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The molecular mechanism of endoplasmic reticulum stress-induced apoptosis in PC-12 neuronal cells: the protective effect of insulin-like growth factor I Zou CG; Cao XZ; Zhao YS; Gao SY; Li SD; Liu XY; Zhang Y; Zhang KQEndocrinology 2009[Jan]; 150 (1): 277-85Endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative diseases. Although CCAAT/enhancer-binding protein homologous protein (CHOP) has been shown to play a critical role in ER stress, the precise apoptosis cascade downstream of CHOP is unknown. In this report, we investigated the mechanism of ER stress-mediated apoptosis as well as the action of IGF-I in PC-12 neuronal cells. Our results demonstrated that tribbles-related protein 3 (TRB3), which is a target gene of CHOP, was responsible for tunicamycin (an ER stress inducer)-induced apoptosis. TRB3 could promote dephosphorylation of Akt in PC-12 cells. IGF-I inhibited ER stress-induced apoptosis by restoring the phosphorylation level of Akt. Both wortmannin (a phosphatidylinositide 3-kinase inhibitor) and SB 212090 (a p38 MAPK inhibitor) suppressed the protective effect of IGF-I on ER stress-induced apoptosis. Interestingly, IGF-I attenuated ER stress-mediated expression of TRB3 but not CHOP. This action of IGF-I was abolished by SB 212090 but not by wortmannin. Immunoprecipitation analysis revealed that IGF-I promoted the phosphorylation of CHOP by activating p38 MAPK, probably leading to a decrease in the transcriptional activity of CHOP. The dephosphorylation of Akt resulted in increased expression of a proapoptotic protein, p53 up-regulated modulator of apoptosis (PUMA), in a forkhead box O3a-dependent manner. Knockdown of PUMA by short hairpin RNA attenuated ER stress-mediated apoptosis. Thus, our current study indicates that both TRB3 and PUMA are critical molecules in ER stress-induced apoptosis. IGF-I effectively protects PC-12 neuronal cells against ER stress-induced apoptosis through the phosphatidylinositide 3-kinase/Akt and p38 MAPK pathways.|Animals[MESH]|Apoptosis/drug effects/*physiology[MESH]|Cell Cycle Proteins/drug effects/genetics[MESH]|DNA Primers[MESH]|DNA, Neoplasm/genetics/isolation & purification[MESH]|Down-Regulation[MESH]|Endoplasmic Reticulum/drug effects/*physiology[MESH]|Gene Expression Regulation, Neoplastic/drug effects[MESH]|Insulin-Like Growth Factor I/*pharmacology[MESH]|Neurons/cytology/*physiology[MESH]|PC12 Cells[MESH]|Pheochromocytoma[MESH]|Protein Serine-Threonine Kinases/drug effects/genetics[MESH]|RNA, Neoplasm/genetics[MESH]|Rats[MESH]|Repressor Proteins/drug effects/genetics[MESH]|Reverse Transcriptase Polymerase Chain Reaction[MESH]|p38 Mitogen-Activated Protein Kinases/metabolism[MESH] |
