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ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis

Abderrahmani, Amar ; Cheviet, Séverine ; Ferdaoussi, Mourad ; Coppola, Thierry ; Waeber, Gérard ; Regazzi, Romano

The EMBO journal, 2006-03, Vol.25 (5), p.977-986 [Periódico revisado por pares]

Chichester, UK: John Wiley & Sons, Ltd

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Título:
ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis
Autor: Abderrahmani, Amar ; Cheviet, Séverine ; Ferdaoussi, Mourad ; Coppola, Thierry ; Waeber, Gérard ; Regazzi, Romano
Assuntos: Animals ; Binding sites ; Biochemistry, Molecular Biology ; cAMP ; Cells ; Cyclic AMP ; Cyclic AMP - metabolism ; Cyclic AMP Response Element Modulator ; Cyclic AMP Response Element Modulator - metabolism ; Diabetes ; DNA, Antisense ; DNA, Antisense - pharmacology ; Electrophoretic Mobility Shift Assay ; Exocytosis ; Exocytosis - physiology ; Gene expression ; Gene Expression Regulation ; Gene Expression Regulation - physiology ; Glucose ; Glucose - metabolism ; GTPase ; Humans ; Hyperglycemia ; Hyperglycemia - metabolism ; ICER ; Insulin ; Insulin - metabolism ; Insulin Secretion ; Islets of Langerhans ; Islets of Langerhans - metabolism ; Life Sciences ; Male ; Neurons and Cognition ; pancreatic islet ; Promoter Regions (Genetics) ; Promoter Regions, Genetic ; Proteins ; Proteins - genetics ; Proteins - metabolism ; rab GTP-Binding Proteins ; rab GTP-Binding Proteins - genetics ; rab GTP-Binding Proteins - metabolism ; rab27 GTP-Binding Proteins ; rab3 GTP-Binding Proteins ; rab3 GTP-Binding Proteins - genetics ; rab3 GTP-Binding Proteins - metabolism ; Rats ; Rats, Sprague-Dawley ; Repressor Proteins ; Repressor Proteins - metabolism ; Response Elements ; Response Elements - genetics ; Vesicular Transport Proteins ; Vesicular Transport Proteins - genetics ; Vesicular Transport Proteins - metabolism
É parte de: The EMBO journal, 2006-03, Vol.25 (5), p.977-986
Notas: ArticleID:EMBJ7601008
Supplementary Figure 1Supplementary Figure 2Supplementary Figure 3
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PMCID: PMC1409716
These authors contributed equally to this work
Descrição: The GTPases Rab3a and Rab27a and their effectors Granuphilin/Slp4 and Noc2 are essential regulators of neuroendocrine secretion. Chronic exposure of pancreatic β‐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 β‐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 β‐cells possibly contributing, in conjunction with other known deleterious effects of hyperglycemia, to defective insulin release in type 2 diabetes.
Editor: Chichester, UK: John Wiley & Sons, Ltd
Idioma: Inglês

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ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis

Abderrahmani, Amar ; Cheviet, Séverine ; Ferdaoussi, Mourad ; Coppola, Thierry ; Waeber, Gérard ; Regazzi, Romano

Chichester, UK: John Wiley & Sons, Ltd

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