Valproate pretreatment protects pancreatic β-cells from palmitate-induced ER stress and apoptosis by inhibiting glycogen synthase kinase-3β

ABSTRACT Inactivation of the tumor suppressor p53 by degradation is a mechanism utilized by cells to adapt to endoplasmic reticulum (ER) stress. However, the mechanisms of p53 destabilization by ER stress are not known. We demonstrate here that the E3 ubiquitin-ligase Hdm2 is essential for the nucleocytoplasmic transport and proteasome-dependent degradation of p53 in ER-stressed cells. We also demonstrate that p53 phosphorylation at S315 and S376 is required for its nuclear export and degradation by Hdm2 without interfering with the ubiquitylation process. Furthermore, we show that p53 destabilization in unstressed cells utilizes the cooperative action of Hdm2 and glycogen synthase kinase 3β, a process that is enhanced in cells exposed to ER stress. In contrast to other stress pathways that stabilize p53, our findings further substantiate a negative role of ER stress in p53 activation with important implications for the function of the tumor suppressor in cells with a dysfunctional ER.

Download Full-text

ER stress-mediated apoptosis induced by celastrol in cancer cells and important role of glycogen synthase kinase-3β in the signal network

Cell Death and Disease ◽

10.1038/cddis.2013.222 ◽

2013 ◽

Vol 4 (7) ◽

pp. e715-e715 ◽

Cited By ~ 38

Author(s):

L Feng ◽

D Zhang ◽

C Fan ◽

C Ma ◽

W Yang ◽

...

Keyword(s):

Er Stress ◽

Cancer Cells ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β ◽

Signal Network

Download Full-text

MafA Stability in Pancreatic β Cells Is Regulated by Glucose and Is Dependent on Its Constitutive Phosphorylation at Multiple Sites by Glycogen Synthase Kinase 3

Molecular and Cellular Biology ◽

10.1128/mcb.01573-06 ◽

2007 ◽

Vol 27 (19) ◽

pp. 6593-6605 ◽

Cited By ~ 51

Author(s):

Song-iee Han ◽

Shinsaku Aramata ◽

Kunio Yasuda ◽

Kohsuke Kataoka

Keyword(s):

Gene Expression ◽

Glycogen Synthase ◽

Glucose Sensing ◽

Insulin Gene ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Β Cells ◽

Pancreatic Β Cells ◽

Amino Terminal ◽

Insulin Gene Expression

ABSTRACT Regulation of insulin gene expression by glucose in pancreatic β cells is largely dependent on a cis-regulatory element, termed RIPE3b/C1, in the insulin gene promoter. MafA, a member of the Maf family of basic leucine zipper (bZip) proteins, is a β-cell-specific transcriptional activator that binds to the C1 element. Based on increased C1-binding activity, MafA protein levels appear to be up-regulated in response to glucose, but the underlying molecular mechanism for this is not well understood. In this study, we show evidence supporting that the amino-terminal region of MafA is phosphorylated at multiple sites by glycogen synthase kinase 3 (GSK3) in β cells. Mutational analysis of MafA and pharmacological inhibition of GSK3 in MIN6 β cells strongly suggest that the rate of MafA protein degradation is regulated by glucose, that MafA is constitutively phosphorylated by GSK3, and that phosphorylation is a prerequisite for rapid degradation of MafA under low-glucose conditions. Our data suggest a new glucose-sensing signaling pathway in islet β cells that regulates insulin gene expression through the regulation of MafA protein stability.

Download Full-text