Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor-binding protein-1 gene expression through a conserved insulin response sequence
Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor-binding protein-1 gene expression through a conserved insulin response sequence
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DOI：
10.1074/jbc.273.11.6482
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发表时间：
1998-03-13
影响因子：
4.8
通讯作者：
Unterman, TG
中科院分区：
文献类型：
--
作者：
Cichy, SB;Uddin, S;Unterman, TG
胰岛素通过一个保守的胰岛素反应序列（IRS）调控多个肝脏基因的表达蛋白激酶B/Akt（PKB/Akt）是PKA/PKC丝氨酸/苏氨酸激酶家族的成员，在磷脂酰肌醇3 '-激酶（PI 3 K）的下游起作用，介导胰岛素对葡萄糖转运和糖原合成的作用，我们使用胰岛素样生长因子结合蛋白-1（IGFBP-1）启动子模型，研究PKB/Akt是否介导胰岛素对肝脏基因表达的序列特异性作用。在HepG 2肝癌细胞中，胰岛素通过PI 3 K依赖性、雷帕霉素不敏感机制降低IGFBP-1 mRNA水平，抑制IGFBP-1启动子活性，并激活PKB/Akt。组成性活性PI 3 K和PKB/ Akt各自足以以非加和方式介导胰岛素对IGFBP-1启动子的作用，显性负性K179 PKB/Akt破坏胰岛素和PI 3 K激活PKB/Akt并抑制蛋白酶活性的能力，IGFBP-1启动子含有两个IRS，每个IRS足以介导胰岛素、PI 3 K和PKB/Akt对启动子活性的序列特异性作用，来自磷酸烯醇丙酮酸羧激酶和载脂蛋白CIII基因的高度相关的IRS在这种情况下也是有效的，这些结果表明，PKB/Akt在PI 3R下游介导胰岛素对IGFBP表达的序列特异性作用。1和可能的多个肝脏基因通过一个保守的IRS。
Insulin regulates the expression of multiple hepatic genes through a conserved insulin response sequence (IRS) (CAAAAC/TAA) by an as yet undetermined mechanism, Protein kinase B/Akt (PKB/Akt), a member of the PKA/PKC serine/threonine kinase family, functions downstream from phosphatidylinositol 3'-kinase (PI3K) in mediating effects of insulin on glucose transport and glycogen synthesis, We asked whether PKB/Akt mediates sequence-specific effects of insulin on hepatic gene expression using the model of the insulin-like growth factor binding protein-1 (IGFBP-1) promoter. Insulin lowers IGFBP-1 mRNA levels, inhibits IGFBP-1 promoter activity, and activates PKB/Akt in HepG2 hepatoma cells through a PI3K-dependent, rapamycin insensitive mechanism, Constitutively active PI3K and PKB/ Akt are each sufficient to mediate effects of insulin on the IGFBP-1 promoter in a nonadditive fashion, Dominant negative K179 PKB/Akt disrupts the ability of insulin and PI3K to activate PKB/Akt and to inhibit pro- meter activity, The IGFBP-1 promoter contains two IRSs each of which is sufficient to mediate sequence-specific effects of insulin, PI3K, and PKB/Akt on promoter activity, Highly related IRSs from the phosphoenolpyruvate carboxykinase and apolipoprotein CIII genes also are effective in this setting, These results indicate that PKB/Akt functions downstream from PI3R in mediating sequence-specific effects of insulin on the expression of IGFBP-1 and perhaps multiple hepatic genes through a conserved IRS.