2,580
Views
5
CrossRef citations to date
0
Altmetric
Review

Targeting the integrated stress response in ophthalmology

, , &
Pages 1075-1088 | Received 21 Sep 2020, Accepted 07 Dec 2020, Published online: 21 Jan 2021

References

  • Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science. 2020;368:6489. doi:10.1126/science.aat5314.
  • Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17(10):1374–95. doi:10.15252/embr.201642195.
  • Seo J, Fortuno ES 3rd, Suh JM, Stenesen D, Tang W, Parks EJ, Adams CM, Townes T, Graff JM. Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes. 2009;58(11):2565–73. doi:10.2337/db09-0335.
  • Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099–108. doi:10.1016/s1097-2765(00)00108-8.
  • Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN, Bobrovnikova-Marjon E, Diehl JA, Ron D, Koumenis C. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. Embo J. 2010;29(12):2082–96. doi:10.1038/emboj.2010.81.
  • Kilberg MS, Shan J, Su N. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol Metab. 2009;20(9):436–43. doi:10.1016/j.tem.2009.05.008.
  • B’Chir W, Maurin AC, Carraro V, Averous J, Jousse C, Muranishi Y, Parry L, Stepien G, Fafournoux P, Bruhat A. The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013;41(16):7683–99. doi:10.1093/nar/gkt563.
  • Chen JJ, Throop MS, Gehrke L, Kuo I, Pal JK, Brodsky M, London IM. Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2 alpha kinase. Proc Natl Acad Sci U S A. 1991;88(17):7729–33. doi:10.1073/pnas.88.17.7729.
  • Clemens MJ, Elia A. The double-stranded RNA-dependent protein kinase PKR: structure and function. J Interferon Cytokine Res. 1997;17(9):503–24. doi:10.1089/jir.1997.17.503.
  • Feldman DE, Chauhan V, Koong AC. The unfolded protein response: a novel component of the hypoxic stress response in tumors. Mol Cancer Res. 2005;3(11):597–605. doi:10.1158/1541-7786.Mcr-05-0221.
  • Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999;397(6716):271–74. doi:10.1038/16729.
  • Rutkowski DT, Arnold SM, Miller CN, Wu J, Li J, Gunnison KM, Mori K, Sadighi Akha AA, Raden D, Kaufman RJ. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol. 2006;4(11):e374. doi:10.1371/journal.pbio.0040374.
  • Bond S, Lopez-Lloreda C, Gannon PJ, Akay-Espinoza C, Jordan-Sciutto KL. The integrated stress response and phosphorylated eukaryotic initiation factor 2α in neurodegeneration. J Neuropathol Exp Neurol. 2020;79:123–43. doi:10.1093/jnen/nlz129.
  • Ariyasu D, Yoshida H, Hasegawa Y. Endoplasmic reticulum (ER) stress and endocrine disorders. Int J Mol Sci. 2017;18(2):382. doi:10.3390/ijms18020382.
  • McConkey DJ. The integrated stress response and proteotoxicity in cancer therapy. Biochem Biophys Res Commun. 2017;482(3):450–53. doi:10.1016/j.bbrc.2016.11.047.
  • Oakes SA. Endoplasmic reticulum proteostasis: a key checkpoint in cancer. Am J Physiol Cell Physiol. 2017;312(2):C93–c102. doi:10.1152/ajpcell.00266.2016.
  • So JS. Roles of endoplasmic reticulum stress in immune responses. Mol Cells. 2018;41(8):705–16. doi:10.14348/molcells.2018.0241.
  • Rodrigues L, Graca RSF, Carneiro LAM. Integrated stress responses to bacterial pathogenesis patterns. Front Immunol. 2018;9:1306. doi:10.3389/fimmu.2018.01306.
  • Bashir H, Seykora JT, Lee V. Invisible Shield: review of the corneal epithelium as a barrier to uv radiation, pathogens, and other environmental stimuli. J Ophthalmic Vis Res. 2017;12(3):305–11. doi:10.4103/jovr.jovr_114_17.
  • Kroeger H, Chiang W-C, Felden J, Nguyen A, Lin JH. ER stress and unfolded protein response in ocular health and disease. Febs J. 2019;286(2):399–412. doi:10.1111/febs.14522.
  • Salminen A, Kauppinen A, Hyttinen JM, Toropainen E, Kaarniranta K. Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization. Mol Med. 2010;16(11–12):535–42. doi:10.2119/molmed.2010.00070.
  • Ghosh R, Lipson KL, Sargent KE, Mercurio AM, Hunt JS, Ron D, Urano F, Blagosklonny MV. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS ONE. 2010;5(3):e9575. doi:10.1371/journal.pone.0009575.
  • Forrester J, Xu H. Good news–bad news: the Yin and Yang of immune privilege in the eye. Front Immunol. 2012;3(338). doi:10.3389/fimmu.2012.00338.
  • Johnston BP, McCormick C. Herpesviruses and the unfolded protein response. Viruses. 2019;12(1):17. doi:10.3390/v12010017.
  • Zode GS, Sharma AB, Lin X, Searby CC, Bugge K, Kim GH, Clark AF, Sheffield VC. Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma. J Clin Invest. 2014;124(5):1956–65. doi:10.1172/JCI69774.
  • Li J, Wang JJ, Yu Q, Wang M, Zhang SX. Endoplasmic reticulum stress is implicated in retinal inflammation and diabetic retinopathy. FEBS Lett. 2009;583(9):1521–27. doi:10.1016/j.febslet.2009.04.007.
  • Yang J, Zhou S, Gu J, Wang Y, Guo M, Liu Y, Pan C-W. Differences in unfolded protein response pathway activation in the lenses of three types of cataracts. PLoS One. 2015;10(6):e0130705. doi:10.1371/journal.pone.0130705.
  • Coursey TG, Tukler Henriksson J, Barbosa FL, De Paiva CS, Pflugfelder SC. Interferon-γ–induced unfolded protein response in conjunctival goblet cells as a cause of mucin deficiency in sjögren syndrome. Am J Pathol. 2016;186(6):1547–58. doi:10.1016/j.ajpath.2016.02.004.
  • Foster JW, Shinde V, Soiberman US, Sathe G, Liu S, Wan J, Qian J, Dauoud Y, Pandey A, Jun AS, et al. Integrated stress response and decreased ECM in cultured stromal cells from keratoconus corneas. Invest Ophthalmol Vis Sci. 2018;59(7):2977–86. doi:10.1167/iovs.18-24367.
  • Tanaka T, Tsujimura T, Takeda K, Sugihara A, Maekawa A, Terada N, Yoshida N, Akira S. Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres. Genes Cells. 1998;3(12):801–10. doi:10.1046/j.1365-2443.1998.00230.x.
  • Starr CR, Gorbatyuk MS. Delineating the role of eIF2α in retinal degeneration. Cell Death Dis. 2019;10(6):409. doi:10.1038/s41419-019-1641-y.
  • Bhootada Y, Kotla P, Zolotukhin S, Gorbatyuk O, Bebok Z, Athar M, Gorbatyuk M, Boulton ME. Limited ATF4 expression in degenerating retinas with ongoing ER stress promotes photoreceptor survival in a mouse model of autosomal dominant retinitis pigmentosa. PLoS One. 2016;11(5):e0154779. doi:10.1371/journal.pone.0154779.
  • Singleton DC, Harris AL. Targeting the ATF4 pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(12):1189–202. doi:10.1517/14728222.2012.728207.
  • Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in disease. Nat Rev Drug Discov. 2013;12(9):703–19. doi:10.1038/nrd3976.
  • Joshi M, Kulkarni A, Pal JK. Small molecule modulators of eukaryotic initiation factor 2α kinases, the key regulators of protein synthesis. Biochimie. 2013;95(11):1980–90. doi:10.1016/j.biochi.2013.07.030.
  • Ameri K, Harris AL. Activating transcription factor 4. Int J Biochem Cell Biol. 2008;40(1):14–21. doi:10.1016/j.biocel.2007.01.020.
  • Donnelly N, Gorman AM, Gupta S, Samali A. The eIF2alpha kinases: their structures and functions. Cell Mol Life Sci. 2013;70(19):3493–511. doi:10.1007/s00018-012-1252-6.
  • Dever TE, Feng L, Wek RC, Cigan AM, Donahue TF, Hinnebusch AG. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell. 1992;68(3):585–96. doi:10.1016/0092-8674(92)90193-g.
  • Kostura M, Mathews MB. Purification and activation of the double-stranded RNA-dependent eIF-2 kinase DAI. Mol Cell Biol. 1989;9(4):1576–86. doi:10.1128/mcb.9.4.1576.
  • Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, Hovanessian AG. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell. 1990;62(2):379–90. doi:10.1016/0092-8674(90)90374-n.
  • Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol. 1998;18(12):7499–509. doi:10.1128/mcb.18.12.7499.
  • Masson GR. Towards a model of GCN2 activation. Biochem Soc Trans. 2019;47(5):1481–88. doi:10.1042/bst20190331.
  • Chen -J-J. Translational control by heme-regulated eIF2α kinase during erythropoiesis. Curr Opin Hematol. 2014;21(3):172–78. doi:10.1097/moh.0000000000000030.
  • Korennykh A, Walter P. Structural basis of the unfolded protein response. Annu Rev Cell Dev Biol. 2012;28:251–77. doi:10.1146/annurev-cellbio-101011-155826.
  • Hinnebusch AG. Molecular mechanism of scanning and start codon selection in eukaryotes. Microbiol Mol Biol Rev. 2011;75(3):434–67. first page of table of contents. doi:10.1128/mmbr.00008-11.
  • Kimball SR. Eukaryotic initiation factor eIF2. Int J Biochem Cell Biol. 1999;31(1):25–29. doi:10.1016/s1357-2725(98)00128-9.
  • Proud CG. eIF2 and the control of cell physiology. Semin Cell Dev Biol. 2005;16(1):3–12. doi:10.1016/j.semcdb.2004.11.004.
  • Rowlands AG, Panniers R, Henshaw EC. The catalytic mechanism of guanine nucleotide exchange factor action and competitive inhibition by phosphorylated eukaryotic initiation factor 2. J Biol Chem. 1988;263:5526–33.
  • Rabouw HH, Visser LJ, Passchier TC, Langereis MA, Liu F, Giansanti P, van Vliet ALW, Dekker JG, van der Grein SG, Saucedo JG, et al. Inhibition of the integrated stress response by viral proteins that block p-eIF2–eIF2B association. Nat Microbiol. 2020;5(11):1361–73. doi:10.1038/s41564-020-0759-0.
  • Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11(3):619–33. doi:10.1016/s1097-2765(03)00105-9.
  • Han AP. Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. Embo J. 2001;20(23):6909–18. doi:10.1093/emboj/20.23.6909.
  • Balachandran S, Roberts PC, Brown LE, Truong H, Pattnaik AK, Archer DR, Barber GN. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity. 2000;13(1):129–41. doi:10.1016/s1074-7613(00)00014-5.
  • Garcia MA, Meurs EF, Esteban M. The dsRNA protein kinase PKR: virus and cell control. Biochimie. 2007;89(6–7):799–811. doi:10.1016/j.biochi.2007.03.001.
  • Ron D. Translational control in the endoplasmic reticulum stress response. J Clin Invest. 2002;110(10):1383–88. doi:10.1172/JCI16784.
  • Chan CP, Kok KH, Tang HM, Wong CM, Jin DY. Internal ribosome entry site-mediated translational regulation of ATF4 splice variant in mammalian unfolded protein response. Biochim Biophys Acta. 2013;1833(10):2165–75. doi:10.1016/j.bbamcr.2013.05.002.
  • Palam LR, Baird TD, Wek RC. Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J Biol Chem. 2011;286(13):10939–49. doi:10.1074/jbc.M110.216093.
  • Lee YY, Cevallos RC, Jan E. An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation. J Biol Chem. 2009;284(11):6661–73. doi:10.1074/jbc.M806735200.
  • Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11(3):619–33. doi:10.1016/s1097-2765(03)00105-9.
  • Yoshizawa T, Hinoi E, Jung DY, Kajimura D, Ferron M, Seo J, Graff JM, Kim JK, Karsenty G. The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J Clin Invest. 2009;119(9):2807–17. doi:10.1172/jci39366.
  • Bretin A, Carriere J, Dalmasso G, Bergougnoux A, B’Chir W, Maurin AC, Muller S, Seibold F, Barnich N, Bruhat A, et al. Activation of the EIF2AK4-EIF2A/eIF2alpha-ATF4 pathway triggers autophagy response to Crohn disease-associated adherent-invasive Escherichia coli infection. Autophagy. 2016;12(5):770–83. doi:10.1080/15548627.2016.1156823.
  • Wang Y, Ning Y, Alam GN, Jankowski BM, Dong Z, Nor JE, Polverini PJ. Amino acid deprivation promotes tumor angiogenesis through the GCN2/ATF4 pathway. Neoplasia. 2013;15(8):989–97. doi:10.1593/neo.13262.
  • Wortel IMN, Van Der Meer LT, Kilberg MS, Van Leeuwen FN. Surviving stress: modulation of ATF4-mediated stress responses in normal and malignant cells. Trends Endocrinol Metab. 2017;28(11):794–806. doi:10.1016/j.tem.2017.07.003.
  • Jousse C, Oyadomari S, Novoa I, Lu P, Zhang Y, Harding HP, Ron D. Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells. J Cell Biol. 2003;163(4):767–75. doi:10.1083/jcb.200308075.
  • Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol. 2001;153(5):1011–22. doi:10.1083/jcb.153.5.1011.
  • Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004;18(24):3066–77. doi:10.1101/gad.1250704.
  • Han J, Back SH, Hur J, Lin Y-H, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013;15(5):481–90. doi:10.1038/ncb2738.
  • Frank CL, Ge X, Xie Z, Zhou Y, Tsai LH. Control of activating transcription factor 4 (ATF4) persistence by multisite phosphorylation impacts cell cycle progression and neurogenesis. J Biol Chem. 2010;285(43):33324–37. doi:10.1074/jbc.m110.140699.
  • Lin H-K, Chen Z, Wang G, Nardella C, Lee S-W, Chan C-H, Yang W-L, Wang J, Egia A, Nakayama KI, et al. Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature. 2010;464(7287):374–79. doi:10.1038/nature08815.
  • Jun AS. One hundred years of Fuchs’ dystrophy. Ophthalmology. 2010;117(5):859–860 e814. doi:10.1016/j.ophtha.2010.03.001.
  • Eghrari AO, Riazuddin SA, Gottsch JD. Fuchs corneal dystrophy. Prog Mol Biol Transl Sci. 2015;134:79–97. doi:10.1016/bs.pmbts.2015.04.005.
  • Engler C, Kelliher C, Spitze AR, Speck CL, Eberhart CG, Jun AS. Unfolded protein response in fuchs endothelial corneal dystrophy: a unifying pathogenic pathway? Am J Ophthalmol. 2010;149(2):194–202.e192. doi:10.1016/j.ajo.2009.09.009.
  • Okumura N, Kitahara M, Okuda H, Hashimoto K, Ueda E, Nakahara M, Kinoshita S, Young RD, Quantock AJ, Tourtas T, et al. Sustained activation of the unfolded protein response induces cell death in fuchs’ endothelial corneal dystrophy. Invest Ophthalmol Vis Sci. 2017;58(9):3697–707. doi:10.1167/iovs.16-21023.
  • Ferrari G, Rama P. The keratoconus enigma: a pathogenesis review. Ocul Surf. 2020 Jul;18(3):363–73. doi:10.1016/j.jtos.2020.03.006.
  • Chaerkady R, Shao H, Scott SG, Pandey A, Jun AS, Chakravarti S. The keratoconus corneal proteome: loss of epithelial integrity and stromal degeneration. J Proteomics. 2013;87:122–31. doi:10.1016/j.jprot.2013.05.023.
  • Klintworth GK. Advances in the molecular genetics of corneal dystrophies. Am J Ophthalmol. 1999;128(6):747–54. doi:10.1016/s0002-9394(99)00358-x.
  • Choi SI, Lee E, Jeong JB, Akuzum B, Maeng YS, Kim TI, Kim EK. 4-Phenylbutyric acid reduces mutant-TGFBIp levels and ER stress through activation of ERAD pathway in corneal fibroblasts of granular corneal dystrophy type 2. Biochem Biophys Res Commun. 2016;477(4):841–46. doi:10.1016/j.bbrc.2016.06.146.
  • Shukla D, Farooq S. The role of herpesviruses in ocular infections. Virus Adapt Treat. 2010;2:115–23. doi:10.2147/vaat.s9500.
  • Valerio GS, Lin CC. Ocular manifestations of herpes simplex virus. Curr Opin Ophthalmol. 2019;30(6):525–31. doi:10.1097/icu.0000000000000618.
  • Burnett HF, Audas TE, Liang G, Lu RR. Herpes simplex virus-1 disarms the unfolded protein response in the early stages of infection. Cell Stress Chaperones. 2012;17(4):473–83. doi:10.1007/s12192-012-0324-8.
  • Poppers J, Mulvey M, Khoo D, Mohr I. Inhibition of PKR activation by the proline-rich RNA binding domain of the herpes simplex virus type 1 Us11 protein. J Virol. 2000;74(23):11215–21. doi:10.1128/jvi.74.23.11215-11221.2000.
  • He B, Gross M, Roizman B. The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc Natl Acad Sci U S A. 1997;94(3):843–48. doi:10.1073/pnas.94.3.843.
  • Charron AJ, Ward SL, North BJ, Ceron S, Leib DA, Longnecker RM. The US11 gene of herpes simplex virus 1 promotes neuroinvasion and periocular replication following corneal infection. J Virol. 2019;93(9):e02246. doi:10.1128/JVI.02246-18.
  • Hejtmancik JF, Riazuddin SA, McGreal R, Liu W, Cvekl A, Shiels A. Lens biology and biochemistry. Prog Mol Biol Transl Sci. 2015;134:(169–201. doi:10.1016/bs.pmbts.2015.04.007.
  • Graw J. Eye development. Curr Top Dev Biol. 2010;90:343–86. doi:10.1016/s0070-2153(10)90010-0.
  • Brennan LA, Kantorow WL, Chauss D, McGreal R, He S, Mattucci L, Wei J, Riazuddin SA, Cvekl A, Hejtmancik JF, et al. Spatial expression patterns of autophagy genes in the eye lens and induction of autophagy in lens cells. Mol Vis. 2012;18:1773–86.
  • Khan SY, Ali M, Kabir F, Renuse S, Na CH, Talbot CC Jr., Hackett SF, Riazuddin SA. Proteome profiling of developing murine lens through mass spectrometry. Invest Ophthalmol Vis Sci. 2018;59(1):100–07. doi:10.1167/iovs.17-21601.
  • Khairallah M, Kahloun R, Bourne R, Limburg H, Flaxman SR, Jonas JB, Keeffe J, Leasher J, Naidoo K, Pesudovs K, et al. Number of people blind or visually impaired by cataract worldwide and in world regions, 1990 to 2010. Invest Ophthalmol Vis Sci. 2015;56(11):6762–69. doi:10.1167/iovs.15-17201.
  • Bron AJ, Vrensen GF, Koretz J, Maraini G, Harding JJ. The ageing lens. Ophthalmologica. 2000;214(1):86–104. doi:10.1159/000027475.
  • Tang HZ, Yang LM. Activation of the unfolded protein response in aged human lenses. Mol Med Rep. 2015;12(1):389–93. doi:10.3892/mmr.2015.3417.
  • Yang J, Zhou S, Gu J, Guo M, Xia H, Liu Y, Nagaraj R. UPR activation and the down-regulation of alpha-crystallin in human high myopia-related cataract lens epithelium. PLoS One. 2015;10(9):e0137582. doi:10.1371/journal.pone.0137582.
  • Ikesugi K, Yamamoto R, Mulhern ML, Shinohara T. Role of the unfolded protein response (UPR) in cataract formation. Exp Eye Res. 2006;83(3):508–16. doi:10.1016/j.exer.2006.01.033.
  • Kroeger H, Chiang WC, Felden J, Nguyen A, Lin JH. ER stress and unfolded protein response in ocular health and disease. Febs J. 2019;286(2):399–412. doi:10.1111/febs.14522.
  • Kobrin Klein BE. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol. 2007;14(4):179–83. doi:10.1080/09286580701396720.
  • Ejaz S. Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy. Diabetes, Obes Metab. 2008;10(1):53–63. doi:10.1111/j.1463-1326.2007.00795.x.
  • Zhong Y, Wang JJ, Zhang SX. Intermittent but not constant high glucose induces ER stress and inflammation in human retinal pericytes. Adv Exp Med Biol. 2012;723:285–92. doi:10.1007/978-1-4614-0631-0_37.
  • Mitchell P, Liew G, Gopinath B, Wong TY. Age-related macular degeneration. Lancet. 2018;392(10153):1147–59. doi:10.1016/s0140-6736(18)31550-2.
  • Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration—emerging pathogenetic and therapeutic concepts. Ann Med. 2006;38(7):450–71. doi:10.1080/07853890600946724.
  • Roybal CN, Hunsaker LA, Barbash O, Vander Jagt DL, Abcouwer SF. The oxidative stressor arsenite activates vascular endothelial growth factor mRNA transcription by an ATF4-dependent mechanism. J Biol Chem. 2005;280(21):20331–39. doi:10.1074/jbc.M411275200.
  • Pollreisz A, Afonyushkin T, Oskolkova OV, Gruber F, Bochkov VN, Schmidt-Erfurth U. Retinal pigment epithelium cells produce VEGF in response to oxidized phospholipids through mechanisms involving ATF4 and protein kinase CK2. Exp Eye Res. 2013;116:177–84. doi:10.1016/j.exer.2013.08.021.
  • Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma. JAMA. 2014;311(18):1901. doi:10.1001/jama.2014.3192.
  • Zode GS, Kuehn MH, Nishimura DY, Searby CC, Mohan K, Grozdanic SD, Bugge K, Anderson MG, Clark AF, Stone EM, et al. Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma. J Clin Invest. 2011;121(9):3542–53. doi:10.1172/JCI58183.
  • Peters JC, Bhattacharya S, Clark AF, Zode GS. Increased endoplasmic reticulum stress in human glaucomatous trabecular meshwork cells and tissues. Invest Ophthalmol Vis Sci. 2015;56(6):3860–68. doi:10.1167/iovs.14-16220.
  • Foufelle F, Fromenty B. Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol Res Perspect. 2016;4(1):e00211. doi:10.1002/prp2.211.
  • Srivastava RK, Li C, Ahmad A, Abrams O, Gorbatyuk MS, Harrod KS, Wek RC, Afaq F, Athar M. ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis. Arch Biochem Biophys. 2016;609:39–50. doi:10.1016/j.abb.2016.09.003.
  • Carlberg M, Dricu A, Blegen H, Kass GEN, Orrenius S, Larsson O. Short exposures to tunicamycin induce apoptosis in SV40-transformed but not in normal human fibroblasts. Carcinogenesis. 1996;17(12):2589–96. doi:10.1093/carcin/17.12.2589.
  • Treiman M, Caspersen C, Christensen SB. A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca(2+)-ATPases. Trends Pharmacol Sci. 1998;19(4):131–35. doi:10.1016/s0165-6147(98)01184-5.
  • Shi K, Wang D, Cao X, Ge Y, Takehara T. Endoplasmic reticulum stress signaling is involved in mitomycin C(MMC)-induced apoptosis in human fibroblasts via PERK pathway. PLoS ONE. 2013;8(3):e59330. doi:10.1371/journal.pone.0059330.
  • Martinez VD, Vucic EA, Becker-Santos DD, Gil L, Lam WL. Arsenic exposure and the induction of human cancers. J Toxicol. 2011;2011:431287. doi:10.1155/2011/431287.
  • Guo Q, Li H, Liu J, Xu L, Yang L, Sun Z, Zhou B. Tunicamycin aggravates endoplasmic reticulum stress and airway inflammation via PERK-ATF4-CHOP signaling in a murine model of neutrophilic asthma. J Asthma. 2017;54(2):125–33. doi:10.1080/02770903.2016.1205085.
  • Shaabani N, Honke N, Lang PA, Gorg B, Proksch P, Gailus N, Gotoh T, Haussinger D, Lang KS. Tunicamycin inhibits diabetes. Cell Physiol Biochem. 2012;29(3–4):595–602. doi:10.1159/000338513.
  • Shehadeh-Mashor R, Srinivasan S, Boimer C, Lee K, Tomkins O, Slomovic AR. Management of recurrent pterygium with intraoperative mitomycin C and conjunctival autograft with fibrin glue. Am J Ophthalmol. 2011;152(5):730–32. doi:10.1016/j.ajo.2011.04.034.
  • Katz GJ, Higginbotham EJ, Lichter PR, Skuta GL, Musch DC, Bergstrom TJ, Johnson AT. Mitomycin C versus 5-fluorouracil in high-risk glaucoma filtering surgery. Extended follow-up. Ophthalmology. 1995;102(9):1263–69. doi:10.1016/s0161-6420(95)30875-5.
  • Doultsinos D, Avril T, Lhomond S, Dejeans N, Guedat P, Chevet E. Control of the unfolded protein response in health and disease. SLAS Discov. 2017;22(7):787–800. doi:10.1177/2472555217701685.
  • Hetz C, Axten JM, Patterson JB. Pharmacological targeting of the unfolded protein response for disease intervention. Nat Chem Biol. 2019;15(8):764–75. doi:10.1038/s41589-019-0326-2.
  • Rabouw HH, Langereis MA, Anand AA, Visser LJ, De Groot RJ, Walter P, Van Kuppeveld FJM. Small molecule ISRIB suppresses the integrated stress response within a defined window of activation. Proc Nat Acad Sci. 2019;116(6):2097–102. doi:10.1073/pnas.1815767116.
  • Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, Gamache K, Gallagher CM, Ang KK, Wilson C, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013;2:e00498. doi:10.7554/eLife.00498.
  • Sidrauski C, Tsai JC, Kampmann M, Hearn BR, Vedantham P, Jaishankar P, Sokabe M, Mendez AS, Newton BW, Tang EL, et al. Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. Elife. 2015;4:e07314. doi:10.7554/eLife.07314.
  • Hearn BR, Jaishankar P, Sidrauski C, Tsai JC, Vedantham P, Fontaine SD, Walter P, Renslo AR. Structure-activity studies of bis-O-arylglycolamides: inhibitors of the integrated stress response. ChemMedChem. 2016;11(8):870–80. doi:10.1002/cmdc.201500483.
  • Bugallo R, Marlin E, Baltanas A, Toledo E, Ferrero R, Vinueza-Gavilanes R, Larrea L, Arrasate M, Aragon T. Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis. Cell Death Dis. 2020;11(5):397. doi:10.1038/s41419-020-2601-2.
  • Halliday M, Radford H, Sekine Y, Moreno J, Verity N, Le Quesne J, Ortori CA, Barrett DA, Fromont C, Fischer PM, et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 2015;6(3):e1672–e1672. doi:10.1038/cddis.2015.49.
  • Chou A, Krukowski K, Jopson T, Zhu PJ, Costa-Mattioli M, Walter P, Rosi S. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc Natl Acad Sci U S A. 2017;114(31):E6420–E6426. doi:10.1073/pnas.1707661114.
  • Zhu PJ, Khatiwada S, Cui Y, Reineke LC, Dooling SW, Kim JJ, Li W, Walter P, Costa-Mattioli M. Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome. Science. 2019;366(6467):843–49. doi:10.1126/science.aaw5185.
  • Soiberman US, Shehata AEM, Lu MX, Young T, Daoud YJ, Chakravarti S, Jun AS, Foster JW. Small molecule modulation of the integrated stress response governs the keratoconic phenotype in vitro. Invest Ophthalmol Vis Sci. 2019;60(10):3422–31. doi:10.1167/iovs.19-27151.
  • Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, Waldner H, et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science. 2009;324(5932):1334–38. doi:10.1126/science.1172638.
  • Bunpo P, Dudley A, Cundiff JK, Cavener DR, Wek RC, Anthony TG. GCN2 protein kinase is required to activate amino acid deprivation responses in mice treated with the anti-cancer agent L-asparaginase. J Biol Chem. 2009;284(47):32742–49. doi:10.1074/jbc.M109.047910.
  • Long Y, Tsai WB, Wangpaichitr M, Tsukamoto T, Savaraj N, Feun LG, Kuo MT. Arginine deiminase resistance in melanoma cells is associated with metabolic reprogramming, glucose dependence, and glutamine addiction. Mol Cancer Ther. 2013;12(11):2581–90. doi:10.1158/1535-7163.MCT-13-0302.
  • Chen T, Ozel D, Qiao Y, Harbinski F, Chen L, Denoyelle S, He X, Zvereva N, Supko JG, Chorev M, et al. Chemical genetics identify eIF2alpha kinase heme-regulated inhibitor as an anticancer target. Nat Chem Biol. 2011;7(9):610–16. doi:10.1038/nchembio.613.
  • Hu W, Hofstetter W, Wei X, Guo W, Zhou Y, Pataer A, Li H, Fang B, Swisher SG. Double-stranded RNA-dependent protein kinase-dependent apoptosis induction by a novel small compound. J Pharmacol Exp Ther. 2009;328(3):866–72. doi:10.1124/jpet.108.141754.
  • Ma C-H, Wu C-H, Jou IM, Tu Y-K, Hung C-H, Chou W-C, Chang Y-C, Hsieh P-L, Tsai K-L. PKR promotes oxidative stress and apoptosis of human articular chondrocytes by causing mitochondrial dysfunction through p38 MAPK activation—PKR activation causes apoptosis in human chondrocytes. Antioxidants. 2019;8(9):370. doi:10.3390/antiox8090370.
  • Stockwell SR, Platt G, Barrie SE, Zoumpoulidou G, Te Poele RH, Aherne GW, Wilson SC, Sheldrake P, McDonald E, Venet M, et al. Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. PLoS One. 2012;7(1):e28568. doi:10.1371/journal.pone.0028568.
  • Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, Sanders B, Goetz A, Gaul N, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013;73(6):1993–2002. doi:10.1158/0008-5472.Can-12-3109.
  • Elkin M, Miao HQ, Nagler A, Aingorn E, Reich R, Hemo I, Dou HL, Pines M, Vlodavsky I. Halofuginone: a potent inhibitor of critical steps in angiogenesis progression. FASEB J. 2000;14(15):2477–85. doi:10.1096/fj.00-0292com.
  • Yang L, Tan D, Piao H. Myelin basic protein citrullination in multiple sclerosis: a potential therapeutic target for the pathology. Neurochem Res. 2016;41(8):1845–56. doi:10.1007/s11064-016-1920-2.
  • Bonilha VL, Shadrach KG, Rayborn ME, Li Y, Pauer GJT, Hagstrom SA, Bhattacharya SK, Hollyfield JG. Retinal deimination and PAD2 levels in retinas from donors with age-related macular degeneration (AMD). Exp Eye Res. 2013;111:71–78. doi:10.1016/j.exer.2013.03.017.
  • Bhattacharya SK, Crabb JS, Bonilha VL, Gu X, Takahara H, Crabb JW. Proteomics implicates peptidyl arginine deiminase 2 and optic nerve citrullination in glaucoma pathogenesis. Invest Ophthalmol Vis Sci. 2006;47(6):2508–14. doi:10.1167/iovs.05-1499.
  • Park JH, Baron S. Herpetic keratoconjunctivitis: therapy with synthetic double-stranded RNA. Science. 1968;162(3855):811–13. doi:10.1126/science.162.3855.811.
  • Kaufman HE, Ellison ED, Waltman SR. Double-stranded RNA, an interferon inducer, in herpes simplex keratitis. Am J Ophthalmol. 1969;68(3):486–91. doi:10.1016/0002-9394(69)90720-x.
  • Robert F, Williams C, Yan Y, Donohue E, Cencic R, Burley SK, Pelletier J. Blocking UV-induced eIF2alpha phosphorylation with small molecule inhibitors of GCN2. Chem Biol Drug Des. 2009;74(1):57–67. doi:10.1111/j.1747-0285.2009.00827.x.
  • Rosen MD, Woods CR, Goldberg SD, Hack MD, Bounds AD, Yang Y, Wagaman PC, Phuong VK, Ameriks AP, Barrett TD, et al. Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase. Bioorg Med Chem Lett. 2009;19(23):6548–51. doi:10.1016/j.bmcl.2009.10.033.
  • Jammi NV, Whitby LR, Beal PA. Small molecule inhibitors of the RNA-dependent protein kinase. Biochem Biophys Res Commun. 2003;308(1):50–57. doi:10.1016/s0006-291x(03)01318-4.
  • Hu Y, Conway TW. 2-Aminopurine inhibits the double-stranded RNA-dependent protein kinase both in vitro and in vivo. J Interferon Res. 1993;13(5):323–28. doi:10.1089/jir.1993.13.323.
  • Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T, et al. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem. 2012;55(16):7193–207. doi:10.1021/jm300713s.
  • Axten JM, Romeril SP, Shu A, Ralph J, Medina JR, Feng Y, Li WH, Grant SW, Heerding DA, Minthorn E, et al. Discovery of GSK2656157: an optimized PERK inhibitor selected for preclinical development. ACS Med Chem Lett. 2013;4(10):964–68. doi:10.1021/ml400228e.
  • Jiang X, Wei Y, Zhang T, Zhang Z, Qiu S, Zhou X, Zhang S. Effects of GSK2606414 on cell proliferation and endoplasmic reticulum stressassociated gene expression in retinal pigment epithelial cells. Mol Med Rep. 2017;15(5):3105–10. doi:10.3892/mmr.2017.6418.
  • Kojima E, Takeuchi A, Haneda M, Yagi F, Hasegawa T, Yamaki K-I, Takeda K, Akira S, Shimokata K, Isobe K-I. The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress—elucidation by GADD34‐deficient mice. Faseb J. 2003;17(11):1–18. doi:10.1096/fj.02-1184fje.
  • Tsaytler P, Bertolotti A. Exploiting the selectivity of protein phosphatase 1 for pharmacological intervention. Febs J. 2013;280(2):766–70. doi:10.1111/j.1742-4658.2012.08535.x.
  • De Gassart A, Bujisic B, Zaffalon L, Decosterd LA, Di Micco A, Frera G, Tallant R, Martinon F. An inhibitor of HIV-1 protease modulates constitutive eIF2alpha dephosphorylation to trigger a specific integrated stress response. Proc Natl Acad Sci U S A. 2016;113(2):E117–126. doi:10.1073/pnas.1514076113.
  • Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, et al. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005;307(5711):935–39. doi:10.1126/science.1101902.
  • Bryant KF, Macari ER, Malik N, Boyce M, Yuan J, Coen DM. ICP34.5-dependent and -independent activities of salubrinal in herpes simplex virus-1 infected cells. Virology. 2008;379(2):197–204. doi:10.1016/j.virol.2008.06.028.
  • Wang Y, Osakue D, Yang E, Zhou Y, Gong H, Xia X, Du Y. Endoplasmic Reticulum Stress Response of Trabecular Meshwork Stem Cells and Trabecular Meshwork Cells and Protective Effects of Activated PERK Pathway. Invest Ophthalmol Vis Sci. 2019;60(1):265–73. doi:10.1167/iovs.18-25477.
  • Hirai S, Kurashima H, Nakamura D, Komatsu T, Yasuda Y, Habashita-Obata S, Ichikawa S, Katsuta O, Iwawaki T, Kohno K. 2-Phenyl-APB-144-induced retinal pigment epithelium degeneration and its underlying mechanisms. J Ocul Pharmacol Ther. 2015;31(9):570–84. doi:10.1089/jop.2014.0076.
  • Zhang L, Xia Q, Zhou Y, Li J. Endoplasmic reticulum stress and autophagy contribute to cadmium-induced cytotoxicity in retinal pigment epithelial cells. Toxicol Lett. 2019;311:105–13. doi:10.1016/j.toxlet.2019.05.001.
  • Imming P, Sinning C, Meyer A. Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006;5(10):821–34. doi:10.1038/nrd2132.
  • Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 2005;434(7032):514–20. doi:10.1038/nature03398.
  • Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM, et al. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell. 2004;117(3):387–98. doi:10.1016/s0092-8674(04)00344-7.
  • Cohen MS, Zhang C, Shokat KM, Taunton J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science. 2005;308(5726):1318–21. doi:10.1126/science1108367.
  • Sapkota GP, Cummings L, Newell FS, Armstrong C, Bain J, Frodin M, Grauert M, Hoffmann M, Schnapp G, Steegmaier M, et al. BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. Biochem J. 2007;401(1):29–38. doi:10.1042/bj20061088.
  • Smith JA, Poteet-Smith CE, Xu Y, Errington TM, Hecht SM, Lannigan DA. Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation. Cancer Res. 2005;65:1027–34.
  • Murray AJ. Pharmacological PKA inhibition: all may not be what it seems. Sci Signal. 2008;1(22):re4. doi:10.1126/scisignal.122re4.
  • Brudvik KW, Paulsen JE, Aandahl EM, Roald B, Tasken K. Protein kinase A antagonist inhibits beta-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice. Mol Cancer. 2011;10:149. doi:10.1186/1476-4598-10-149.
  • Fenton TR, Gout IT. Functions and regulation of the 70kDa ribosomal S6 kinases. Int J Biochem Cell Biol. 2011;43(1):47–59. doi:10.1016/j.biocel.2010.09.018.
  • Kotani T. Protein kinase A activity and Hedgehog signaling pathway. Vitam Horm. 2012;88:273–91. doi:10.1016/B978-0-12-394622-5.00012-2.
  • Wang Y, Alam GN, Ning Y, Visioli F, Dong Z, Nor JE, Polverini PJ. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. Cancer Res. 2012;72(20):5396–406. doi:10.1158/0008-5472.can-12-0474.
  • Gargalovic PS, Imura M, Zhang B, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Patel S, et al. Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids. Proc Natl Acad Sci U S A. 2006;103(34):12741–46. doi:10.1073/pnas.0605457103.
  • Fallah A, Sadeghinia A, Kahroba H, Samadi A, Heidari HR, Bradaran B, Zeinali S, Molavi O. Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases. Biomed Pharmacother. 2019;110:775–85. doi:10.1016/j.biopha.2018.12.022.
  • Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, et al. Molecular definitions of autophagy and related processes. Embo J. 2017;36(13):1811–36. doi:10.15252/embj.201796697.
  • Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest. 2010;120(1):127–41. doi:10.1172/jci40027.
  • Yang X, Pan X, Zhao X, Luo J, Xu M, Bai D, Hu Y, Liu X, Yu Q, Gao D. Autophagy and age-related eye diseases. Biomed Res Int. 2019;2019:1–12. doi:10.1155/2019/5763658.
  • Claessen JH, Kundrat L, Ploegh HL. Protein quality control in the ER: balancing the ubiquitin checkbook. Trends Cell Biol. 2012;22(1):22–32. doi:10.1016/j.tcb.2011.09.010.
  • Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr., Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107(12):4907–16. doi:10.1182/blood-2005-08-3531.
  • Chen F-T, Yang C-M, Yang C-H, Mohanraj R. The protective effects of the proteasome inhibitor bortezomib (velcade) on ischemia-reperfusion injury in the rat retina. PLoS ONE. 2013;8(5):e64262. doi:10.1371/journal.pone.0064262.
  • Hsu S-M, Yang C-H, Shen F-H, Chen S-H, Lin C-J, Shieh C-C. Proteasome inhibitor bortezomib suppresses nuclear factor-kappa B activation and ameliorates eye inflammation in experimental autoimmune uveitis. Mediators Inflamm. 2015;2015:1–10. doi:10.1155/2015/847373.
  • Wang W, Lian N, Li L, Moss HE, Wang W, Perrien DS, Elefteriou F, Yang X. Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription. Development. 2009;136(24):4143–53. doi:10.1242/dev.043281.
  • Hettmann T, Barton K, Leiden JM. Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial cells in mice lacking the CREB-2 transcription factor. Dev Biol. 2000;222(1):110–23. doi:10.1006/dbio.2000.9699.
  • Iida K, Li Y, McGrath BC, Frank A, Cavener DR. PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice. BMC Cell Biol. 2007;8:38. doi:10.1186/1471-2121-8-38.
  • Zhang P, McGrath BC, Reinert J, Olsen DS, Lei L, Gill S, Wek SA, Vattem KM, Wek RC, Kimball SR, et al. The GCN2 eIF2α kinase is required for adaptation to amino acid deprivation in mice. Mol Cell Bio. 2002;22(19):6681–88. doi:10.1128/mcb.22.19.6681-6688.2002.
  • Abraham N, Stojdl DF, Duncan PI, Méthot N, Ishii T, Dubé M, Vanderhyden BC, Atkins HL, Gray DA, McBurney MW, et al. Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR. J Biol Chem. 1999;274(9):5953–62. doi:10.1074/jbc.274.9.5953.
  • Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001;7(6):1153–63. doi:10.1016/s1097-2765(01)00264-7.
  • Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, Gannon M, Ma K, McNaughton K, Cavener DR. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol. 2002;22(11):3864–74. doi:10.1128/mcb.22.11.3864-3874.2002.
  • Wei J, Sheng X, Feng D, McGrath B, Cavener DR. PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. J Cell Physiol. 2008;217(3):693–707. doi:10.1002/jcp.21543.
  • Saito A, Ochiai K, Kondo S, Tsumagari K, Murakami T, Cavener DR, Imaizumi K. Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem. 2011;286(6):4809–18. doi:10.1074/jbc.M110.152900.
  • Gao Y, Sartori DJ, Li C, Yu QC, Kushner JA, Simon MC, Diehl JA. PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis. Mol Cell Biol. 2012;32(24):5129–39. doi:10.1128/mcb.01009-12.
  • Trinh MA, Kaphzan H, Wek RC, Pierre P, Cavener DR, Klann E. Brain-specific disruption of the eIF2alpha kinase PERK decreases ATF4 expression and impairs behavioral flexibility. Cell Rep. 2012;1(6):676–88. doi:10.1016/j.celrep.2012.04.010.
  • Harding HP, Zhang Y, Scheuner D, Chen -J-J, Kaufman RJ, Ron D. Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development. Proc Natl Acad Sci U S A. 2009;106(6):1832–37. doi:10.1073/pnas.0809632106.
  • Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S, Kaufman RJ. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell. 2001;7(6):1165–76. doi:10.1016/s1097-2765(01)00265-9.
  • Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JW, Tsukamoto K, Ribick M, Schuit FC, Kaufman RJ. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat Med. 2005;11(7):757–64. doi:10.1038/nm1259.
  • Back SH, Scheuner D, Han J, Song B, Ribick M, Wang J, Gildersleeve RD, Pennathur S, Kaufman RJ. Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metab. 2009;10(1):13–26. doi:10.1016/j.cmet.2009.06.002.
  • Chen CM, Wu CT, Chiang CK, Liao BW, Liu SH. C/EBP homologous protein (CHOP) deficiency aggravates hippocampal cell apoptosis and impairs memory performance. PLoS One. 2012;7(7):e40801. doi:10.1371/journal.pone.0040801.
  • Cornejo VH, Pihan P, Vidal RL, Hetz C. Role of the unfolded protein response in organ physiology: lessons from mouse models. IUBMB Life. 2013;65(12):962–75. doi:10.1002/iub.1224.
  • Valenzuela V, Collyer E, Armentano D, Parsons GB, Court FA, Hetz C. Activation of the unfolded protein response enhances motor recovery after spinal cord injury. Cell Death Dis. 2012;3:e272. doi:10.1038/cddis.2012.8.
  • Jousse C, Oyadomari S, Novoa I, Lu P, Zhang Y, Harding HP, Ron D. Inhibition of a constitutive translation initiation factor 2α phosphatase, CReP, promotes survival of stressed cells. J Cell Biol. 2003;163(4):767–75. doi:10.1083/jcb.200308075.
  • Dever TE. Gene-specific regulation by general translation factors. Cell. 2002;108(4):545–56. doi:10.1016/s0092-8674(02)00642-6.
  • Endo M, Oyadomari S, Suga M, Mori M, Gotoh T. The ER stress pathway involving CHOP is activated in the lungs of LPS-treated mice. J Biochem. 2005;138(4):501–07. doi:10.1093/jb/mvi143.
  • Tajiri S, Oyadomari S, Yano S, Morioka M, Gotoh T, Hamada JI, Ushio Y, Mori M. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ. 2004;11(4):403–15. doi:10.1038/sj.cdd.4401365.