSYLATION; NONHUMAN; OXIDATIVE STRESS; PROTEIN BINDING; PROTEIN DEPHOSPHORYLATION; PROTEIN DEPLETION; PROTEIN DNA BINDING; PROTEIN EXPRESSION; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN STRUCTURE; PROTEIN SYNTHESIS; REVIEW; TRANSLATION REGULATION; UPREGULATION; VIRUS INFECTION; VIRUS REPLICATION;

EUKARYOTA;

EID: 84884353774     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-012-1252-6     Document Type: Review

References (216)

1. Abraham N, Stojdl DF, Duncan PI, Methot N, Ishii T, Dube 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
2. Acharya P, Chen JJ, Correia MA (2010) Hepatic heme-regulated inhibitor (HRI) eukaryotic initiation factor 2alpha kinase: a protagonist of heme-mediated translational control of CYP2B enzymes and a modulator of basal endoplasmic reticulum stress tone. Mol Pharmacol 77:575-592
3. Acharya P, Engel JC, Correia MA (2009) Hepatic CYP3A suppression by high concentrations of proteasomal inhibitors: a consequence of endoplasmic reticulum (ER) stress induction, activation of RNA-dependent protein kinase-like ER-bound eukaryotic initiation factor 2alpha (eIF2alpha)-kinase (PERK) and general control nonderepressible-2 eIF2alpha kinase (GCN2), and global translational shutoff. Mol Pharmacol 76:503-515
4. Ameri K, Harris AL (2008) Activating transcription factor 4. Int J Biochem Cell Biol 40:14-21
5. Anderson E, Cole JL (2008) Domain stabilities in protein kinase R (PKR): evidence for weak interdomain interactions. Biochemistry 47:4887-4897
6. Anthony TG, McDaniel BJ, Byerley RL, McGrath BC, Cavener DR, McNurlan MA, Wek RC (2004) Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. J Biol Chem 279:36553-36561
7. Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP (2010) Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. J Biol Chem 285:6091-6100
8. Auch CJ, Saha RN, Sheikh FG, Liu X, Jacobs BL, Pahan K (2004) Role of protein kinase R in double-stranded RNA-induced expression of nitric oxide synthase in human astroglia. FEBS Lett 563:223-228
9. Back SH, Scheuner D, Han J, Song B, Ribick M, Wang J, Gildersleeve RD, Pennathur S, Kaufman RJ (2009) Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metab 10:13-26
10. Balachandran S, Roberts PC, Brown LE, Truong H, Pattnaik AK, Archer DR, Barber GN (2000) Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 13:129-141
11. Baltzis D, Pluquet O, Papadakis AI, Kazemi S, Qu LK, Koromilas AE (2007) The eIF2alpha kinases PERK and PKR activate glycogen synthase kinase 3 to promote the proteasomal degradation of p53. J Biol Chem 282:31675-31687
12. Barber GN, Tomita J, Hovanessian AG, Meurs E, Katze MG (1991) Functional expression and characterization of the interferon-induced double-stranded RNA activated P68 protein kinase from Escherichia coli. Biochemistry 30:10356-10361
13. Bauer BN, Rafie-Kolpin M, Lu L, Han A, Chen JJ (2001) Multiple autophosphorylation is essential for the formation of the active and stable homodimer of heme-regulated eIF2alpha kinase. Biochemistry 40:11543-11551
14. Berlanga JJ, Ventoso I, Harding HP, Deng J, Ron D, Sonenberg N, Carrasco L, de Haro C (2006) Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses. EMBO J 25:1730-1740
15. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2:326-332
16. Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, Cavener D, Diehl JA (2010) PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 29:3881-3895
17. Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C, Romero M, Cavener DR, Thompson CB, Diehl JA (2008) PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differentiation. Proc Natl Acad Sci USA 105:16314-16319
18. Bollo M, Paredes RM, Holstein D, Zheleznova N, Camacho P, Lechleiter JD (2010) Calcineurin interacts with PERK and dephosphorylates calnexin to relieve ER stress in mammals and frogs. PLoS ONE 5:e11925
19. Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci USA 97:12625-12630
20. Bromati CR, Lellis-Santos C, Yamanaka TS, Nogueira TC, Leonelli M, Caperuto LC, Gorjao R, Leite AR, Anhe GF, Bordin S (2011) UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression. Am J Physiol Regul Integr Comp Physiol 300:R92-R100
21. 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
22. Brush MH, Weiser DC, Shenolikar S (2003) Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Mol Cell Biol 23:1292-1303
23. Cavener DR, Gupta S, McGrath BC (2010) PERK in beta cell biology and insulin biogenesis. Trends Endocrinol Metab 21:714-721
24. Chen JJ (2007) Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood 109:2693-2699
25. Chen T, Ozel D, Qiao Y, Harbinski F, Chen L, Denoyelle S, He X, Zvereva N, Supko JG, Chorev M, Halperin JA, Aktas BH (2011) Chemical genetics identify eIF2alpha kinase heme-regulated inhibitor as an anticancer target. Nat Chem Biol 7:610-616
26. Chen YJ, Tan BC, Cheng YY, Chen JS, Lee SC (2010) Differential regulation of CHOP translation by phosphorylated eIF4E under stress conditions. Nucleic Acids Res 38:764-777
27. Cherkasova V, Qiu H, Hinnebusch AG (2010) Snf1 promotes phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 by activating Gcn2 and inhibiting phosphatases Glc7 and Sit4. Mol Cell Biol 30:2862-2873
28. Cherkasova VA, Hinnebusch AG (2003) Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. Genes Dev 17:859-872
29. Cheshire JL, Williams BR, Baldwin AS Jr (1999) Involvement of double-stranded RNA-activated protein kinase in the synergistic activation of nuclear factor-kappaB by tumor necrosis factor-alpha and gamma-interferon in preneuronal cells. J Biol Chem 274:4801-4806
30. Chu WM, Ostertag D, Li ZW, Chang L, Chen Y, Hu Y, Williams B, Perrault J, Karin M (1999) JNK2 and IKKbeta are required for activating the innate response to viral infection. Immunity 11:721-731
31. Cole JL (2007) Activation of PKR: an open and shut case? Trends Biochem Sci 32:57-62
32. Crosby JS, Lee K, London IM, Chen JJ (1994) Erythroid expression of the heme-regulated eIF-2 alpha kinase. Mol Cell Biol 14:3906-3914
33. Cuddihy AR, Li S, Tam NW, Wong AH, Taya Y, Abraham N, Bell JC, Koromilas AE (1999) Double-stranded-RNA-activated protein kinase PKR enhances transcriptional activation by tumor suppressor p53. Mol Cell Biol 19:2475-2484
34. Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE (1999) 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
35. Cui W, Li J, Ron D, Sha B (2011) The structure of the PERK kinase domain suggests the mechanism for its activation. Acta Crystallogr D Biol Crystallogr 67:423-428
36. Cullinan SB, Diehl JA (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38:317-332
37. D'Acquisto F, Ghosh S (2001) PACT and PKR: turning on NF-kappa B in the absence of virus. Sci STKE 2001: re1
38. Dang Do AN, Kimball SR, Cavener DR, Jefferson LS (2009) eIF2alpha kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver. Physiological genomics 38:328-341
39. Dar AC, Dever TE, Sicheri F (2005) Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR. Cell 122:887-900
40. Deb A, Zamanian-Daryoush M, Xu Z, Kadereit S, Williams BR (2001) Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3. EMBO J 20:2487-2496
41. Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 25:406-409
42. Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D (2004) Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 24:10161-10168
43. Deval C, Chaveroux C, Maurin AC, Cherasse Y, Parry L, Carraro V, Milenkovic D, Ferrara M, Bruhat A, Jousse C, Fafournoux P (2009) Amino acid limitation regulates the expression of genes involved in several specific biological processes through GCN2-dependent and GCN2-independent pathways. FEBS J 276:707-718
44. Dever TE, Hinnebusch AG (2005) GCN2 whets the appetite for amino acids. Mol Cell 18:141-142
45. Dey M, Cao C, Dar AC, Tamura T, Ozato K, Sicheri F, Dever TE (2005) Mechanistic link between PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition. Cell 122:901-913
46. Dey M, Trieselmann B, Locke EG, Lu J, Cao C, Dar AC, Krishnamoorthy T, Dong J, Sicheri F, Dever TE (2005) PKR and GCN2 kinases and guanine nucleotide exchange factor eukaryotic translation initiation factor 2B (eIF2B) recognize overlapping surfaces on eIF2alpha. Mol Cell Biol 25:3063-3075
47. Dey M, Velyvis A, Li JJ, Chiu E, Chiovitti D, Kay LE, Sicheri F, Dever TE (2011) Requirement for kinase-induced conformational change in eukaryotic initiation factor 2alpha (eIF2alpha) restricts phosphorylation of Ser51. Proc Natl Acad Sci USA 108:4316-4321
48. Dey S, Baird TD, Zhou D, Palam LR, Spandau DF, Wek RC (2010) Both transcriptional regulation and translational control of ATF4 are central to the integrated stress response. J Biol Chem 285:33165-33174
49. Dong J, Qiu H, Garcia-Barrio M, Anderson J, Hinnebusch AG (2000) Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol Cell 6:269-279
50. Donze O, Abbas-Terki T, Picard D (2001) The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR. EMBO J 20:3771-3780
51. Donze O, Jagus R, Koromilas AE, Hershey JW, Sonenberg N (1995) Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J 14:3828-3834
52. DuRose JB, Tam AB, Niwa M (2006) Intrinsic capacities of molecular sensors of the unfolded protein response to sense alternate forms of endoplasmic reticulum stress. Mol Biol Cell 17:3095-3107
53. Fernandez BO, Lorkovic IM, Ford PC (2004) Mechanisms of ferriheme reduction by nitric oxide: nitrite and general base catalysis. Inorg Chem 43:5393-5402
54. Fonseca SG, Urano F, Burcin M, Gromada J (2010) Stress hypERactivation in the beta-cell. Islets 2:1-9
55. Frank CL, Ge X, Xie Z, Zhou Y, Tsai LH (2010) Control of activating transcription factor 4 (ATF4) persistence by multisite phosphorylation impacts cell cycle progression and neurogenesis. J Biol Chem 285:33324-33337
56. Galluzzi L, Brenner C, Morselli E, Touat Z, Kroemer G (2008) Viral control of mitochondrial apoptosis. PLoS Pathog 4:e1000018
57. Garcia-Barrio M, Dong J, Cherkasova VA, Zhang X, Zhang F, Ufano S, Lai R, Qin J, Hinnebusch AG (2002) Serine 577 is phosphorylated and negatively affects the tRNA binding and eIF2alpha kinase activities of GCN2. J Biol Chem 277:30675-30683
58. Garcia MA, Meurs EF, Esteban M (2007) The dsRNA protein kinase PKR: virus and cell control. Biochimie 89:799-811
59. Georgescu MM (2010) PTEN tumor suppressor network in PI3 K-Akt pathway control. Genes Cancer 1:1170-1177
60. Gil J, Alcami 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
61. Goh KC, de Veer MJ, Williams BR (2000) The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin. EMBO J 19:4292-4297
62. Gotoh T, Mori M (2006) Nitric oxide and endoplasmic reticulum stress. Arterioscler Thromb Vasc Biol 26:1439-1446
63. Grallert B, Boye E (2007) The Gcn2 kinase as a cell cycle regulator. Cell Cycle Georgetown Tex 6:2768-2772
64. Guo F, Cavener DR (2007) The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 5:103-114
65. Gupta S, Cuffe L, Szegezdi E, Logue SE, Neary C, Healy S, Samali A (2010) Mechanisms of ER stress-mediated mitochondrial membrane permeabilization. Int J Cell Biol 2010:170215
66. Gupta S, McGrath B, Cavener DR (2010) PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 59:1937-1947
67. Hai T, Curran T (1991) Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci USA 88:3720-3724
68. Hamanaka RB, Bennett BS, Cullinan SB, Diehl JA (2005) PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell 16:5493-5501
69. Han AP, Fleming MD, Chen JJ (2005) Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. J Clin Investig 115:1562-1570
70. Han AP, Yu C, Lu L, Fujiwara Y, Browne C, Chin G, Fleming M, Leboulch P, Orkin SH, Chen JJ (2001) Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. EMBO J 20:6909-6918
71. Hao S, Sharp JW, Ross-Inta CM, McDaniel BJ, Anthony TG, Wek RC, Cavener DR, McGrath BC, Rudell JB, Koehnle TJ, Gietzen DW (2005) Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307:1776-1778
72. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099-1108
73. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153-1163
74. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897-904
75. Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271-274
76. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619-633
77. He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J (2001) Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem 276:20858-20865
78. Healy SJ, Gorman AM, Mousavi-Shafaei P, Gupta S, Samali A (2009) Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur J Pharmacol 625:234-246
79. Heinicke LA, Wong CJ, Lary J, Nallagatla SR, Diegelman-Parente A, Zheng X, Cole JL, Bevilacqua PC (2009) RNA dimerization promotes PKR dimerization and activation. J Mol Biol 390:319-338
80. Hinnebusch AG (1984) Evidence for translational regulation of the activator of general amino acid control in yeast. Proc Natl Acad Sci USA 81:6442-6446
81. Hinnebusch AG (2005) Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 59:407-450
82. Hinnebusch AG, Natarajan K (2002) Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryot Cell 1:22-32
83. Holcik M, Sonenberg N (2005) Translational control in stress and apoptosis. Nat Rev Mol Cell Biol 6:318-327
84. Hu P, Han Z, Couvillon AD, Exton JH (2004) Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. J Biol Chem 279:49420-49429
85. 2+ regulation in secretory and muscle cells from PERK-knockout mice. J Cell Sci 119:153-161
86. Igarashi J, Sato A, Kitagawa T, Yoshimura T, Yamauchi S, Sagami I, Shimizu T (2004) Activation of heme-regulated eukaryotic initiation factor 2alpha kinase by nitric oxide is induced by the formation of a five-coordinate NO-heme complex: optical absorption, electron spin resonance, and resonance Raman spectral studies. J Biol Chem 279:15752-15762
87. Ito T, Yang M, May WS (1999) RAX, a cellular activator for double-stranded RNA-dependent protein kinase during stress signaling. J Biol Chem 274:15427-15432
88. Iwanaga T, Yamazaki T, Kominami S (1999) Kinetic studies on the successive reaction of neuronal nitric oxide synthase from l-arginine to nitric oxide and l-citrulline. Biochemistry 38:16629-16635
89. Iwawaki T, Akai R, Kohno K (2010) IRE1alpha disruption causes histological abnormality of exocrine tissues, increase of blood glucose level, and decrease of serum immunoglobulin level. PLoS ONE 5:e13052
90. Jackson RJ, Hellen CU, Pestova TV (2010) The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 11:113-127
91. Jiang HY, Wek RC (2005) GCN2 phosphorylation of eIF2alpha activates NF-kappaB in response to UV irradiation. Biochem J 385:371-380
92. Jiang HY, Wek RC (2005) Phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition. J Biol Chem 280:14189-14202
93. Jiang HY, Wek SA, McGrath BC, Lu D, Hai T, Harding HP, Wang X, Ron D, Cavener DR, Wek RC (2004) Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 24:1365-1377
94. Jiang HY, Wek SA, McGrath BC, Scheuner D, Kaufman RJ, Cavener DR, Wek RC (2003) Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Mol Cell Biol 23:5651-5663
95. Jousse C, Bruhat A, Carraro V, Urano F, Ferrara M, Ron D, Fafournoux P (2001) Inhibition of CHOP translation by a peptide encoded by an open reading frame localized in the chop 5′UTR. Nucleic Acids Res 29:4341-4351
96. Kawagishi-Kobayashi M, Silverman JB, Ung TL, Dever TE (1997) Regulation of the protein kinase PKR by the vaccinia virus pseudosubstrate inhibitor K3L is dependent on residues conserved between the K3L protein and the PKR substrate eIF2alpha. Mol Cell Biol 17:4146-4158
97. Kedersha NL, Gupta M, Li W, Miller I, Anderson P (1999) RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. J Cell Biol 147:1431-1442
98. Kilberg MS, Pan YX, Chen H, Leung-Pineda V (2005) Nutritional control of gene expression: how mammalian cells respond to amino acid limitation. Annu Rev Nutr 25:59-85
99. Kim SH, Forman AP, Mathews MB, Gunnery S (2000) Human breast cancer cells contain elevated levels and activity of the protein kinase, PKR. Oncogene 19:3086-3094
100. Kim SH, Gunnery S, Choe JK, Mathews MB (2002) Neoplastic progression in melanoma and colon cancer is associated with increased expression and activity of the interferon-inducible protein kinase, PKR. Oncogene 21:8741-8748
101. Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, Stroud RM, Walter P (2009) The unfolded protein response signals through high-order assembly of Ire1. Nature 457:687-693
102. Koumenis C (2006) ER stress, hypoxia tolerance and tumor progression. Curr Mol Med 6:55-69
103. Krishnamoorthy J, Mounir Z, Raven JF, Koromilas AE (2008) The eIF2alpha kinases inhibit vesicular stomatitis virus replication independently of eIF2alpha phosphorylation. Cell cycle Georgetown Tex 7:2346-2351
104. Kumar A, Haque J, Lacoste J, Hiscott J, Williams BR (1994) Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. Proc Natl Acad Sci USA 91:6288-6292
105. Kumar R, Azam S, Sullivan JM, Owen C, Cavener DR, Zhang P, Ron D, Harding HP, Chen JJ, Han A, White BC, Krause GS, DeGracia DJ (2001) Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. J Neurochem 77:1418-1421
106. Langland JO, Cameron JM, Heck MC, Jancovich JK, Jacobs BL (2006) Inhibition of PKR by RNA and DNA viruses. Virus Res 119:100-110
107. Lee ES, Yoon CH, Kim YS, Bae YS (2007) The double-strand RNA-dependent protein kinase PKR plays a significant role in a sustained ER stress-induced apoptosis. FEBS Lett 581:4325-4332
108. Lee J, Ryu H, Ferrante RJ, Morris SM Jr, Ratan RR (2003) Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci USA 100:4843-4848
109. Lee JH, Park EJ, Kim OS, Kim HY, Joe EH, Jou I (2005) Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells. Glia 50:66-79
110. Lee YY, Cevallos RC, Jan E (2009) An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation. J Biol Chem 284:6661-6673
111. Lemaire PA, Tessmer I, Craig R, Erie DA, Cole JL (2006) Unactivated PKR exists in an open conformation capable of binding nucleotides. Biochemistry 45:9074-9084
112. Li G, Mongillo M, Chin KT, Harding H, Ron D, Marks AR, Tabas I (2009) Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J Cell Biol 186:783-792
113. Li G, Scull C, Ozcan L, Tabas I (2010) NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J Cell Biol 191:1113-1125
114. Liao M, Pabarcus MK, Wang Y, Hefner C, Maltby DA, Medzihradszky KF, Salas-Castillo SP, Yan J, Maher JJ, Correia MA (2007) Impaired dexamethasone-mediated induction of tryptophan 2,3-dioxygenase in heme-deficient rat hepatocytes: translational control by a hepatic eIF2alpha kinase, the heme-regulated inhibitor. J Pharma Exp Ther 323:979-989
115. Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM, Walter P (2007) IRE1 signaling affects cell fate during the unfolded protein response. Science 318:944-949
116. Lin JH, Li H, Zhang Y, Ron D, Walter P (2009) Divergent effects of PERK and IRE1 signaling on cell viability. PLoS ONE 4:e4170
117. Liu S, Bhattacharya S, Han A, Suragani RN, Zhao W, Fry RC, Chen JJ (2008) Heme-regulated eIF2alpha kinase is necessary for adaptive gene expression in erythroid precursors under the stress of iron deficiency. Br J Haematol 143:129-137
118. Liu S, Suragani RN, Han A, Zhao W, Andrews NC, Chen JJ (2008) Deficiency of heme-regulated eIF2alpha kinase decreases hepcidin expression and splenic iron in HFE-/- mice. Haematologica 93:753-756
119. Liu S, Suragani RN, Wang F, Han A, Zhao W, Andrews NC, Chen JJ (2007) The function of heme-regulated eIF2alpha kinase in murine iron homeostasis and macrophage maturation. J Clin Investig 117:3296-3305
120. Liu Y, Laszlo C, Liu W, Chen X, Evans SC, Wu S (2010) Regulation of G(1) arrest and apoptosis in hypoxia by PERK and GCN2-mediated eIF2alpha phosphorylation. Neoplasia 12:61-68
121. Lo SC, Li X, Henzl MT, Beamer LJ, Hannink M (2006) Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J 25:3605-3617
122. Lozon TI, Eastman AJ, Matute-Bello G, Chen P, Hallstrand TS, Altemeier WA (2011) PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 300:L422-L429
123. Lu L, Han AP, Chen JJ (2001) Translation initiation control by heme-regulated eukaryotic initiation factor 2alpha kinase in erythroid cells under cytoplasmic stresses. Mol Cell Biol 21:7971-7980
124. Ma Y, Brewer JW, Diehl JA, Hendershot LM (2002) Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 318:1351-1365
125. Malzer E, Daly ML, Moloney A, Sendall TJ, Thomas SE, Ryder E, Ryoo HD, Crowther DC, Lomas DA, Marciniak SJ (2010) Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response. J Cell Sci 123:2892-2900
126. Maurin AC, Jousse C, Averous J, Parry L, Bruhat A, Cherasse Y, Zeng H, Zhang Y, Harding HP, Ron D, Fafournoux P (2005) The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Cell Metab 1:273-277
127. McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21:1249-1259
128. Mellor H, Proud CG (1991) A synthetic peptide substrate for initiation factor-2 kinases. Biochem Biophys Res Commun 178:430-437
129. Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, Hovanessian AG (1990) Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62:379-390
130. Mounir Z, Krishnamoorthy JL, Robertson GP, Scheuner D, Kaufman RJ, Georgescu MM, Koromilas AE (2009) Tumor suppression by PTEN requires the activation of the PKR-eIF2alpha phosphorylation pathway. Sci Signal 2:ra85
131. Mounir Z, Krishnamoorthy JL, Wang S, Papadopoulou B, Campbell S, Muller WJ, Hatzoglou M, Koromilas AE (2011) Akt determines cell fate through inhibition of the PERK-eIF2alpha phosphorylation pathway. Sci Signal 4: ra62
132. Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS (2010) Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140:338-348
133. Nanduri S, Rahman F, Williams BR, Qin J (2000) A dynamically tuned double-stranded RNA binding mechanism for the activation of antiviral kinase PKR. EMBO J 19:5567-5574
134. Narasimhan J, Staschke KA, Wek RC (2004) Dimerization is required for activation of eIF2 kinase Gcn2 in response to diverse environmental stress conditions. J Biol Chem 279:22820-22832
135. Naugler WE, Karin M (2008) NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev 18:19-26
136. Neznanov N, Dragunsky EM, Chumakov KM, Neznanova L, Wek RC, Gudkov AV, Banerjee AK (2008) Different effect of proteasome inhibition on vesicular stomatitis virus and poliovirus replication. PLoS ONE 3:e1887
137. Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291-13295
138. Niture SK, Kaspar JW, Shen J, Jaiswal AK (2010) Nrf2 signaling and cell survival. Toxicol Appl Pharmacol 244:37-42
139. Novoa I, Zeng H, Harding HP, Ron D (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 153:1011-1022
140. Novoa I, Zhang Y, Zeng H, Jungreis R, Harding HP, Ron D (2003) Stress-induced gene expression requires programmed recovery from translational repression. EMBO J 22:1180-1187
141. Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H (2005) TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 24:1243-1255
142. Onuki R, Bando Y, Suyama E, Katayama T, Kawasaki H, Baba T, Tohyama M, Taira K (2004) An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease. EMBO J 23:959-968
143. Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381-389
144. Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18:6853-6866
145. Palam LR, Baird TD, Wek RC (2011) Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J Biol Chem 286:10939-10949
146. Pang Q, Christianson TA, Koretsky T, Carlson H, David L, Keeble W, Faulkner GR, Speckhart A, Bagby GC (2003) Nucleophosmin interacts with and inhibits the catalytic function of eukaryotic initiation factor 2 kinase PKR. J Biol Chem 278:41709-41717
147. Pataer A, Swisher SG, Roth JA, Logothetis CJ, Corn PG (2009) Inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity. Cancer Biol Ther 8:245-252
148. Pataer A, Vorburger SA, Barber GN, Chada S, Mhashilkar AM, Zou-Yang H, Stewart AL, Balachandran S, Roth JA, Hunt KK, Swisher SG (2002) Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase (PKR). Cancer Res 62:2239-2243
149. Pataer A, Vorburger SA, Chada S, Balachandran S, Barber GN, Roth JA, Hunt KK, Swisher SG (2005) Melanoma differentiation-associated gene-7 protein physically associates with the double-stranded RNA-activated protein kinase PKR. Mol Ther 11:717-723
150. Patel CV, Handy I, Goldsmith T, Patel RC (2000) PACT, a stress-modulated cellular activator of interferon-induced double-stranded RNA-activated protein kinase, PKR. J Biol Chem 275:37993-37998
151. Patel RC, Sen GC (1998) PACT, a protein activator of the interferon-induced protein kinase, PKR. EMBO J 17:4379-4390
152. Perkins DJ, Barber GN (2004) Defects in translational regulation mediated by the alpha subunit of eukaryotic initiation factor 2 inhibit antiviral activity and facilitate the malignant transformation of human fibroblasts. Mol Cell Biol 24:2025-2040
153. Pervin S, Tran AH, Zekavati S, Fukuto JM, Singh R, Chaudhuri G (2008) Increased susceptibility of breast cancer cells to stress-mediated inhibition of protein synthesis. Cancer Res 68:4862-4874
154. Peters GA, Hartmann R, Qin J, Sen GC (2001) Modular structure of PACT: distinct domains for binding and activating PKR. Mol Cell Biol 21:1908-1920
155. Pomar N, Berlanga JJ, Campuzano S, Hernández G, Elías M, de Haro C (2003) Functional characterization of Drosophila melanogaster PERK eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Eur J Biochem 270:293-306
156. Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337-1349
157. Rafie-Kolpin M, Chefalo PJ, Hussain Z, Hahn J, Uma S, Matts RL, Chen JJ (2000) Two heme-binding domains of heme-regulated eukaryotic initiation factor-2alpha kinase. N terminus and kinase insertion. J Biol Chem 275:5171-5178
158. Rafie-Kolpin M, Han AP, Chen JJ (2003) Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI. Biochemistry 42:6536-6544
159. Rahman M, Lem C, Muaddi H, Koromilas AE (2009) PKR is not a universal target of tumor suppressor p53 in response to genotoxic stress. Cell cycle Georgetown Tex 8:3598-3599
160. 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
161. Ramana CV, Grammatikakis N, Chernov M, Nguyen H, Goh KC, Williams BR, Stark GR (2000) Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. EMBO J 19:263-272
162. Ramelot TA, Cort JR, Yee AA, Liu F, Goshe MB, Edwards AM, Smith RD, Arrowsmith CH, Dever TE, Kennedy MA (2002) Myxoma virus immunomodulatory protein M156R is a structural mimic of eukaryotic translation initiation factor eIF2alpha. J Mol Biol 322:943-954
163. Ranganathan AC, Ojha S, Kourtidis A, Conklin DS, Aguirre-Ghiso JA (2008) Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. Cancer Res 68:3260-3268
164. Romano PR, Garcia-Barrio MT, Zhang X, Wang Q, 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 2alpha kinases PKR and GCN2. Mol Cell Biol 18:2282-2297
165. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel AJ, Koritzinsky M, Wouters BG (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 120:127-141
166. Rutkowski DT, Kang SW, Goodman AG, Garrison JL, Taunton J, Katze MG, Kaufman RJ, Hegde RS (2007) The role of p58IPK in protecting the stressed endoplasmic reticulum. Mol Biol Cell 18:3681-3691
167. Ruvolo PP, Gao F, Blalock WL, Deng X, May WS (2001) Ceramide regulates protein synthesis by a novel mechanism involving the cellular PKR activator RAX. J Biol Chem 276:11754-11758
168. Rzymski T, Milani M, Pike L, Buffa F, Mellor HR, Winchester L, Pires I, Hammond E, Ragoussis I, Harris AL (2010) Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene 29:4424-4435
169. Sanderson TH, Deogracias MP, Nangia KK, Wang J, Krause GS, Kumar R (2010) PKR-like endoplasmic reticulum kinase (PERK) activation following brain ischemia is independent of unfolded nascent proteins. Neuroscience 169:1307-1314
170. Scheuner D, Patel R, Wang F, Lee K, Kumar K, Wu J, Nilsson A, Karin M, Kaufman RJ (2006) Double-stranded RNA-dependent protein kinase phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 mediates apoptosis. J Biol Chem 281:21458-21468
171. Schrier SL (1994) Thalassemia: pathophysiology of red cell changes. Annu Rev Med 45:211-218
172. Sevier CS, Kaiser CA (2008) Ero1 and redox homeostasis in the endoplasmic reticulum. Biochim Biophys Acta 1783:549-556
173. Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D (2003) Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev 29:297-307
174. Sharp TV, Witzel JE, Jagus R (1997) Homologous regions of the alpha subunit of eukaryotic translational initiation factor 2 (eIF2alpha) 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
175. Shimizu Y, Hendershot LM (2009) Oxidative folding: cellular strategies for dealing with the resultant equimolar production of reactive oxygen species. Antioxid Redox Signal 11:2317-2331
176. Singh M, Castillo D, Patel CV, Patel RC (2011) Stress-induced phosphorylation of PACT reduces its interaction with TRBP and leads to PKR activation. Biochemistry 50:4550-4560
177. Singh M, Fowlkes V, Handy I, Patel CV, Patel RC (2009) Essential role of PACT-mediated PKR activation in tunicamycin-induced apoptosis. J Mol Biol 385:457-468
178. Sonenberg N, Dever TE (2003) Eukaryotic translation initiation factors and regulators. Curr Opin Struct Biol 13:56-63
179. Sood R, Porter AC, Ma K, Quilliam LA, Wek RC (2000) 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. Biochem J 346(Pt 2):281-293
180. Srivastava SP, Kumar KU, Kaufman RJ (1998) Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase. J Biol Chem 273:2416-2423
181. Stojdl DF, Abraham N, Knowles S, Marius R, Brasey A, Lichty BD, Brown EG, Sonenberg N, Bell JC (2000) The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus. J Virol 74:9580-9585
182. Su N, Kilberg MS (2008) C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. J Biol Chem 283:35106-35117
183. Su Q, Wang S, Baltzis D, Qu LK, Wong AH, Koromilas AE (2006) Tyrosine phosphorylation acts as a molecular switch to full-scale activation of the eIF2alpha RNA-dependent protein kinase. Proc Natl Acad Sci USA 103:63-68
184. Su Q, Wang S, Gao HQ, Kazemi S, Harding HP, Ron D, Koromilas AE (2008) Modulation of the eukaryotic initiation factor 2 alpha-subunit kinase PERK by tyrosine phosphorylation. J Biol Chem 283:469-475
185. Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880-885
186. 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
187. Thireos G, Penn MD, Greer H (1984) 5′ untranslated sequences are required for the translational control of a yeast regulatory gene. Proc Natl Acad Sci USA 81:5096-5100
188. Thomas MG, Loschi M, Desbats MA, Boccaccio GL (2011) RNA granules: the good, the bad and the ugly. Cell Signal 23:324-334
189. Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA (2006) S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441:513-517
190. Uetani K, Der SD, Zamanian-Daryoush M, de La Motte C, Lieberman BY, Williams BR, Erzurum SC (2000) Central role of double-stranded RNA-activated protein kinase in microbial induction of nitric oxide synthase. J Immunol 165:988-996
191. Ung TL, Cao C, Lu J, Ozato K, Dever TE (2001) Heterologous dimerization domains functionally substitute for the double-stranded RNA binding domains of the kinase PKR. EMBO J 20:3728-3737
192. van Huizen R, Martindale JL, Gorospe M, Holbrook NJ (2003) P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. J Biol Chem 278:15558-15564
193. VanOudenhove J, Anderson E, Krueger S, Cole JL (2009) Analysis of PKR structure by small-angle scattering. J Mol Biol 387:910-920
194. Vattem KM, Staschke KA, Wek RC (2001) 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). Eur J Biochem 268:3674-3684
195. Vazquez de Aldana CR, Dever TE, Hinnebusch AG (1993) Mutations in the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2 alpha) that overcome the inhibitory effect of eIF-2 alpha phosphorylation on translation initiation. Proc Natl Acad Sci USA 90:7215-7219
196. Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, Ron D, Chen W, Trenkle W, Wiestner A, Ye Y (2009) ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proc Natl Acad Sci USA 106:2200-2205
197. Wei CL, Wu Q, Vega VB, Chiu KP, Ng P, Zhang T, Shahab A, Yong HC, Fu Y, Weng Z, Liu J, Zhao XD, Chew JL, Lee YL, Kuznetsov VA, Sung WK, Miller LD, Lim B, Liu ET, Yu Q, Ng HH, Ruan Y (2006) A global map of p53 transcription-factor binding sites in the human genome. Cell 124:207-219
198. Wethmar K, Smink JJ, Leutz A (2010) Upstream open reading frames: molecular switches in (patho)physiology. BioEssays 32:885-893
199. Williams BR (1999) PKR; a sentinel kinase for cellular stress. Oncogene 18:6112-6120
200. Wu S, Kaufman RJ (1997) A model for the double-stranded RNA (dsRNA)-dependent dimerization and activation of the dsRNA-activated protein kinase PKR. J Biol Chem 272:1291-1296
201. Xu WM, Liu LZ (1998) Nitric oxide: from a mysterious labile factor to the molecule of the Nobel Prize. Recent progress in nitric oxide research. Cell Res 8:251-258
202. Yamaguchi H, Wang HG (2004) CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 279:45495-45502
203. Yan W, Gale MJ Jr, Tan SL, Katze MG (2002) Inactivation of the PKR protein kinase and stimulation of mRNA translation by the cellular co-chaperone P58(IPK) does not require J domain function. Biochemistry 41:4938-4945
204. Yang R, Wek SA, Wek RC (2000) Glucose limitation induces GCN4 translation by activation of Gcn2 protein kinase. Mol Cell Biol 20:2706-2717
205. Yang YL, Reis LF, Pavlovic J, Aguzzi A, Schafer R, Kumar A, Williams BR, Aguet M, Weissmann C (1995) Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J 14:6095-6106
206. Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN, Bobrovnikova-Marjon E, Diehl JA, Ron D, Koumenis C (2010) The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J 29:2082-2096
207. Yerlikaya A, Kimball SR, Stanley BA (2008) Phosphorylation of eIF2alpha in response to 26S proteasome inhibition is mediated by the heme-regulated inhibitor (HRI) kinase. Biochem J 412:579-588
208. 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
209. Yoon CH, Lee ES, Lim DS, Bae YS (2009) PKR, a p53 target gene, plays a crucial role in the tumor-suppressor function of p53. Proc Natl Acad Sci USA 106:7852-7857
210. Zhang F, Hamanaka RB, Bobrovnikova-Marjon E, Gordan JD, Dai MS, Lu H, Simon MC, Diehl JA (2006) Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest. J Biol Chem 281:30036-30045
211. Zhang P, McGrath BC, Reinert J, Olsen DS, Lei L, Gill S, Wek SA, Vattem KM, Wek RC, Kimball SR, Jefferson LS, Cavener DR (2002) The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Mol Cell Biol 22:6681-6688
212. Zhang S, Yu D (2010) PI(3)king apart PTEN's role in cancer. Clin Cancer Res 16:4325-4330
213. Zhang W, Feng D, Li Y, Iida K, McGrath B, Cavener DR (2006) PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab 4:491-497
214. Zhou D, Palam LR, Jiang L, Narasimhan J, Staschke KA, Wek RC (2008) Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem 283:7064-7073
215. Zhu S, Wek RC (1998) Ribosome-binding domain of eukaryotic initiation factor-2 kinase GCN2 facilitates translation control. J Biol Chem 273:1808-1814
216. Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982-995