The MAPK pathway and HIF-1 are involved in the induction of the human PAI-1 gene expression by insulin in the human hepatoma cell line HepG2

被引:23
作者
Dimova, Elitsa Y. [1 ]
Kietzmann, Thomas [1 ]
机构
[1] Univ Kaiserslautern, Fac Chem, Dept Biochem, D-67663 Kaiserslautern, Germany
来源
SIGNAL TRANSDUCTION PATHWAYS, PT A: APOPTOTIC AND EXTRACELLULAR SIGNALING | 2006年 / 1090卷
关键词
insulin; human plasminogen-activator inhibitor-1; hypoxiainducible factor-1; MAPK;
D O I
10.1196/annals.1378.039
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Enhanced levels of plasminogen activator inhibitor-1 (PAI-1) are considered to be a risk factor for pathological conditions associated with hypoxia or hyperinsulinemia. The expression of the PAI-1 gene is increased by insulin in different cells, although, the molecular mechanisms behind insulin-induced PAI-1 expression are not fully known yet. Here, we show that insulin upregulates human PAI-1 gene expression and promoter activity in HepG2 cells and that mutation of the hypoxia-responsive element (HRE)-binding hypoxia-inducible factor-1 (HIF-1) abolished the insulin effects. Mutation of E-boxes E4 and E5 abolished the insulin-dependent activation of the PAI-1 promoter only under normoxia, but did not affect it under hypoxia. Furthermore, the insulin effect was associated with activation of HIF-1 alpha via mitogen-activated protein kinases (MAPKs) but not PDK1 and PKB in HepG2 cells. Furthermore, mutation of a putative FoxO1 binding site which was supposed to be involved in insulin-dependent PAI-1 gene expression influenced the insulin-dependent activation only under normoxia. Thus, insulin-dependent PAI-1 gene expression might be regulated by the action of both HIF-1 and FoxO1 transcription factors.
引用
收藏
页码:355 / 367
页数:13
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