Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass.
The glucoincretin hormone glucagon-like peptide-1 (GLP-1) increases pancreatic beta-cell proliferation and survival through sequential activation of the epidermal growth factor receptor (EGFR), phosphatidylinositol-3 kinase (PI 3-kinase), and Akt. We investigated the role of transcription factor FoxO1 in the proliferative and antiapoptotic actions of GLP-1 in beta-cells. GLP-1 inhibited FoxO1 through phosphorylation-dependent nuclear exclusion in pancreatic beta (INS832/13) cells. The effect of GLP-1 was suppressed by inhibitors of EGFR (AG1478) and PI 3-kinase (LY294002). In contrast, LY294002 but not AG1478 suppressed insulin-induced FoxO1 phosphorylation. Expression of constitutively nuclear FoxO1 in beta-cells prevented the proliferative and antiapoptotic actions of GLP-1 in cultured beta-cells and the increase in pancreatic beta-cell mass in response to Exendin4 in transgenic mice. Gene expression and chromatin immunoprecipitation assays demonstrated that GLP-1 increases pancreatic and duodenal homeobox gene-1 and Foxa2 expression and inhibits FoxO1 binding to both promoters. We propose that FoxO1 mediates the pleiotropic effects of the glucoincretin hormone on cell proliferation and survival.
Buteau
Jean
J
Department of Medicine, Naomi Berrie Diabetes Center, Columbia University Medical Center, Berrie Research Pavilion, 1150 St. Nicholas Ave., Room 238, New York, NY 10032, USA.
Spatz
Marianne L
ML
Accili
Domenico
D
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides / Q000494:pharmacology*; D005947:Glucose / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D007328:Insulin / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000494:pharmacology*
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D049452:Green Fluorescent Proteins; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose