Abstract
Exposure of cells to endoplasmic reticulum (ER) stress leads to activation of phosphatidylinositol 3-kinase (PI3K)–Akt signaling pathway and transcriptional induction of the inhibitor of apoptosis family of proteins. One of the proximal effectors of the ER stress response, the PKR-like ER kinase (PERK), leads to cellular adaptation to stress by multiple mechanisms, including attenuation of protein synthesis and transcriptional induction of pro-survival genes. Although PERK activity leads to cellular adaptation to ER stress, we now demonstrate that PERK activity also inhibits the ER stress-induced apoptotic program through the induction of cellular inhibitor of apoptosis (cIAP1 and cIAP2) proteins. This induction of IAPs occurs through both transcriptional and translational responses that are PERK dependent. Reintroduction of cIAP1 or cIAP2 expression into PERK-/- murine embryonic fibroblasts during ER stress delays the early onset of ER stress-induced caspase activation and apoptosis observed in these cells. Furthermore, we demonstrate that the activation of the PI3K–Akt pathway by ER stress is dependent on PERK, suggesting additional ways in which PERK activity protects cells from ER stress-induced apoptosis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bellacosa A, Testa JR, Moore R, Larue L . (2004). A portrait of AKT kinases: human cancer and animal models depict a family with strong individualities. Cancer Biol Ther 3: 268–275.
Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J et al. (2008). cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell 30: 689–700.
Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N et al. (2005). ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 24: 3470–3481.
Brewer JW, Diehl JA . (2000). PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci USA 97: 12625–12630.
Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ . (2001). Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276: 38349–38352.
Clem RJ, Sheu TT, Richter BW, He WW, Thornberry NA, Duckett CS et al. (2001). c-IAP1 is cleaved by caspases to produce a proapoptotic C-terminal fragment. J Biol Chem 276: 7602–7608.
Cox JS, Shamu CE, Walter P . (1993). Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73: 1197–1206.
Crook NE, Clem RJ, Miller LK . (1993). An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol 67: 2168–2174.
Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA . (2003). Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23: 7198–7209.
Dan HC, Sun M, Kaneko S, Feldman RI, Nicosia SV, Wang HG et al. (2004). Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem 279: 5405–5412.
Debatin KM, Krammer PH . (2004). Death receptors in chemotherapy and cancer. Oncogene 23: 2950–2966.
Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N et al. (2004). Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 24: 10161–10168.
Deniaud A, Sharaf el dein O, Maillier E, Poncet D, Kroemer G, Lemaire C et al. (2008). Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 27: 285–299.
Deveraux QL, Takahashi R, Salvesen GS, Reed JC . (1997). X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388: 300–304.
Di Sano F, Ferraro E, Tufi R, Achsel T, Piacentini M, Cecconi F . (2006). Endoplasmic reticulum stress induces apoptosis by an apoptosome-dependent but caspase 12-independent mechanism. J Biol Chem 281: 2693–2700.
Eckelman BP, Salvesen GS . (2006). The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases. J Biol Chem 281: 3254–3260.
Fels DR, Koumenis C . (2006). The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol Ther 5: 723–728.
Fernandez J, Bode B, Koromilas A, Diehl JA, Krukovets I, Snider MD et al (2002a). Translation mediated by the internal ribosome entry site of the cat-1 mRNA is regulated by glucose availability in a PERK kinase-dependent manner. J Biol Chem 277: 11780–11787.
Fernandez J, Yaman I, Sarnow P, Snider MD, Hatzoglou M . (2002b). Regulation of internal ribosomal entry site-mediated translation by phosphorylation of the translation initiation factor eIF2alpha. J Biol Chem 277: 19198–19205.
Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M et al. (2000a). Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6: 1099–1108.
Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D . (2000b). Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5: 897–904.
Harding HP, Zhang Y, Ron D . (1999). Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397: 271–274.
Haze K, Yoshida H, Yanagi H, Yura T, Mori K . (1999). Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10: 3787–3799.
Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y et al. (2004). Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165: 347–356.
Hosoi T, Hyoda K, Okuma Y, Nomura Y, Ozawa K . (2007). Akt up- and down-regulation in response to endoplasmic reticulum stress. Brain Res 1152: 27–31.
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.
Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH . (2006). Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26: 3071–3084.
Jamora C, Dennert G, Lee AS . (1996). Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci USA 93: 7690–7694.
Ji X, Kong J, Liebhaber SA . (2003). In vivo association of the stability control protein alphaCP with actively translating mRNAs. Mol Cell Biol 23: 899–907.
Jiang HY, Wek SA, McGrath BC, Scheuner D, Kaufman RJ, Cavener DR et al (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.
Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M . (2004). Induction of neuronal death by ER stress in Alzheimer's disease. J Chem Neuroanat 28: 67–78.
Kaufman RJ . (2004). Regulation of mRNA translation by protein folding in the endoplasmic reticulum. Trends Biochem Sci 29: 152–158.
Kazemi S, Mounir Z, Baltzis D, Raven JF, Wang S, Krishnamoorthy JL et al. (2007). A novel function of eIF2alpha kinases as inducers of the phosphoinositide-3 kinase signaling pathway. Mol Biol Cell 18: 3635–3644.
Li J, Lee B, Lee AS . (2006). Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J Biol Chem 281: 7260–7270.
Liston P, Fong WG, Korneluk RG . (2003). The inhibitors of apoptosis: there is more to life than Bcl2. Oncogene 22: 8568–8580.
Mathai JP, Germain M, Shore GC . (2005). BH3-only BIK regulates BAX,BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death. J Biol Chem 280: 23829–23836.
Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y . (2002). An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem 277: 34287–34294.
Morishima N, Nakanishi K, Tsuchiya K, Shibata T, Seiwa E . (2004). Translocation of Bim to the endoplasmic reticulum (ER) mediates ER stress signaling for activation of caspase-12 during ER stress-induced apoptosis. J Biol Chem 279: 50375–50381.
Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA et al. (2000). Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403: 98–103.
Orth K, Dixit VM . (1997). Bik and Bak induce apoptosis downstream of CrmA but upstream of inhibitor of apoptosis. J Biol Chem 272: 8841–8844.
Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J et al. (2007). Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12: 445–456.
Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND et al. (2007). ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129: 1337–1349.
Rao RV, Castro-Obregon S, Frankowski H, Schuler M, Stoka V, del Rio G et al. (2002). Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J Biol Chem 277: 21836–21842.
Reimertz C, Kogel D, Rami A, Chittenden T, Prehn JH . (2003). Gene expression during ER stress-induced apoptosis in neurons: induction of the BH3-only protein Bbc3/PUMA and activation of the mitochondrial apoptosis pathway. J Cell Biol 162: 587–597.
Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H et al. (2004). XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 64: 5943–5947.
Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC . (1997). The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J 16: 6914–6925.
Salvesen GS, Duckett CS . (2002). IAP proteins: blocking the road to death's door. Nat Rev Mol Cell Biol 3: 401–410.
Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P et al. (2001). Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell 7: 1165–1176.
Schroder M, Kaufman RJ . (2005). The mammalian unfolded protein response. Annu Rev Biochem 74: 739–789.
Scott FL, Denault JB, Riedl SJ, Shin H, Renatus M, Salvesen GS . (2005). XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs. EMBO J 24: 645–655.
Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L et al. (1998). Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18: 7499–7509.
Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM et al. (2003). Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell 11: 519–527.
Shiraishi H, Okamoto H, Yoshimura A, Yoshida H . (2006). ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci 119: 3958–3966.
Simons M, Beinroth S, Gleichmann M, Liston P, Korneluk RG, MacKenzie AE et al. (1999). Adenovirus-mediated gene transfer of inhibitors of apoptosis protein delays apoptosis in cerebellar granule neurons. J Neurochem 72: 292–301.
Tirasophon W, Welihinda AA, Kaufman RJ . (1998). A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12: 1812–1824.
Todaro GJ, Green H . (1963). Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J Cell Biol 17: 299–313.
Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P et al. (2007). IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 131: 669–681.
Vattem KM, Wek RC . (2004). Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci USA 101: 11269–11274.
Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU et al. (2007). IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131: 682–693.
Vucic D, Fairbrother WJ . (2007). The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res 13: 5995–6000.
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin Jr AS . (1998a). NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281: 1680–1683.
Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M, Ron D . (1998b). Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J 17: 5708–5717.
Warnakulasuriyarachchi D, Cerquozzi S, Cheung HH, Holcik M . (2004). Translational induction of the inhibitor of apoptosis protein HIAP2 during endoplasmic reticulum stress attenuates cell death and is mediated via an inducible internal ribosome entry site element. J Biol Chem 279: 17148–17157.
Acknowledgements
We thank M Romero for technical assistance and X Yang for providing IAP expression vectors. This study was supported by a grant from the National Institutes of Health F32CA1238252 (EBM); P01 CA104838, a Leukemia & Lymphoma Scholar award and the Abramson Family Cancer Research Institute (JAD).
Author information
Authors and Affiliations
Corresponding author
Additional information
Conflict of interest
The authors declare that they have no conflict of interst.
Rights and permissions
About this article
Cite this article
Hamanaka, R., Bobrovnikova-Marjon, E., Ji, X. et al. PERK-dependent regulation of IAP translation during ER stress. Oncogene 28, 910–920 (2009). https://doi.org/10.1038/onc.2008.428
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2008.428
Keywords
This article is cited by
-
Effect of anthocyanin-rich blackberry juice on endoplasmic reticulum stress in streptozotocin-induced diabetic rats
Environmental Science and Pollution Research (2023)
-
Aplysia Neurons as a Model of Alzheimer’s Disease: Shared Genes and Differential Expression
Journal of Molecular Neuroscience (2022)
-
Disulfide bond-disrupting agents activate the tumor necrosis family-related apoptosis-inducing ligand/death receptor 5 pathway
Cell Death Discovery (2019)
-
Smac mimetic suppresses tunicamycin-induced apoptosis via resolution of ER stress
Cell Death & Disease (2019)
-
Pituitary cell translation and secretory capacities are enhanced cell autonomously by the transcription factor Creb3l2
Nature Communications (2019)