ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis.
Details
Serval ID
serval:BIB_BE0F9F308CB1
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis.
Journal
EMBO journal
ISSN
0261-4189
Publication state
Published
Issued date
2006
Peer-reviewed
Oui
Volume
25
Number
5
Pages
977-986
Language
english
Abstract
The GTPases Rab3a and Rab27a and their effectors Granuphilin/Slp4 and Noc2 are essential regulators of neuroendocrine secretion. Chronic exposure of pancreatic beta-cells to supraphysiological glucose levels decreased selectively the expression of these proteins. This glucotoxic effect was mimicked by cAMP-raising agents and blocked by PKA inhibitors. We demonstrate that the transcriptional repressor ICER, which is induced in a PKA-dependent manner by chronic hyperglycemia and cAMP-raising agents, is responsible for the decline of the four genes. ICER overexpression diminished the level of Granuphilin, Noc2, Rab3a and Rab27a by binding to cAMP responsive elements located in the promoters of these genes and inhibited exocytosis of beta-cells in response to secretagogues. Moreover, the loss in the expression of the genes of the secretory machinery caused by glucose and cAMP-raising agents was prevented by an antisense construct that reduces ICER levels. We propose that induction of inappropriate ICER levels lead to defects in the secretory process of pancreatic beta-cells possibly contributing, in conjunction with other known deleterious effects of hyperglycemia, to defective insulin release in type 2 diabetes.
Keywords
Animals, Cyclic AMP, Cyclic AMP Response Element Modulator, DNA, Antisense, Electrophoretic Mobility Shift Assay, Exocytosis, Gene Expression Regulation, Glucose, Humans, Hyperglycemia, Insulin, Islets of Langerhans, Male, Promoter Regions, Genetic, Proteins, Rats, Rats, Sprague-Dawley, Repressor Proteins, Response Elements, Vesicular Transport Proteins, rab GTP-Binding Proteins, rab3 GTP-Binding Proteins
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 14:30
Last modification date
20/08/2019 15:32