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RETRACTED ARTICLE: XBP1S protects cells from ER stress-induced apoptosis through Erk1/2 signaling pathway involving CHOP

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This article was retracted on 01 July 2021

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Abstract

The mammalian unfolded protein response (UPR) protects the cell against the stress of misfolded proteins in the endoplasmic reticulum (ER), and the transcription factor X-box binding protein 1 spliced (XBP1S), a regulator of the UPR, is known to be important for ER stress (ERS)-mediated apoptosis and cell growth, but the molecular mechanism underlying these processes remains unexplored. Here, we report that knockdown of XBP1S by an siRNA silencing approach increased the expression of ERS-associated molecules. The overexpression of XBP1S stimulated, whereas its knockdown inhibited, cell proliferation in chondrocytes and chondrosarcoma cells; in addition, overexpression of XBP1S inhibited, while its repression enhanced, ERS-mediated apoptosis in chondrocytes and chondrosarcoma cells. Furthermore, XBP1S-mediated inhibition of apoptosis in response to ERS is through the Erk1/2 signaling pathway and down-regulation CHOP transcription factor. CHOP is one of the key downstream molecules known to be involved in ERS-mediated apoptosis. Collectively, these findings reveal a novel critical role of XBP1S in ERS-mediated apoptosis and the molecular mechanisms involved.

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References

  • Back SH, Lee K, Vink E, Kaufman RJ (2006) Cytoplasmic IRE1alpha-mediated XBP1 mRNA splicing in the absence of nuclear processing and endoplasmic reticulum stress. J Biol Chem 281(27):18691–18706

    Article  CAS  PubMed  Google Scholar 

  • Barone MV, Crozat A, Tabaee A, Philipson L, Ron D (1994) CHOP (GADD153) and its oncogenic variant, TLS-CHOP, have opposing effects on the induction of G1/S arrest. Genes Dev 8:453–464

    Article  CAS  PubMed  Google Scholar 

  • 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 XBP1 mRNA. Nature 415:92–96

    Article  CAS  PubMed  Google Scholar 

  • Carrasco DR, Sukhdeo K, Protopopova M, Sinha R, Enos M, Carrasco DE, Zheng M, Mani M, Henderson J, Pinkus GS, Munshi N, Horner J, Ivanova EV, Protopopov A, Anderson KC, Tonon G, DePinho RA (2007) The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 11:349–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Degterev A, Boyce M, Yuan J (2003) A decade of caspases. Oncogene 22(53):8543–8567

    Article  CAS  PubMed  Google Scholar 

  • Feng JQ, Guo F-J, Jiang B-C, Zhang Y, Frenkel S, Wang D-W, Tang W, Xie Y, Liu C-J (2010) Granulin epithelin precursor: a bone morphogenic protein 2- inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis. FASEB J 24(6):1879–1892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fulda S, Gorman AM, Hori O, Samali A (2010) Cellular stress responses: cell survival and cell death. Int J Cell Biol 2010:214074. Epub 2010 Feb 21

  • Gotoh T, Oyadomari S, Mori K, Mori M (2002) Nitric oxide-induced apoptosis in RAW 264. 7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP. J Biol Chem 277:12343–12350

    Article  CAS  PubMed  Google Scholar 

  • Guo F, Lin EA, Liu P, Lin J, Liu C (2010) XBP1U inhibits the XBP1S-mediated upregulation of the iNOS gene expression in mammalian ER stress response. Cell Signal 22:1818–1828

    Article  CAS  PubMed  Google Scholar 

  • Gupta S, Deepti A, Deegan S, Lisbona F, Hetz C, Samali A (2010) HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction. PLoS Biol 8(7):1–15

    Article  CAS  Google Scholar 

  • Hitomi J, Katayama T, Eguchi Y et al (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J Cell Biol 165(3):347–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(47):49420–49429

    Article  CAS  PubMed  Google Scholar 

  • Iwakoshi NN, Pypaert M, Glimcher LH (2007) The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J Exp Med 204(10):2267–2275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joo JH, Liao G, Collins JB, Grissom SF, Jetten AM (2007) Farnesol-induced apoptosis in human lung carcinoma cells is coupled to the endoplasmic reticulum stress response. Cancer Res 67:7929–7936

    Article  CAS  PubMed  Google Scholar 

  • Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13(10):1211–1233

    Article  CAS  PubMed  Google Scholar 

  • Kawahara K, Oyadomari S, Gotoh T, Kohsaka S, Nakayama H, Mori M (2001) Induction of CHOP and apoptosis by nitric oxide in p53-deficient microglial cells. FEBS Lett 506:135–139

    Article  CAS  PubMed  Google Scholar 

  • Kim R, Emi M, Tanabe K, Murakami S (2006) Role of the unfolded protein response in cell death. Apoptosis 11(1):5–13

    Article  CAS  PubMed  Google Scholar 

  • Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, Stroud RM, Walter P (2009) The unfolded protein response signals through high-order assembly of IRE1. Nature 457(7230):687–693

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin JH, Li H, Yasumura D et al (2007) IRE1 signaling affects cell fate during the unfolded protein response. Science 318(5852):944–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marciniak SJ, Ron D (2006) Endoplasmic reticulum stress signaling in disease. Physiol Rev 86(4):1133–1149

    Article  CAS  PubMed  Google Scholar 

  • McCullough KD, Martindale JL, Klotz L-O, Aw T-Y, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bc12 and perturbing the cellular redox state. Mol Cell Biol 21(4):1249–1259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y (2002) An ER stress-specific caspase cascade in apoptosis: cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem 277(37):34287–34294

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa T, Yuan J (2000) Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 150:804–887

    Article  Google Scholar 

  • Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403(6765):98–103

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi K, Sudo T, Morishima N (2005) Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development. J Cell Biol 169(4):555–560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oyadomari S, Takeda K, Takiguchi M, Gotoh T, Matsumoto M, Wada I, Akira S, Araki E, Mori M (2001) Nitric oxide-induced apoptosis in pancreatic betacells is mediated by the endoplasmic reticulum stress pathway. Proc Natl Acad Sci USA 98:10845–10850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puthalakath H, O’Reilly LA, Gunn P et al (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129(7):1337–1349

    Article  CAS  PubMed  Google Scholar 

  • Rajpar MH, McDermott B, Kung L, Eardley R, Knowles L, Heeran M, Thornton DJ, Wilson R, Bateman JF, Poulsom R, Arvan P, Kadler KE, Briggs MD, Boot-Handford RP (2009) Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genet 5(10):1–15

    Article  CAS  Google Scholar 

  • Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee A-H, Yoshida H, Mori K, Glimcher LH, Denko NC, Giaccia AJ, Le Q-Thu, Koong AC (2004) XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 64:5943–5947

    Article  CAS  PubMed  Google Scholar 

  • Ron D, Habener JF (1992) CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant- negative inhibitor of gene transcription. Genes Dev 6:439–453

    Article  CAS  PubMed  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum Unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  CAS  PubMed  Google Scholar 

  • Saito A, Hino S, Murakami T, Kanemoto S, Kondo S, Saitoh M, Nishimura R, Yoneda T, Furuichi T, Ikegawa S, Ikawa M, Okabe M, Imaizumi K (2009) Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis. Nat Cell Biol 11(10):1197–1204

    Article  CAS  PubMed  Google Scholar 

  • Samali A, Zhivotovsky B, Jones D, Nagata S, Orrenius S (1999) Apoptosis: cell death defined by caspase activation. Cell Death Differ 6(6):495–496

    Article  CAS  PubMed  Google Scholar 

  • Sha H, He Y, Chen H, Wang C, Zenno A, Shi H, Yang X, Zhang X, Qi L (2009) The IRE1alpha-XBP1 pathway of the unfolded protein response is required for adipogenesis. Cell Metab 9(6):556–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7(9):880–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tajiri S, Oyadomari S, Yano S, Morioka M, Gotoh T, Hamada J-I, Ushio Y, Mori M (2004) Disruption of the CHOP gene protects ischemia induced neuronal cell death in mice. Cell Death Differ 11:403–415

    Article  CAS  PubMed  Google Scholar 

  • Urano F, Wang X, Bertolotti A et al (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287(5453):664–666

    Article  CAS  PubMed  Google Scholar 

  • Xu K, Zhang Y, Ilalov K, Carlson CS, Feng JQ, Di Cesare PE, Liu C-j (2007) Cartilage oligomeric matrix protein associates with granulin-epithelin precursor (GEP) and potentiates GEP-stimulated chondrocyte proliferation. J Biol Chem 282(15):11347–11355

    Article  CAS  PubMed  Google Scholar 

  • Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891

    Article  CAS  PubMed  Google Scholar 

  • 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(4):565–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang K, Kaufman RJ (2004) Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem 279(25):25935–25938

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Science Foundation of China (No. 81171697 and No. 31040019); and the Natural Science Foundation Project of CQ CSTC (No. 2011jjA10047).

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Correspondence to Feng-Jin Guo.

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Guo, FJ., Liu, Y., Zhou, J. et al. RETRACTED ARTICLE: XBP1S protects cells from ER stress-induced apoptosis through Erk1/2 signaling pathway involving CHOP. Histochem Cell Biol 138, 447–460 (2012). https://doi.org/10.1007/s00418-012-0967-7

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  • DOI: https://doi.org/10.1007/s00418-012-0967-7

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