MAP kinases and hypoxia in the control of VEGF expression

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.