Regulation of glucose-6-phosphatase gene expression by protein kinase Bα and the forkhead transcription factor FKHR -: Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity
Regulation of glucose-6-phosphatase gene expression by protein kinase Bα and the forkhead transcription factor FKHR -: Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity
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DOI：
10.1074/jbc.m003616200
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发表时间：
2000-11-17
影响因子：
4.8
通讯作者：
Unterman, TG
中科院分区：
文献类型：
--
作者：
Schmoll, D;Walker, KS;Unterman, TG
葡萄糖-6-磷酸酶在肝脏葡萄糖生成的调节中起重要作用，胰岛素抑制葡萄糖-6-磷酸酶基因的表达。最近的研究表明，蛋白激酶B和叉头蛋白有助于胰岛素调节基因在肝脏中的表达。在这里，我们研究了蛋白激酶B和叉头蛋白在介导胰岛素对葡萄糖-6-磷酸酶启动子活性的影响中的作用。报告基因构建体的瞬时转染研究表明，胰岛素抑制H4 IIE肝癌细胞中葡萄糖-6-磷酸酶启动子的基础和地塞米松/cAMP诱导的活性。这两种效应都部分地被蛋白激酶B α的共表达所模拟。Forkhead转录因子FKHR的共表达通过与胰岛素应答单位（IRU）的相互作用刺激葡萄糖-6-磷酸酶启动子活性，并且这种激活被蛋白激酶B抑制，不能被蛋白激酶B磷酸化的FKHR突变形式的共表达消除了蛋白激酶B对葡萄糖-6-磷酸酶启动子的调节，并破坏了胰岛素调节葡萄糖-6-磷酸酶启动子的能力。葡萄糖-6-磷酸酶启动子的胰岛素应答单位的突变也阻止FKHR和蛋白激酶B对启动子活性的调节，但仅部分损害胰岛素抑制基础和地塞米松/cAMP刺激的启动子功能的能力。总之，这些结果表明，通过蛋白激酶B向叉头蛋白的信号传导可以解释胰岛素通过IRU调节葡萄糖-6-磷酸酶启动子活性的能力，并且独立于IRU、蛋白激酶B和叉头蛋白的其他机制在介导胰岛素对葡萄糖-6-磷酸酶基因表达的影响中也是重要的。
Glucose-6-phosphatase plays an important role in the regulation of hepatic glucose production, and insulin suppresses glucose-6-phosphatase gene expression. Recent Studies indicate that protein kinase B and Forkhead proteins contribute to insulin-regulated gene expression in the liver. Here, we examined the role of protein kinase B and Forkhead proteins in mediating effects of insulin on glucose-6-phosphatase promoter activity. Transient transfection studies with reporter gene constructs demonstrate that insulin suppresses both basal and dexamethasone/cAMP-induced activity of the glucose-6-phosphatase promoter in H4IIE hepatoma cells. Both effects are partially mimicked by coexpression bf protein kinase B alpha. Coexpression of the Forkhead transcription factor FKHR stimulates the glucose-6-phosphatase promoter activity via interaction with an insulin response unit (IRU), and this activation is suppressed by protein kinase B, Coexpression of a mutated form of FKHR that cannot be phosphorylated by protein kinase B abolishes the regulation of the glucose-6-phosphatase promoter by protein kinase B and disrupts the ability of insulin to regulate the glucose-6-phosphatase promoter via the IRU, Mutation of the insulin response unit of the glucose-6-phosphatase promoter also prevents the regulation of promoter activity by FKHR and protein kinase B but only partially impairs the ability of insulin: to suppress both basal and dexamethasone/cAMP-stimulated promoter function. Taken together, these results indicate that signaling by protein kinase B to Forkhead proteins can account for the ability of insulin to regulate glucose-6-phosphatase promoter activity via the IRU and that other mechanisms that are independent of the IRU, protein kinase B, and Forkhead proteins also are important in mediating effects of in insulin-on glucose-6-phosphatase gene expression.