Dickens M, Svitek C A, Culbert A A, O'Brien R M, Tavaré J M
Department of Biochemistry, School of Medical Sciences, University of Bristol, BS8 1TD, United Kingdom.
J Biol Chem. 1998 Aug 7;273(32):20144-9. doi: 10.1074/jbc.273.32.20144.
Transcription of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase) is stimulated by glucocorticoids and strongly repressed by insulin. We have explored the signaling pathways by which insulin mediates the repression of G6Pase transcription in H4IIE cells. Wortmannin, a phosphatidylinositide 3-kinase (PtdIns 3-kinase) inhibitor blocked the repression of G6Pase mRNA expression by insulin. However, both rapamycin, which inhibits p70S6 kinase activation, and PD98059, an inhibitor of mitogen-activated protein kinase activation, were without effect. Insulin inhibited dexamethasone-induced luciferase expression from a transiently transfected plasmid that places the luciferase gene under the control of the G6Pase promoter. This effect of insulin was mimicked by the overexpression of a constitutively active PtdIns 3-kinase but not by a constitutively active protein kinase B. Taken together, these data demonstrate that PtdIns 3-kinase activation is both necessary and at least partly sufficient for the repression of G6Pase expression by insulin, but neither mitogen-activated protein kinase nor p70S6 kinase are involved. In addition, activation of protein kinase B alone is not sufficient for repression of the G6Pase gene. These results imply the existence of a novel signaling pathway downstream of PtdIns 3 kinase that is involved in the regulation of G6Pase expression by insulin.
编码葡萄糖-6-磷酸酶（G6Pase）催化亚基的基因转录受糖皮质激素刺激，并被胰岛素强烈抑制。我们已经探究了胰岛素介导H4IIE细胞中G6Pase转录抑制的信号通路。渥曼青霉素，一种磷脂酰肌醇3-激酶（PtdIns 3-激酶）抑制剂，可阻断胰岛素对G6Pase mRNA表达的抑制作用。然而，抑制p70S6激酶激活的雷帕霉素和有丝分裂原激活蛋白激酶激活抑制剂PD98059均无作用。胰岛素抑制了地塞米松诱导的荧光素酶表达，该荧光素酶表达来自一个将荧光素酶基因置于G6Pase启动子控制下的瞬时转染质粒。胰岛素的这种作用可被组成型活性PtdIns 3-激酶的过表达模拟，但不能被组成型活性蛋白激酶B模拟。综上所述，这些数据表明PtdIns 3-激酶激活对于胰岛素抑制G6Pase表达既是必要的，也是至少部分充分的，但有丝分裂原激活蛋白激酶和p70S6激酶均未参与。此外，单独激活蛋白激酶B不足以抑制G6Pase基因。这些结果暗示了PtdIns 3激酶下游存在一条新的信号通路，该通路参与胰岛素对G6Pase表达的调控。
