title: c-Jun inhibits thapsigargin-induced ER stress through up-regulation of DSCR1/Adapt78.
abstract: The endoplasmic reticulum (ER) is exquisitely sensitive to changes in its internal environment. Various conditions, collectively termed "ER stress", can perturb ER function, leading to the activation of a complex response known as the unfolded protein response (UPR). Although c-Jun N-terminal kinase (JNK) activation is nearly always associated with cell death by various stimuli, the functional role of JNK in ER stress-induced cell death remains unclear. JNK regulates gene expression through the phosphorylation and activation of transcription factors, such as c-Jun. Here, we investigated the role of c-Jun in the regulation of ER stress-related genes. c-Jun expression levels determined the response of mouse fibroblasts to ER stress induced by thapsigargin (TG, an inhibitor of sarco/endoplasmic reticulum Ca(2+) ATPase). c-jun(-/-) mouse fibroblast cells were more sensitive to TG-induced cell death compared to wild-type mouse fibroblasts, while reconstitution of c-Jun expression in c-jun(-/-) cells (c-Jun Re) enhanced resistance to TG-induced cell death. The expression levels of ER chaperones Grp78 and Gadd153 induced by TG were lower in c-Jun Re than in c-jun(-/-) cells. Moreover, TG treatment significantly increased calcineurin activity in c-jun(-/-) cells, but not in c-Jun Re cells. In c-Jun Re cells, TG induced the expression of Adapt78, also known as the Down syndrome critical region 1 (DSCR1), which is known to block calcineurin activity. Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death.
authors.affiliation: School of Pharmacy, University of Wyoming, Laramie, WY 82071, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xiao
authors.forename: Agnes S
authors.initials: AS
authors.lastname: Kim
authors.forename: M Fatima
authors.initials: MF
authors.lastname: Leite
authors.forename: Jinxia
authors.initials: J
authors.lastname: Xu
authors.forename: Xinglei
authors.initials: X
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Ji
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002135:Calcium-Binding Proteins; D053454:Caspase 12 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; C000717248:Hspa5 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D016755:Proto-Oncogene Proteins c-jun; D019284:Thapsigargin; D019703:Calcineurin; D053454:Caspase 12