XBP1S protects cells from ER stress-induced apoptosis through Erk1/2 signaling pathway involving CHOP
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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.
KeywordsEndoplasmic reticulum stress Apoptosis Unfolded protein response X-box binding protein 1 spliced CHOP
- 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 11:349–360PubMedCrossRefGoogle 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):1879–1892PubMedCrossRefGoogle 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 21Google 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):1197–1204PubMedCrossRefGoogle Scholar