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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-06-1693. This Article Full Text (PDF) All Versions of this Article: 2002-06-1693v1 101/3/907    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kietzmann, T. Articles by Jungermann, K. Search for Related Content PubMed PubMed Citation Articles by Kietzmann, T. Articles by Jungermann, K. Social Bookmarking                   What's this? Submitted June 10, 2002 Accepted August 26, 2002 Hypoxia-inducible factor-1 and hypoxia response elements mediate the induction of plasminogen activator inhibitor-1 gene expression by insulin in primary rat hepatocytes Thomas Kietzmann*, Anatoly Samoylenko, Ulrike Roth, and Kurt Jungermann Institut fur Biochemie und Molekulare Zellbiologie, Georg-August-University Gottingen, Gottingen, Germany * Corresponding author; email: tkietzm{at}gwdg.de. The expression of the plasminogen activator inhibitor-1 (PAI-1) gene is enhanced by insulin both in vivo and in various cell types. Since insulin exerts a number of its biological activities via the PI3K/PKB signalling pathway, it was the aim of the present study to investigate the role of the PI3K/PKB pathway in the expression of the PAI-1 gene and to identify the insulin responsive promoter sequences. It was shown that the induction of PAI-1 mRNA and protein expression by insulin and mild hypoxia could be repressed by the PI3K inhibitor wortmannin. Overexpression of a constitutively active PKB led to induction of PAI-1 mRNA expression and of Luc activity from a gene construct containing 766 bp of the rat PAI-1 promoter. Mutation of the hypoxia response elements in rat PAI-1 promoter (HRE-1 and HRE-2), which could bind hypoxia inducible factor-1 (HIF-1), abolished the induction of PAI-1 by insulin and PKB. Insulin and the constitutive active PKB also induced Luc expression in cells transfected with the pGl3EPO-HRE Luc construct, containing three copies of the HRE from the erythropioetin gene in front of the SV40 promoter. Furthermore, insulin and the active PKB enhanced all three HIF -subunit protein levels and HIF-1 DNA-binding activity, as shown by electrophoretic mobility shift assays (EMSA). 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