Vascular endothelial growth factor (VEGF), a potent cytokine secreted by vi
rtually all cells plays a key role in tumor angiogenesis. Disruption of one
VEGF allele in mice has revealed a dramatic lethal effect in early embryog
enesis, suggesting a very tight regulation of this gene. This commentary re
views the mechanisms whereby VEGF mRNA is controlled within the tumor envir
onment by hypoxia and the MAP kinase signaling cascades. Using hamster fibr
oblasts as a cellular model, we demonstrated that the Ras-mediated activati
on of p42/p44 MAP kinases exerts a prominent action at the transcriptional
level. In normoxic conditions, p42/p44 MAPKs activate the VEGF promoter at
the proximal (-88/-66) region where Sp1/AP-2 transcriptional factor complex
es are recruited. At low O-2 tension, the stabilized and nuclear hypoxia in
ducible factor-1 alpha (HIF-1 alpha) is directly phosphorylated by p42/p44
MAPKs, an action which enhances HIF-1-dependent transcriptional activition
of VEGF. In addition, MAPKs activated under various cellular stresses (p38M
APK and JNK), contribute to the increased expression of this angiogenic gro
wth and survival factor by stabilizing the VEGF mRNA.