Circadian clock genes cause activation of the human PAI-1 gene promoter with 4G/5G allelic preference

FEBS Lett. 2006 Aug 7;580(18):4469-72. doi: 10.1016/j.febslet.2006.07.014. Epub 2006 Jul 14.

Abstract

Increased plasminogen activator inhibitor-1 (PAI-1) activity is associated with greater risk of myocardial infarction. PAI-1 expression is regulated by a 4G/5G promoter polymorphism. The 4G allele is associated with higher PAI-levels and greater circadian variation. Here we show that clock protein heterodimers BMAL/CLOCK cause greater activation (approximately 2-fold, P<0.05) of the 4G allele. Site-directed mutagenesis studies suggest that clock genes act on two canonical E-boxes to regulate PAI-1 promoter activity. These results identify a potential novel mechanism whereby allele-specific clock genes - mediated modulation of PAI-1 expression may contribute to circadian variation in cardiac risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • CLOCK Proteins
  • COS Cells
  • Chlorocebus aethiops
  • Circadian Rhythm / genetics
  • E-Box Elements
  • Humans
  • Mutagenesis, Site-Directed
  • Plasminogen Activator Inhibitor 1 / genetics*
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic*
  • Trans-Activators / metabolism
  • Transcriptional Activation*

Substances

  • Plasminogen Activator Inhibitor 1
  • Trans-Activators
  • CLOCK Proteins
  • CLOCK protein, human