Insulin modulates induction of glucose-regulated protein 78 during endoplasmic reticulum stress via augmentation of ATF4 expression in human neuroblastoma cells

Inageda, Kiyoshi

doi:10.1016/j.febslet.2010.07.040

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Volume 584, Issue 16 , Pages 3649-3654, 20 August 2010

Insulin modulates induction of glucose-regulated protein 78 during endoplasmic reticulum stress via augmentation of ATF4 expression in human neuroblastoma cells

Edited by Robert Barouki

Department of Hygiene and Public Health I, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan

Received 14 February 2010; received in revised form 19 July 2010; accepted 22 July 2010. published online 26 July 2010.

Abstract

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.

Abbreviation: Ac-DEVD-MCA, acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspartic acid a-(4-methylcoumaryl-7-amide), S.D., standard deviation

Keywords: Insulin, ATF4, ER stress, GRP78, SH-SY5Y