Buteau Jean, Spatz Marianne L, Accili Domenico
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.
Diabetes. 2006 May;55(5):1190-6. doi: 10.2337/db05-0825.
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.
胰高血糖素样肽-1（GLP-1）这种肠促胰岛素激素通过依次激活表皮生长因子受体（EGFR）、磷脂酰肌醇-3激酶（PI 3-激酶）和Akt，增加胰腺β细胞的增殖和存活。我们研究了转录因子FoxO1在GLP-1对β细胞的增殖和抗凋亡作用中的作用。在胰腺β（INS832/13）细胞中，GLP-1通过磷酸化依赖性核排除抑制FoxO1。EGFR抑制剂（AG1478）和PI 3-激酶抑制剂（LY294002）抑制了GLP-1的作用。相反，LY294002而非AG1478抑制胰岛素诱导的FoxO1磷酸化。β细胞中组成型核FoxO1的表达阻止了GLP-1在培养的β细胞中的增殖和抗凋亡作用，以及转基因小鼠中对艾塞那肽4反应时胰腺β细胞质量的增加。基因表达和染色质免疫沉淀分析表明，GLP-1增加胰腺和十二指肠同源盒基因-1以及Foxa2的表达，并抑制FoxO1与两个启动子的结合。我们提出，FoxO1介导了肠促胰岛素激素对细胞增殖和存活的多效性作用。
