Regulation of PGG1 promoter activity by protein kinase B and the forkhead transcription factor FKHR
Regulation of PGG1 promoter activity by protein kinase B and the forkhead transcription factor FKHR
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DOI：
10.2337/diabetes.52.3.642
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发表时间：
2003-03-01
期刊：
影响因子：
7.7
通讯作者：
Fukamizu, A
中科院分区：
文献类型：
--
作者：
Daitoku, H;Yamagata, K;Fukamizu, A
过氧化物酶体增殖物激活受体-γ共激活因子-1(PGC-1)在介导肝脏糖异生反应中起重要作用，在此过程中，PGC-1由环状AMP反应元件结合蛋白诱导。虽然观察到胰岛素抑制PGC-1转录，但胰岛素抑制PGG-1转录的机制尚不清楚。在这里，我们证明了叉头转录因子FKHR有助于介导胰岛素对PGC-1启动子活性的影响。报告分析表明，在HepG2细胞中，胰岛素抑制PGG-1启动子的基本活性，蛋白激酶(PK)-B的共表达与胰岛素的作用相似。胰岛素反应序列(IRS)在PGG-1启动子中被定位为FKHR的体内直接靶点。FKHR的共表达通过与IRS的相互作用刺激PGC-1启动子的活性，而FKHR(U)的共表达主要取消了PKB的抑制作用，其中FKHR的三个可能的PKB位点发生突变。虽然IRSS的缺失阻止了FKHR对启动子的刺激，但这种活性仍然被胰岛素部分抑制。这些结果表明，通过PKB向FKHR传递信号可以部分解释胰岛素通过IRSS调节PGG-1启动子活性的作用。
Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) plays a major role in mediating hepatic gluconeogenesis in response to starvation, during which PGC-1 is induced by the cyclic AMP response element binding protein. Although it is observed that insulin counteracts PGC-1 transcription, the mechanism by which insulin suppresses the transcription of PGG-1 is still unclear. Here, we show that forkhead transcription factor FKHR contributes to mediating the effects of insulin on PGC-1 promoter activity. Reporter assays demonstrate that insulin suppresses the basal PGG-1 promoter activity and that coexpression of protein kinase (PK)-B mimics the effect of insulin in HepG2 cells. Insulin response sequences (IRSs) are addressed in the PGG-1 promoter as the direct target for FKHR in vivo. Coexpression of FKHR stimulates the PGC-1 promoter activity via interaction with the IRSs, while coexpression of FKHR (U), in which the three putative PKB sites in FKHR are mutated, mainly abolishes the suppressive effect of PKB. Whereas deletion of the IRSs prevents the promoter stimulation by FKHR, that activity is still partially inhibited by insulin. These results indicate that signaling via PKB to FKHR can partly account for the effect of insulin to regulate the PGG-1 promoter activity via the IRSs.