Nuclear factor-kappaB and cAMP response element binding protein mediate opposite transcriptional effects on the Flk-1/KDR gene promoter

Circ Res. 2000 Jun 23;86(12):E110-7.

Abstract

-The vascular endothelial growth factor receptor Flk-1/KDR is highly expressed during development and almost disappears in adult tissues. Despite its biological relevance, little is known about the molecular mechanisms controlling its expression. In the present work, it is shown that cAMP response element binding protein (CREB) and nuclear factor-kappaB (NF-kappaB)-related antigens bind specific sequences in the Flk-1/KDR promoter. Functional studies demonstrate that cAMP represses whereas tumor necrosis factor-alpha, an activator of NF-kappaB, stimulates promoter activity. Histone acetyltransferases (HATs) P/CAF and CBP/p300 together with p65/RelA, the catalytic subunit of NF-kappaB, increase Flk-1/KDR promoter activity 10- to 20-fold. Consistently, inhibition by cAMP is reverted by increasing intracellular HATs and is completely abolished by site-specific mutagenesis of the cAMP response element. In contrast, specific mutations in the NF-kappaB response element abolish responsiveness to p65/RelA and HATs without affecting cAMP-dependent repression. These results suggest that opposing signaling pathways, activating NF-kappaB or CREB and requiring HAT molecules, control Flk-1/KDR promoter activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / metabolism
  • Animals
  • Aorta / cytology
  • Blotting, Northern
  • Cattle
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • Endothelium, Vascular / cytology
  • Gene Expression Regulation
  • Histone Acetyltransferases
  • Mutagenesis, Site-Directed
  • NF-kappa B / agonists
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Promoter Regions, Genetic*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / metabolism*
  • Receptors, Vascular Endothelial Growth Factor
  • Saccharomyces cerevisiae Proteins*
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Cyclic AMP Response Element-Binding Protein
  • NF-kappa B
  • Receptors, Growth Factor
  • Saccharomyces cerevisiae Proteins
  • Tumor Necrosis Factor-alpha
  • Acetyltransferases
  • Histone Acetyltransferases
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor