A Forkhead/winged helix-related transcription factor mediates insulin-increased plasminogen activator inhibitor-1 gene transcription.

The Journal of Biological Chemistry
Anthony Igor Vulin, Frederick M Stanley

Abstract

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. ...Continue Reading

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Citations

Nov 30, 2005·Molecular and Cellular Biology·Gilles BuchwalterBohdan Wasylyk
Jul 18, 2009·Molecular Endocrinology·Ushma R JagFrederick M Stanley
Sep 26, 2006·Canadian Journal of Physiology and Pharmacology·Catherine Mounier, Barry I Posner
Jan 18, 2016·Medical Hypotheses·Silvia Hoirisch-ClapauchAntonio E Nardi
Jul 23, 2003·Journal of Thrombosis and Haemostasis : JTH·I Juhan-VagueP E Morange
Mar 31, 2004·Journal of Internal Medicine·A MavriI Juhan-Vague
Apr 24, 2016·Cellular Oncology (Dordrecht)·Luis Antonio Flores-LópezLuis Arturo Baiza-Gutman
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Apr 14, 2018·Circulation Research·David H WassermanNancy J Brown
Jul 15, 2003·Current Opinion in Obstetrics & Gynecology·Raj Rai

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