B. Illi et al., Nuclear factor-kappa B and cAMP response element binding protein mediate opposite transcriptional effects on the Flk-1/KDR gene promoter, CIRCUL RES, 86(12), 2000, pp. E110-E121
The vascular endothelial growth factor receptor Flk-1/KDR is highly express
ed during development and almost disappears in adult tissues. Despite its b
iological relevance, little is known about the molecular mechanisms control
ling its expression. In the present work, it is shown that cAMP response el
ement binding protein (CREB) and nuclear factor-kappa B (NF-kappa B)-relate
d antigens bind specific sequences in the Flk-1/KDR promoter. Functional st
udies demonstrate that cAMP represses whereas tumor necrosis factor-alpha,
an activator of NF-kappa B, stimulates promoter activity. Histone acetyltra
nsferases (HATs) P/CAF and CBP/p300 together with p65/RelA, the catalytic s
ubunit of NF-kappa B, increase Flk-1/KDR promoter activity 10- to 20-fold.
Consistently, inhibition by cAMP is reverted by increasing intracellular HA
Ts and is completely abolished by site-specific mutagenesis of the cAMP res
ponse element. In contrast, specific mutations in the NF-kappa B response e
lement abolish responsiveness to p65/RelA and HATs without affecting cAMP-d
ependent repression. These results suggest that opposing signaling pathways
, activating NF-kappa B or CREB and requiring HAT molecules, control Flk-1/
KDR promoter activity. The full text of this article is available at http:/
/www.circresaha.org.