The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth
The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth
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DOI：
10.1172/jci200216857
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发表时间：
2002-12-01
影响因子：
15.9
通讯作者：
Accili, D
中科院分区：
文献类型：
--
作者：
Kitamura, T;Nakae, J;Accili, D
糖尿病是由产生胰岛素的β细胞的绝对（1型）或相对（2型）缺乏引起的。终末分化β细胞的复制和祖细胞新生的机制尚不清楚。缺乏胰岛素受体底物-2（Irs 2）的小鼠发生β细胞衰竭，表明胰岛素信号传导是维持足够的β细胞群所必需的。我们报道叉头转录因子Foxo 1的单倍不足通过部分恢复β细胞增殖和胰腺转录因子胰腺/十二指肠同源盒基因-1（Pdx 1）的表达来逆转Irs 2（-/-）小鼠的β细胞衰竭。Foxo 1和Pdx 1在β细胞中表现出相互排斥的核定位模式，突变型Foxo 1的组成性核表达与Pdx 1表达的缺乏相关。我们表明，Foxo 1作为Foxa 2依赖（HNF-3 β依赖）的表达从Pdx 1启动子的阻遏物。我们认为胰岛素/IGFs通过缓解Foxo 1对胰腺导管内细胞亚群中Pdx 1表达的抑制来调节β细胞增殖。
Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. The mechanisms governing replication of terminally differentiated beta cells and neogenesis from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop beta cell failure, suggesting that insulin signaling is required to maintain an adequate beta cell mass. We report that haploinsufficiency for the forkhead transcription factor Foxo1 reverses beta cell failure in Irs2(-/-) mice through partial restoration of beta cell proliferation and increased expression of the pancreatic transcription factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually exclusive patterns of nuclear localization in beta cells, and constitutive nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression. We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3beta-dependent) expression from the Pdx1 promoter. We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.