A Forkhead/Winged Helix-related Transcription Factor Mediates Insulin-increased Plasminogen Activator Inhibitor-1 Gene Transcription*

Plasminogen activator inhibitor-1 (PAI-1) is an important regulator of fibrinolysis by its inhibition of both tissue-type and urokinase plasminogen activators. PAI-1 levels are elevated in type II diabetes and this elevation correlates with macro- and microvascular complications of diabetes. Insulin increases PAI-1 production in several experimental systems, but the mechanism of insulin-activated PAI-1 transcription remains to be determined. Deletion analysis of the PAI-1 promoter revealed that the insulin response element is between −117 and −7. Mutation of the AT-rich site at −52/−45 abolished the insulin responsiveness of the PAI-1 promoter. This sequence is similar to the inhibitory sequence found in the phosphoenolpyruvate carboxylkinase/insulin-like growth factor-I-binding protein I promoters. Gel-mobility shift assays demonstrated that the forkhead bound to the PAI-1 promoter insulin response element. Expression of the DNA-binding domain of FKHR acted as a dominant negative to block insulin-increased PAI-1-CAT expression. A LexA-FKHR construct was also insulin responsive. These data suggested that a member of the Forkhead/winged helix family of transcription factors mediated the effect of insulin on PAI-1 transcription. Inhibition of phosphatidylinositol 3-kinase reduced the effect of insulin on PAI-1 gene expression, a result consistent with activation through FKHR. However, it was likely that a different member of the FKHR family (not FKHR) mediated this effect since FKHR was present in both insulin-responsive and non-responsive cell lines.

• Publication year

  2002

• Venue

  Journal of Biological Chemistry

• Publication date

  2002-06-07

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M112073200PMID 11919188
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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