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Apoptosis

, Volume 14, Issue 8, pp 996–1007 | Cite as

Cellular responses to endoplasmic reticulum stress and apoptosis

  • Vanya I. Rasheva
  • Pedro M. DomingosEmail author
Apoptosis in Drosophila

Abstract

The endoplasmic reticulum (ER) is the cell organelle where secretory and membrane proteins are synthesized and folded. Correctly folded proteins exit the ER and are transported to the Golgi and other destinations within the cell, but proteins that fail to fold properly—misfolded proteins—are retained in the ER and their accumulation may constitute a form of stress to the cell—ER stress. Several signaling pathways, collectively known as unfolded protein response (UPR), have evolved to detect the accumulation of misfolded proteins in the ER and activate a cellular response that attempts to maintain homeostasis and a normal flux of proteins in the ER. In certain severe situations of ER stress, however, the protective mechanisms activated by the UPR are not sufficient to restore normal ER function and cells die by apoptosis. Most research on the UPR used yeast or mammalian model systems and only recently Drosophila has emerged as a system to study the molecular and cellular mechanisms of the UPR. Here, we review recent advances in Drosophila UPR research, in the broad context of mammalian and yeast literature.

Keywords

Unfolded protein response (UPR) Misfolded proteins Apoptosis Drosophila Ire1 Perk Atf6 

Notes

Acknowledgement

We thank Bertrand Mollereau for communicating results before publication.

References

  1. 1.
    Adesnik M, Lande M, Martin T, Sabatini DD (1976) Retention of mRNA on the endoplasmic reticulum membranes after in vivo disassembly of polysomes by an inhibitor of initiation. J Cell Biol 71:307–313. doi: 10.1083/jcb.71.1.307 PubMedCrossRefGoogle Scholar
  2. 2.
    Lande MA, Adesnik M, Sumida M, Tashiro Y, Sabatini DD (1975) Direct association of messenger RNA with microsomal membranes in human diploid fibroblasts. J Cell Biol 65:513–528. doi: 10.1083/jcb.65.3.513 PubMedCrossRefGoogle Scholar
  3. 3.
    Dobson CM (2004) Principles of protein folding, misfolding and aggregation. Semin Cell Dev Biol 15:3–16. doi: 10.1016/j.semcdb.2003.12.008 PubMedCrossRefGoogle Scholar
  4. 4.
    Karplus M, Weaver DL (1994) Protein folding dynamics: the diffusion-collision model and experimental data. Protein Sci 3:650–668PubMedCrossRefGoogle Scholar
  5. 5.
    Cheung MS, Garcia AE, Onuchic JN (2002) Protein folding mediated by solvation: water expulsion and formation of the hydrophobic core occur after the structural collapse. Proc Natl Acad Sci USA 99:685–690. doi: 10.1073/pnas.022387699 PubMedCrossRefGoogle Scholar
  6. 6.
    Saliba RS, Munro PM, Luthert PJ, Cheetham ME (2002) The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation. J Cell Sci 115:2907–2918PubMedGoogle Scholar
  7. 7.
    Koo EH, Lansbury PT Jr, Kelly JW (1999) Amyloid diseases: abnormal protein aggregation in neurodegeneration. Proc Natl Acad Sci USA 96:9989–9990. doi: 10.1073/pnas.96.18.9989 PubMedCrossRefGoogle Scholar
  8. 8.
    Petkova AT, Ishii Y, Balbach JJ et al (2002) A structural model for Alzheimer’s beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci USA 99:16742–16747. doi: 10.1073/pnas.262663499 PubMedCrossRefGoogle Scholar
  9. 9.
    Lomas DA, Evans DL, Finch JT, Carrell RW (1992) The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357:605–607. doi: 10.1038/357605a0 PubMedCrossRefGoogle Scholar
  10. 10.
    Celotto AM, Palladino MJ (2005) Drosophila: a “model” model system to study neurodegeneration. Mol Interv 5:292–303. doi: 10.1124/mi.5.5.9 PubMedCrossRefGoogle Scholar
  11. 11.
    Bilen J, Bonini NM (2005) Drosophila as a model for human neurodegenerative disease. Annu Rev Genet 39:153–171. doi: 10.1146/annurev.genet.39.110304.095804 PubMedCrossRefGoogle Scholar
  12. 12.
    Lu B, Vogel H (2008) Drosophila models of neurodegenerative diseases. Annu Rev Pathol 4:315–342. doi: 10.1146/annurev.pathol.3.121806.151529 CrossRefGoogle Scholar
  13. 13.
    Haas IG, Wabl M (1983) Immunoglobulin heavy chain binding protein. Nature 306:387–389. doi: 10.1038/306387a0 PubMedCrossRefGoogle Scholar
  14. 14.
    Munro S, Pelham HR (1986) An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell 46:291–300. doi: 10.1016/0092-8674(86)90746-4 PubMedCrossRefGoogle Scholar
  15. 15.
    Hendershot L, Wei J, Gaut J, Melnick J, Aviel S, Argon Y (1996) Inhibition of immunoglobulin folding and secretion by dominant negative BiP ATPase mutants. Proc Natl Acad Sci USA 93:5269–5274. doi: 10.1073/pnas.93.11.5269 PubMedCrossRefGoogle Scholar
  16. 16.
    Feldheim D, Rothblatt J, Schekman R (1992) Topology and functional domains of Sec63p, an endoplasmic reticulum membrane protein required for secretory protein translocation. Mol Cell Biol 12:3288–3296PubMedGoogle Scholar
  17. 17.
    Schlenstedt G, Harris S, Risse B, Lill R, Silver PA (1995) A yeast DnaJ homologue, Scj1p, can function in the endoplasmic reticulum with BiP/Kar2p via a conserved domain that specifies interactions with Hsp70s. J Cell Biol 129:979–988. doi: 10.1083/jcb.129.4.979 PubMedCrossRefGoogle Scholar
  18. 18.
    Chevalier M, Rhee H, Elguindi EC, Blond SY (2000) Interaction of murine BiP/GRP78 with the DnaJ homologue MTJ1. J Biol Chem 275:19620–19627. doi: 10.1074/jbc.M001333200 PubMedCrossRefGoogle Scholar
  19. 19.
    Cunnea PM, Miranda-Vizuete A, Bertoli G et al (2003) ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and thioredoxin domains, is expressed in secretory cells or following ER stress. J Biol Chem 278:1059–1066. doi: 10.1074/jbc.M206995200 PubMedCrossRefGoogle Scholar
  20. 20.
    Ellgaard L, Helenius A (2003) Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4:181–191. doi: 10.1038/nrm1052 PubMedCrossRefGoogle Scholar
  21. 21.
    Bourbon HM, Gonzy-Treboul G, Peronnet F et al (2002) A P-insertion screen identifying novel X-linked essential genes in Drosophila. Mech Dev 110:71–83. doi: 10.1016/S0925-4773(01)00566-4 PubMedCrossRefGoogle Scholar
  22. 22.
    Christodoulou S, Lockyer AE, Foster JM, Hoheisel JD, Roberts DB (1997) Nucleotide sequence of a Drosophila melanogaster cDNA encoding a calnexin homologue. Gene 191:143–148. doi: 10.1016/S0378-1119(97)00025-5 PubMedCrossRefGoogle Scholar
  23. 23.
    Hong CS, Ganetzky B (1996) Molecular characterization of neurally expressing genes in the para sodium channel gene cluster of drosophila. Genetics 142:879–892PubMedGoogle Scholar
  24. 24.
    Rosenbaum EE, Hardie RC, Colley NJ (2006) Calnexin is essential for rhodopsin maturation, Ca2+ regulation, and photoreceptor cell survival. Neuron 49:229–241. doi: 10.1016/j.neuron.2005.12.011 PubMedCrossRefGoogle Scholar
  25. 25.
    Price ER, Zydowsky LD, Jin MJ, Baker CH, McKeon FD, Walsh CT (1991) Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proc Natl Acad Sci USA 88:1903–1907. doi: 10.1073/pnas.88.5.1903 PubMedCrossRefGoogle Scholar
  26. 26.
    Bryant Z, Subrahmanyan L, Tworoger M et al (1999) Characterization of differentially expressed genes in purified Drosophila follicle cells: toward a general strategy for cell type-specific developmental analysis. Proc Natl Acad Sci USA 96:5559–5564. doi: 10.1073/pnas.96.10.5559 PubMedCrossRefGoogle Scholar
  27. 27.
    Freedman RB (1989) Protein disulfide isomerase: multiple roles in the modification of nascent secretory proteins. Cell 57:1069–1072. doi: 10.1016/0092-8674(89)90043-3 PubMedCrossRefGoogle Scholar
  28. 28.
    Anelli T, Alessio M, Bachi A et al (2003) Thiol-mediated protein retention in the endoplasmic reticulum: the role of ERp44. EMBO J 22:5015–5022. doi: 10.1093/emboj/cdg491 PubMedCrossRefGoogle Scholar
  29. 29.
    Tien AC, Rajan A, Schulze KL et al (2008) Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster. J Cell Biol 182:1113–1125. doi: 10.1083/jcb.200805001 PubMedCrossRefGoogle Scholar
  30. 30.
    Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789. doi: 10.1146/annurev.biochem.73.011303.074134 PubMedCrossRefGoogle Scholar
  31. 31.
    Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529. doi: 10.1038/nrm2199 PubMedCrossRefGoogle Scholar
  32. 32.
    Bonifacino JS, Weissman AM (1998) Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annu Rev Cell Dev Biol 14:19–57. doi: 10.1146/annurev.cellbio.14.1.19 PubMedCrossRefGoogle Scholar
  33. 33.
    Tsai B, Ye Y, Rapoport TA (2002) Retro-translocation of proteins from the endoplasmic reticulum into the cytosol. Nat Rev Mol Cell Biol 3:246–255. doi: 10.1038/nrm780 PubMedCrossRefGoogle Scholar
  34. 34.
    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. doi: 10.1016/0092-8674(93)90648-A PubMedCrossRefGoogle Scholar
  35. 35.
    Mori K, Ma W, Gething MJ, Sambrook J (1993) A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus. Cell 74:743–756. doi: 10.1016/0092-8674(93)90521-Q PubMedCrossRefGoogle Scholar
  36. 36.
    Koizumi N, Martinez IM, Kimata Y, Kohno K, Sano H, Chrispeels MJ (2001) Molecular characterization of two Arabidopsis Ire1 homologs, endoplasmic reticulum-located transmembrane protein kinases. Plant Physiol 127:949–962. doi: 10.1104/pp.010636 PubMedCrossRefGoogle Scholar
  37. 37.
    Sidrauski C, Walter P (1997) The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90:1031–1039. doi: 10.1016/S0092-8674(00)80369-4 PubMedCrossRefGoogle Scholar
  38. 38.
    Liu CY, Schroder M, Kaufman RJ (2000) Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum. J Biol Chem 275:24881–24885. doi: 10.1074/jbc.M004454200 PubMedCrossRefGoogle Scholar
  39. 39.
    Plongthongkum N, Kullawong N, Panyim S, Tirasophon W (2007) Ire1 regulated XBP1 mRNA splicing is essential for the unfolded protein response (UPR) in Drosophila melanogaster. Biochem Biophys Res Commun 354:789–794. doi: 10.1016/j.bbrc.2007.01.056 PubMedCrossRefGoogle Scholar
  40. 40.
    Hollien J, Weissman JS (2006) Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313:104–107. doi: 10.1126/science.1129631 PubMedCrossRefGoogle Scholar
  41. 41.
    Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M, Ron D (1998) Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J 17:5708–5717. doi: 10.1093/emboj/17.19.5708 PubMedCrossRefGoogle Scholar
  42. 42.
    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. doi: 10.1101/gad.12.12.1812 PubMedCrossRefGoogle Scholar
  43. 43.
    Bertolotti A, Wang X, Novoa I et al (2001) Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest 107:585–593. doi: 10.1172/JCI11476 PubMedCrossRefGoogle Scholar
  44. 44.
    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. doi: 10.1038/35014014 PubMedCrossRefGoogle Scholar
  45. 45.
    Okamura K, Kimata Y, Higashio H, Tsuru A, Kohno K (2000) Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers the unfolded protein response in yeast. Biochem Biophys Res Commun 279:445–450. doi: 10.1006/bbrc.2000.3987 PubMedCrossRefGoogle Scholar
  46. 46.
    Kimata Y, Oikawa D, Shimizu Y, Ishiwata-Kimata Y, Kohno K (2004) A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1. J Cell Biol 167:445–456. doi: 10.1083/jcb.200405153 PubMedCrossRefGoogle Scholar
  47. 47.
    Oikawa D, Kimata Y, Kohno K (2007) Self-association and BiP dissociation are not sufficient for activation of the ER stress sensor Ire1. J Cell Sci 120:1681–1688. doi: 10.1242/jcs.002808 PubMedCrossRefGoogle Scholar
  48. 48.
    Credle JJ, Finer-Moore JS, Papa FR, Stroud RM, Walter P (2005) On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc Natl Acad Sci USA 102:18773–18784. doi: 10.1073/pnas.0509487102 PubMedCrossRefGoogle Scholar
  49. 49.
    Shamu CE, Walter P (1996) Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J 15:3028–3039PubMedGoogle Scholar
  50. 50.
    Welihinda AA, Kaufman RJ (1996) The unfolded protein response pathway in Saccharomyces cerevisiae. Oligomerization and trans-phosphorylation of Ire1p (Ern1p) are required for kinase activation. J Biol Chem 271:18181–18187. doi: 10.1074/jbc.271.30.18181 PubMedCrossRefGoogle Scholar
  51. 51.
    Liu CY, Wong HN, Schauerte JA, Kaufman RJ (2002) The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domain. J Biol Chem 277:18346–18356. doi: 10.1074/jbc.M112454200 PubMedCrossRefGoogle Scholar
  52. 52.
    Papa FR, Zhang C, Shokat K, Walter P (2003) Bypassing a kinase activity with an ATP-competitive drug. Science 302:1533–1537. doi: 10.1126/science.1090031 PubMedCrossRefGoogle Scholar
  53. 53.
    Cox JS, Walter P (1996) A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell 87:391–404. doi: 10.1016/S0092-8674(00)81360-4 PubMedCrossRefGoogle Scholar
  54. 54.
    Mori K, Kawahara T, Yoshida H, Yanagi H, Yura T (1996) Signalling from endoplasmic reticulum to nucleus: transcription factor with a basic-leucine zipper motif is required for the unfolded protein-response pathway. Genes Cells 1:803–817. doi: 10.1046/j.1365-2443.1996.d01-274.x PubMedCrossRefGoogle Scholar
  55. 55.
    Nikawa J, Akiyoshi M, Hirata S, Fukuda T (1996) Saccharomyces cerevisiae IRE2/HAC1 is involved in IRE1-mediated KAR2 expression. Nucleic Acids Res 24:4222–4226. doi: 10.1093/nar/24.21.4222 PubMedCrossRefGoogle Scholar
  56. 56.
    Shen X, Ellis RE, Lee K, Liu CY, Yang K, Solomon A, Yoshida H, Morimoto R, Kurnit DM, Mori K, Kaufman RJ (2001) Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 107:893–903. doi: 10.1016/S0092-8674(01)00612-2 PubMedCrossRefGoogle Scholar
  57. 57.
    Yoshida H, Okada T, Haze K et al (2001) Endoplasmic reticulum stress-induced formation of transcription factor complex ERSF including NF-Y (CBF) and activating transcription factors 6alpha and 6beta that activates the mammalian unfolded protein response. Mol Cell Biol 21:1239–1248. doi: 10.1128/MCB.21.4.1239-1248.2001 PubMedCrossRefGoogle Scholar
  58. 58.
    Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415:92–96. doi: 10.1038/415092a PubMedCrossRefGoogle Scholar
  59. 59.
    Sidrauski C, Cox JS, Walter P (1996) tRNA ligase is required for regulated mRNA splicing in the unfolded protein response. Cell 87:405–413. doi: 10.1016/S0092-8674(00)81361-6 PubMedCrossRefGoogle Scholar
  60. 60.
    Chapman RE, Walter P (1997) Translational attenuation mediated by an mRNA intron. Curr Biol 7:850–859. doi: 10.1016/S0960-9822(06)00373-3 PubMedCrossRefGoogle Scholar
  61. 61.
    Ruegsegger U, Leber JH, Walter P (2001) Block of HAC1 mRNA translation by long-range base pairing is released by cytoplasmic splicing upon induction of the unfolded protein response. Cell 107:103–114. doi: 10.1016/S0092-8674(01)00505-0 PubMedCrossRefGoogle Scholar
  62. 62.
    Yoshida H, Oku M, Suzuki M, Mori K (2006) pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. J Cell Biol 172:565–575. doi: 10.1083/jcb.200508145 PubMedCrossRefGoogle Scholar
  63. 63.
    Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P (2000) Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101:249–258. doi: 10.1016/S0092-8674(00)80835-1 PubMedCrossRefGoogle Scholar
  64. 64.
    Friedlander R, Jarosch E, Urban J, Volkwein C, Sommer T (2000) A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat Cell Biol 2:379–384. doi: 10.1038/35017001 PubMedCrossRefGoogle Scholar
  65. 65.
    Yoshida H, Matsui T, Hosokawa N, Kaufman RJ, Nagata K, Mori K (2003) A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell 4:265–271. doi: 10.1016/S1534-5807(03)00022-4 PubMedCrossRefGoogle Scholar
  66. 66.
    Lee AH, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23:7448–7459. doi: 10.1128/MCB.23.21.7448-7459.2003 PubMedCrossRefGoogle Scholar
  67. 67.
    Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K, Mori K (2006) Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol 172:383–393. doi: 10.1083/jcb.200507057 PubMedCrossRefGoogle Scholar
  68. 68.
    Sriburi R, Jackowski S, Mori K, Brewer JW (2004) XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol 167:35–41. doi: 10.1083/jcb.200406136 PubMedCrossRefGoogle Scholar
  69. 69.
    Acosta-Alvear D, Zhou Y, Blais A et al (2007) XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell 27:53–66. doi: 10.1016/j.molcel.2007.06.011 PubMedCrossRefGoogle Scholar
  70. 70.
    Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F, Glimcher LH (2001) Plasma cell differentiation requires the transcription factor XBP-1. Nature 412:300–307. doi: 10.1038/35085509 PubMedCrossRefGoogle Scholar
  71. 71.
    Reimold AM, Etkin A, Clauss I et al (2000) An essential role in liver development for transcription factor XBP-1. Genes Dev 14:152–157PubMedGoogle Scholar
  72. 72.
    Niwa M, Patil CK, DeRisi J, Walter P (2005) Genome-scale approaches for discovering novel nonconventional splicing substrates of the Ire1 nuclease. Genome Biol 6:R3. doi: 10.1186/gb-2004-6-1-r3 PubMedCrossRefGoogle Scholar
  73. 73.
    Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinase by transmembrane protein kinase IRE1. Science 287:664–666. doi: 10.1126/science.287.5453.664 PubMedCrossRefGoogle Scholar
  74. 74.
    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 10:3787–3799PubMedGoogle Scholar
  75. 75.
    Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ, Prywes R (2000) Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem 275:27013–27020PubMedGoogle Scholar
  76. 76.
    Yoshida H, Okada T, Haze K et al (2000) ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol 20:6755–6767. doi: 10.1128/MCB.20.18.6755-6767.2000 PubMedCrossRefGoogle Scholar
  77. 77.
    Shen J, Snapp EL, Lippincott-Schwartz J, Prywes R (2005) Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response. Mol Cell Biol 25:921–932. doi: 10.1128/MCB.25.3.921-932.2005 PubMedCrossRefGoogle Scholar
  78. 78.
    Ye J, Rawson RB, Komuro R et al (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6:1355–1364. doi: 10.1016/S1097-2765(00)00133-7 PubMedCrossRefGoogle Scholar
  79. 79.
    Shen J, Chen X, Hendershot L, Prywes R (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3:99–111. doi: 10.1016/S1534-5807(02)00203-4 PubMedCrossRefGoogle Scholar
  80. 80.
    Hong M, Luo S, Baumeister P et al (2004) Underglycosylation of ATF6 as a novel sensing mechanism for activation of the unfolded protein response. J Biol Chem 279:11354–11363. doi: 10.1074/jbc.M309804200 PubMedCrossRefGoogle Scholar
  81. 81.
    Yoshida H, Haze K, Yanagi H, Yura T, Mori K (1998) Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem 273:33741–33749. doi: 10.1074/jbc.273.50.33741 PubMedCrossRefGoogle Scholar
  82. 82.
    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. doi: 10.1074/jbc.M212074200 PubMedCrossRefGoogle Scholar
  83. 83.
    Kokame K, Kato H, Miyata T (2001) Identification of ERSE-II, a new cis-acting element responsible for the ATF6-dependent mammalian unfolded protein response. J Biol Chem 276:9199–9205. doi: 10.1074/jbc.M010486200 PubMedCrossRefGoogle Scholar
  84. 84.
    Shi Y, Vattem KM, Sood R et al (1998) Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18:7499–7509PubMedGoogle Scholar
  85. 85.
    Shi Y, An J, Liang J et al (1999) Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin in islet delta cells. J Biol Chem 274:5723–5730. doi: 10.1074/jbc.274.9.5723 PubMedCrossRefGoogle Scholar
  86. 86.
    Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274. doi: 10.1038/16729 PubMedCrossRefGoogle Scholar
  87. 87.
    Marciniak SJ, Garcia-Bonilla L, Hu J, Harding HP, Ron D (2006) Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK. J Cell Biol 172:201–209. doi: 10.1083/jcb.200508099 PubMedCrossRefGoogle Scholar
  88. 88.
    Harding HP, Novoa I, Zhang Y et al (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108. doi: 10.1016/S1097-2765(00)00108-8 PubMedCrossRefGoogle Scholar
  89. 89.
    Lu PD, Harding HP, Ron D (2004) Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol 167:27–33. doi: 10.1083/jcb.200408003 PubMedCrossRefGoogle Scholar
  90. 90.
    Vattem KM, Wek RC (2004) Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci USA 101:11269–11274. doi: 10.1073/pnas.0400541101 PubMedCrossRefGoogle Scholar
  91. 91.
    Harding HP, Zhang Y, Zeng H et al (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633. doi: 10.1016/S1097-2765(03)00105-9 PubMedCrossRefGoogle Scholar
  92. 92.
    Jiang HY, Wek SA, McGrath BC et al (2004) Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 24:1365–1377. doi: 10.1128/MCB.24.3.1365-1377.2004 PubMedCrossRefGoogle Scholar
  93. 93.
    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. doi: 10.1016/S0022-2836(02)00234-6 PubMedCrossRefGoogle Scholar
  94. 94.
    Pomar N, Berlanga JJ, Campuzano S, Hernandez G, Elias M, de Haro C (2003) Functional characterization of Drosophila melanogaster PERK eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Eur J Biochem 270:293–306. doi: 10.1046/j.1432-1033.2003.03383.x PubMedCrossRefGoogle Scholar
  95. 95.
    Yan W, Frank CL, Korth MJ et al (2002) Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc Natl Acad Sci USA 99:15920–15925. doi: 10.1073/pnas.252341799 PubMedCrossRefGoogle Scholar
  96. 96.
    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. doi: 10.1128/MCB.23.4.1292-1303.2003 PubMedCrossRefGoogle Scholar
  97. 97.
    Ma Y, Hendershot LM (2003) Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J Biol Chem 278:34864–34873. doi: 10.1074/jbc.M301107200 PubMedCrossRefGoogle Scholar
  98. 98.
    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. doi: 10.1093/emboj/cdg112 PubMedCrossRefGoogle Scholar
  99. 99.
    Meusser B, Hirsch C, Jarosch E, Sommer T (2005) ERAD: the long road to destruction. Nat Cell Biol 7:766–772. doi: 10.1038/ncb0805-766 PubMedCrossRefGoogle Scholar
  100. 100.
    Ruddock LW, Molinari M (2006) N-glycan processing in ER quality control. J Cell Sci 119:4373–4380. doi: 10.1242/jcs.03225 PubMedCrossRefGoogle Scholar
  101. 101.
    Hosokawa N, Wada I, Hasegawa K et al (2001) A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation. EMBO Rep 2:415–422PubMedGoogle Scholar
  102. 102.
    Molinari M, Calanca V, Galli C, Lucca P, Paganetti P (2003) Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science 299:1397–1400. doi: 10.1126/science.1079474 PubMedCrossRefGoogle Scholar
  103. 103.
    Oda Y, Hosokawa N, Wada I, Nagata K (2003) EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science 299:1394–1397. doi: 10.1126/science.1079181 PubMedCrossRefGoogle Scholar
  104. 104.
    Szathmary R, Bielmann R, Nita-Lazar M, Burda P, Jakob CA (2005) Yos9 protein is essential for degradation of misfolded glycoproteins and may function as lectin in ERAD. Mol Cell 19:765–775. doi: 10.1016/j.molcel.2005.08.015 PubMedCrossRefGoogle Scholar
  105. 105.
    Plemper RK, Bohmler S, Bordallo J, Sommer T, Wolf DH (1997) Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature 388:891–895. doi: 10.1038/42276 PubMedCrossRefGoogle Scholar
  106. 106.
    Pilon M, Schekman R, Romisch K (1997) Sec61p mediates export of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation. EMBO J 16:4540–4548. doi: 10.1093/emboj/16.15.4540 PubMedCrossRefGoogle Scholar
  107. 107.
    Zhou M, Schekman R (1999) The engagement of Sec61p in the ER dislocation process. Mol Cell 4:925–934. doi: 10.1016/S1097-2765(00)80222-1 PubMedCrossRefGoogle Scholar
  108. 108.
    Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429:841–847. doi: 10.1038/nature02656 PubMedCrossRefGoogle Scholar
  109. 109.
    Lilley BN, Ploegh HL (2004) A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429:834–840. doi: 10.1038/nature02592 PubMedCrossRefGoogle Scholar
  110. 110.
    Carvalho P, Goder V, Rapoport TA (2006) Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126:361–373. doi: 10.1016/j.cell.2006.05.043 PubMedCrossRefGoogle Scholar
  111. 111.
    Denic V, Quan EM, Weissman JS (2006) A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126:349–359. doi: 10.1016/j.cell.2006.05.045 PubMedCrossRefGoogle Scholar
  112. 112.
    Gauss R, Jarosch E, Sommer T, Hirsch C (2006) A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nat Cell Biol 8:849–854. doi: 10.1038/ncb1445 PubMedCrossRefGoogle Scholar
  113. 113.
    Elsasser S, Finley D (2005) Delivery of ubiquitinated substrates to protein-unfolding machines. Nat Cell Biol 7:742–749. doi: 10.1038/ncb0805-742 PubMedCrossRefGoogle Scholar
  114. 114.
    Nakagawa T, Yuan J (2000) Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 150:887–894. doi: 10.1083/jcb.150.4.887 PubMedCrossRefGoogle Scholar
  115. 115.
    Nakagawa T, Zhu H, Morishima N et al (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403:98–103. doi: 10.1038/47513 PubMedCrossRefGoogle Scholar
  116. 116.
    Tan Y, Dourdin N, Wu C, De Veyra T, Elce JS, Greer PA (2006) Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis. J Biol Chem 281:16016–16024. doi: 10.1074/jbc.M601299200 PubMedCrossRefGoogle Scholar
  117. 117.
    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. doi: 10.1074/jbc.M204973200 PubMedCrossRefGoogle Scholar
  118. 118.
    Rao RV, Castro-Obregon S, Frankowski H et al (2002) Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J Biol Chem 277:21836–21842. doi: 10.1074/jbc.M202726200 PubMedCrossRefGoogle Scholar
  119. 119.
    Fischer H, Koenig U, Eckhart L, Tschachler E (2002) Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun 293:722–726. doi: 10.1016/S0006-291X(02)00289-9 PubMedCrossRefGoogle Scholar
  120. 120.
    Hitomi J, Katayama T, Eguchi 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. doi: 10.1083/jcb.200310015 PubMedCrossRefGoogle Scholar
  121. 121.
    Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ (1999) Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J 339(Pt 1):135–141. doi: 10.1042/0264-6021:3390135 PubMedCrossRefGoogle Scholar
  122. 122.
    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. doi: 10.1371/journal.pone.0004170 PubMedCrossRefGoogle Scholar
  123. 123.
    Zinszner H, Kuroda M, Wang X et al (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995. doi: 10.1101/gad.12.7.982 PubMedCrossRefGoogle Scholar
  124. 124.
    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. doi: 10.1128/MCB.21.4.1249-1259.2001 PubMedCrossRefGoogle Scholar
  125. 125.
    Puthalakath H, O’Reilly LA, Gunn P et al (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337–1349. doi: 10.1016/j.cell.2007.04.027 PubMedCrossRefGoogle Scholar
  126. 126.
    Haynes CM, Titus EA, Cooper AA (2004) Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell 15:767–776. doi: 10.1016/j.molcel.2004.08.025 PubMedCrossRefGoogle Scholar
  127. 127.
    Marciniak SJ, Yun CY, Oyadomari S et al (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18:3066–3077. doi: 10.1101/gad.1250704 PubMedCrossRefGoogle Scholar
  128. 128.
    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. doi: 10.1128/MCB.23.20.7198-7209.2003 PubMedCrossRefGoogle Scholar
  129. 129.
    Venugopal R, Jaiswal AK (1998) Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17:3145–3156. doi: 10.1038/sj.onc.1202237 PubMedCrossRefGoogle Scholar
  130. 130.
    He CH, Gong P, Hu B et al (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. doi: 10.1074/jbc.M101198200 PubMedCrossRefGoogle Scholar
  131. 131.
    Nguyen T, Sherratt PJ, Nioi P, Yang CS, Pickett CB (2005) Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem 280:32485–32492. doi: 10.1074/jbc.M503074200 PubMedCrossRefGoogle Scholar
  132. 132.
    Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K (2002) Takeda. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16:1345–1355. doi: 10.1101/gad.992302 PubMedCrossRefGoogle Scholar
  133. 133.
    Lin JH, Li H, Yasumura D et al (2007) IRE1 signaling affects cell fate during the unfolded protein response. Science 318:944–949. doi: 10.1126/science.1146361 PubMedCrossRefGoogle Scholar
  134. 134.
    Ryoo HD, Domingos PM, Kang MJ, Steller H (2007) Unfolded protein response in a Drosophila model for retinal degeneration. EMBO J 26:242–252. doi: 10.1038/sj.emboj.7601477 PubMedCrossRefGoogle Scholar
  135. 135.
    Colley NJ, Cassill JA, Baker EK, Zuker CS (1995) Defective intracellular transport is the molecular basis of rhodopsin-dependent dominant retinal degeneration. Proc Natl Acad Sci USA 92:3070–3074. doi: 10.1073/pnas.92.7.3070 PubMedCrossRefGoogle Scholar
  136. 136.
    Davidson FF, Steller H (1998) Blocking apoptosis prevents blindness in Drosophila retinal degeneration mutants. Nature 391:587–591. doi: 10.1038/35385 PubMedCrossRefGoogle Scholar
  137. 137.
    Mendes CS, Levet C, Chatelain G, et al. (2009) ER stress protects from retinal degeneration. EMBO J (in press)Google Scholar
  138. 138.
    Pizzo P, Pozzan T (2007) Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol 17:511–517. doi: 10.1016/j.tcb.2007.07.011 PubMedCrossRefGoogle Scholar
  139. 139.
    Wei MC, Zong WX, Cheng EH et al (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730. doi: 10.1126/science.1059108 PubMedCrossRefGoogle Scholar
  140. 140.
    Scorrano L, Oakes SA, Opferman JT et al (2003) BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300:135–139. doi: 10.1126/science.1081208 PubMedCrossRefGoogle Scholar
  141. 141.
    Zong WX, Li C, Hatzivassiliou G et al (2003) Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 162:59–69. doi: 10.1083/jcb.200302084 PubMedCrossRefGoogle Scholar
  142. 142.
    Hetz C, Bernasconi P, Fisher J et al (2006) Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312:572–576. doi: 10.1126/science.1123480 PubMedCrossRefGoogle Scholar
  143. 143.
    Chae HJ, Kim HR, Xu C et al (2004) BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol Cell 15:355–366. doi: 10.1016/j.molcel.2004.06.038 PubMedCrossRefGoogle Scholar
  144. 144.
    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. doi: 10.1074/jbc.M500800200 PubMedCrossRefGoogle Scholar
  145. 145.
    Sevrioukov EA, Burr J, Huang EW et al (2007) Drosophila Bcl-2 proteins participate in stress-induced apoptosis, but are not required for normal development. Genesis 45:184–193. doi: 10.1002/dvg.20279 PubMedCrossRefGoogle Scholar
  146. 146.
    Galindo KA, Lu WJ, Park JH, Abrams JM (2009) The Bax/Bak ortholog in Drosophila, Debcl, exerts limited control over programmed cell death. Development 136:275–283. doi: 10.1242/dev.019042 PubMedCrossRefGoogle Scholar
  147. 147.
    Doumanis J, Dorstyn L, Kumar S (2007) Molecular determinants of the subcellular localization of the Drosophila Bcl-2 homologues DEBCL and BUFFY. Cell Death Differ 14:907–915PubMedGoogle Scholar
  148. 148.
    Chami M, Oules B, Szabadkai G, Tacine R, Rizzuto R, Paterlini-Brechot P (2008) Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. Mol Cell 32:641–651. doi: 10.1016/j.molcel.2008.11.014 PubMedCrossRefGoogle Scholar
  149. 149.
    Rutkowski DT, Arnold SM, Miller CN et al (2006) Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol 4:e374. doi: 10.1371/journal.pbio.0040374 PubMedCrossRefGoogle Scholar
  150. 150.
    Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555. doi: 10.1126/science.292.5521.1552 PubMedCrossRefGoogle Scholar
  151. 151.
    Cooper AA, Gitler AD, Cashikar A et al (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313:324–328. doi: 10.1126/science.1129462 PubMedCrossRefGoogle Scholar
  152. 152.
    Humphries P, Kenna P, Farrar GJ (1992) On the molecular genetics of retinitis pigmentosa. Science 256:804–808. doi: 10.1126/science.1589761 PubMedCrossRefGoogle Scholar
  153. 153.
    Colley NJ, Cassill JA, Baker EK, Zuker CS (1995) Defective intracellular transport is the molecular basis of rhodopsin-dependent dominant retinal degeneration. Proc Natl Acad Sci USA 92:3070–3074. doi: 10.1073/pnas.92.7.3070 PubMedCrossRefGoogle Scholar
  154. 154.
    Kurada P, O’Tousa JE (1995) Retinal degeneration caused by dominant rhodopsin mutations in Drosophila. Neuron 14:571–579. doi: 10.1016/0896-6273(95)90313-5 PubMedCrossRefGoogle Scholar
  155. 155.
    Galy A, Roux MJ, Sahel JA, Leveillard T, Giangrande A (2005) Rhodopsin maturation defects induce photoreceptor death by apoptosis: a fly model for RhodopsinPro23His human retinitis pigmentosa. Hum Mol Genet 14:2547–2557. doi: 10.1093/hmg/ddi258 PubMedCrossRefGoogle Scholar
  156. 156.
    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. doi: 10.1038/78085 PubMedCrossRefGoogle Scholar
  157. 157.
    Harding HP, Zeng H, Zhang Y et al (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. doi: 10.1016/S1097-2765(01)00264-7 PubMedCrossRefGoogle Scholar
  158. 158.
    Fonseca SG, Fukuma M, Lipson KL et al (2005) WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem 280:39609–39615. doi: 10.1074/jbc.M507426200 PubMedCrossRefGoogle Scholar
  159. 159.
    Yamada T, Ishihara H, Tamura A et al (2006) WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet 15:1600–1609. doi: 10.1093/hmg/ddl081 PubMedCrossRefGoogle Scholar
  160. 160.
    Lee AH, Chu GC, Iwakoshi NN, Glimcher LH (2005) XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J 24:4368–4380. doi: 10.1038/sj.emboj.7600903 PubMedCrossRefGoogle Scholar
  161. 161.
    Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4:966–977. doi: 10.1038/nrc1505 PubMedCrossRefGoogle Scholar
  162. 162.
    Koumenis C, Naczki C, Koritzinsky M et al (2002) Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol 22:7405–7416. doi: 10.1128/MCB.22.21.7405-7416.2002 PubMedCrossRefGoogle Scholar
  163. 163.
    Koritzinsky M, Magagnin MG, van den Beucken T et al (2006) Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J 25:1114–1125. doi: 10.1038/sj.emboj.7600998 PubMedCrossRefGoogle Scholar
  164. 164.
    Blais JD, Filipenko V, Bi M et al (2004) Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol 24:7469–7482. doi: 10.1128/MCB.24.17.7469-7482.2004 PubMedCrossRefGoogle Scholar
  165. 165.
    Feldman DE, Chauhan V, Koong AC (2005) The unfolded protein response: a novel component of the hypoxic stress response in tumors. Mol Cancer Res 3:597–605. doi: 10.1158/1541-7786.MCR-05-0221 PubMedCrossRefGoogle Scholar
  166. 166.
    Romero-Ramirez L, Cao H, Nelson D et al (2004) XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 64:5943–5947. doi: 10.1158/0008-5472.CAN-04-1606 PubMedCrossRefGoogle Scholar
  167. 167.
    Carrasco DR, Sukhdeo K, Protopopova M et al (2007) The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 11:349–360. doi: 10.1016/j.ccr.2007.02.015 PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Instituto de Tecnologia Química e Biológica (ITQB)OeirasPortugal

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