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.

Abstract

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-1alpha 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.

• Authors: Elitsa Y Dimova, Thomas Kietzmann
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1090 Pg. 355-67 (Dec 2006) ISSN: 0077-8923 [Print] United States
• PMID: 17384280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Insulin
• Plasminogen Activator Inhibitor 1
• RNA, Messenger

Topics

• Carcinoma, Hepatocellular (enzymology, genetics, metabolism, pathology)
• Cell Line, Tumor
• Gene Expression Regulation (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
• Insulin (pharmacology)
• Liver Neoplasms (enzymology, genetics, metabolism, pathology)
• MAP Kinase Signaling System
• Plasminogen Activator Inhibitor 1 (genetics, metabolism)
• Promoter Regions, Genetic
• RNA, Messenger (genetics)