Insulin modulates induction of glucose-regulated protein 78 during endoplasmic reticulum stress via augmentation of ATF4 expression in human neuroblastoma cells.
The effect of insulin on endoplasmic reticulum (ER) stress was investigated. Insulin protected cell death induced by ER stress and increased glucose-regulated protein 78 (GRP78) mRNA and protein levels. Insulin also significantly increased activating transcription factor-4 (ATF4) protein in the nucleus, which was inhibited by LY294002, a phosphatidylinositol 3-kinase (PI-3 kinase) inhibitor. The increase of ATF4 protein by insulin was not due to transcriptional or translational up-regulation but to a post-translational mechanism. Knockdown of ATF4 by siRNA significantly inhibited GRP78 induction by insulin. These results indicate that insulin modulated ER stress-induced GRP78 expression occurs via ATF4 up-regulation.
Inageda
Kiyoshi
K
Department of Hygiene and Public Health I, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. inageda@research.twmu.ac.jp
D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D013312:Stress, Physiological; D015854:Up-Regulation / Q000187:drug effects
C497109:ATF4 protein, human; D002867:Chromones; D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007328:Insulin; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D051701:Activating Transcription Factor 4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C505407:CASP3 protein, human; D053148:Caspase 3