Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence
Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence
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DOI：
10.1074/jbc.274.24.17184
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发表时间：
1999-06-11
影响因子：
4.8
通讯作者：
Unterman, T
中科院分区：
文献类型：
--
作者：
Guo, SD;Rena, G;Unterman, T
胰岛素抑制肝脏中含有胰岛素反应序列（IRS）（CAAAA（C/T）AA）的多个基因的表达，我们已经报道了蛋白激酶B（PKB）介导胰岛素的这种作用。秀丽隐杆线虫的遗传研究表明，daf-16是胰岛素受体-PKB信号通路的主要靶点。FKHR是daf-16的人类同源物，含有三个PKB位点，并在肝脏中表达。在HepG 2肝癌细胞中的报告基因研究表明，FKHR通过IRS刺激胰岛素样生长因子结合蛋白-1启动子活性，IRS的引入赋予异源启动子这种效应。胰岛素通过FKHR破坏IRS依赖性反式激活，PKB对Ser-256的磷酸化是必要的，足以介导这种作用。反义研究表明FKHR参与启动子的基础功能，并通过IRS介导胰岛素和PKB对启动子活性的影响。据我们所知，这些结果首次报道了FKHR通过IRS刺激启动子活性，PKB磷酸化FKHR介导胰岛素对基因表达的影响。通过PKB向FKHR相关叉头蛋白的信号传导可能提供了胰岛素和相关因子调节基因表达的进化保守机制。
Insulin inhibits the expression of multiple genes in the liver containing an insulin response sequence (IRS) (CAAAA(C/T)AA), and we have reported that protein kinase B (PKB) mediates this effect of insulin, Genetic studies in Caenorhabditis elegans indicate that daf-16, a forkhead/winged-helix transcription factor, is a major target of the insulin receptor-PKB signaling pathway. FKHR, a human homologue of daf-16, contains three PKB sites and is expressed in the liver. Reporter gene studies in HepG2 hepatoma cells show that FKHR stimulates insulin-like growth factor-binding protein-1 promoter activity through an IRS, and introduction of IRSs confers this effect on a heterologous promoter. Insulin disrupts IRS-dependent transactivation by FKHR, and phosphorylation of Ser-256 by PKB is necessary and sufficient to mediate this effect. Antisense studies indicate that FKHR contributes to basal promoter function and is required to mediate effects of insulin and PKB on promoter activity via an IRS, To our knowledge, these results provide the first report that FKHR stimulates promoter activity through an IRS and that phosphorylation of FKHR by PKB mediates effects of insulin on gene expression. Signaling to FKHR-related forkhead proteins via PKB may provide an evolutionarily conserved mechanism by which insulin and related factors regulate gene expression.