title: Attenuation of unfolded protein response and apoptosis by mReg2 induced GRP78 in mouse insulinoma cells.
abstract: Murine regenerating (mReg) genes have been implicated in preserving islet cell biology. Expanding on our previous work showing that overexpression of mReg2 protects MIN6 insulinoma cells against streptozotocin-induced apoptosis, we now demonstrate that mReg2 induces glucose-regulated peptide 78 (GRP78) expression via the Akt-mTORC1 axis and protects MIN6 cells against ER stress induced by thapsigargin and glucolipotoxicity. Activation of mTORC1 activity results from both mReg2-induced increased mTOR phosphorylation as well as increased expression of Raptor and GβL. Inhibition of Akt and mTORC1 blunted the ability of mReg2 to induce GRP78 and attenuate unfolded protein response (UPR). Knockdown of GRP78 sensitized the cells overexpressing mReg2 to UPR without affecting its ability to activate Akt-mTORC1 signaling. Induced expression of mReg2 may protect insulin producing cells from ER stress in diabetes.
authors.affiliation: Fraser Laboratories, Department of Medicine, McGill University Health Centre and Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Fraser Laboratories, Department of Medicine, McGill University Health Centre and Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Fraser Laboratories, Department of Medicine, McGill University Health Centre and Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Fang
authors.affiliation: Fraser Laboratories, Department of Medicine, McGill University Health Centre and Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Liu
authors.affiliation: Fraser Laboratories, Department of Medicine, McGill University Health Centre and Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada. Electronic address: coimbatore.srikant@mcgill.ca.
authors.forename: Coimbatore B
authors.initials: CB
authors.lastname: Srikant
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007340:Insulinoma; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015533:Transcriptional Activation; D056811:Unfolded Protein Response
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D046912:Multiprotein Complexes; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C490253:Reg3b protein, mouse; C510185:Ern1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: Apoptosis; ER stress; Glucose-regulated peptide 78; Unfolded protein response; mTORC1; siRNA interference