Insulin-regulated gene expression
Insulin-regulated gene expression
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DOI：
10.1042/bst0290552
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发表时间：
2001-08-01
影响因子：
3.9
通讯作者：
Hornbuckle, LA
中科院分区：
文献类型：
--
作者：
O'Brien, RM;Streeper, RS;Hornbuckle, LA
胰岛素调节150多个基因的表达，表明这是胰岛素的主要作用。至少有8种不同的胰岛素反应序列（IRSs）被确定，胰岛素可以通过这些序列调节基因转录。其中包括血清反应元件、激活蛋白1 （AP-1）基序、Ets基序、E-box基序和甲状腺转录因子2 （TTF-2）基序。所有这些IRSs介导胰岛素对基因转录的刺激作用。相比之下，具有一致序列T(G/A)TTT(T/G)（G/T）的元件，我们称之为磷酸烯醇丙酮酸羧激酶（PEPCK）样基序，介导胰岛素对编码PEPCK、胰岛素样生长因子结合蛋白1 （IGFBP-1）、酪氨酸转氨酶和葡萄糖-6-磷酸酶（G6Pase）催化亚基的基因转录的抑制作用。叉头转录因子FKHR最近被证明与pepck样IRS基序结合，并提出了胰岛素通过刺激FKHR的磷酸化和核输出来抑制基因转录的模型。我们的结果表明，该模型与胰岛素对编码IGFBP-1的基因转录的作用一致，但与G6Pase催化亚基的作用不一致。因此，尽管两个启动子中的IRSs看起来相同，但它们在功能上是不同的。此外，在G6Pase催化亚基启动子中，肝细胞核因子I （HNF-1）作为辅助因子增强胰岛素通过IRS介导的作用。
Insulin regulates the expression of more than 150 genes, indicating that this is a major action of this hormone. At least eight distinct consensus insulin response sequence (IRSs) have been defined through which insulin can regulate gene transcription. These include the serum response element, the activator protein 1 ('AP-1') motif, the Ets motif, the E-box motif and the thyroid transcription factor 2 ('TTF-2') motif. All of these IRSs mediate stimulatory effects of insulin on gene transcription. In contrast, an element with the consensus sequence T(G/A)TTT(T/G)(G/T), which we refer to as the phosphoenolpyruvate carboxykinase (PEPCK)-like motif, mediates the inhibitory effect of insulin on transcription of the genes encoding PEPCK, insulin-like- growth-factor-binding protein 1 (IGFBP-1), tyrosine aminotransferase and the glucose-6-phosphatase (G6Pase) catalytic subunit. The forkhead transcription factor FKHR has recently been shown to bind this PEPCK-like IRS motif and a model has been proposed in which insulin inhibits gene transcription by stimulating the phosphorylation and nuclear export of FKHR. Our results suggest that this model is consistent with the action of insulin on transcription of the gene encoding IGFBP-1 but not that of the G6Pase catalytic subunit. Thus, even though the IRSs in both promoters seem identical, they are functionally distinct. In addition, in the G6Pase catalytic subunit promoter, hepatocyte nuclear factor I ('HNF-1'), acts as an accessory factor to enhance the effect of insulin mediated through the IRS.