Showing papers by "Gilles Pagès published in 2000"
TL;DR: It is demonstrated that the Ras-mediated activation of p42/p44 MAP kinases exerts a prominent action at the transcriptional level and contributes to the increased expression of this angiogenic growth and survival factor by stabilizing the VEGF mRNA.
Abstract: Vascular endothelial growth factor (VEGF), a potent cytokine secreted by virtually all cells plays a key role in tumor angiogenesis. Disruption of one VEGF allele in mice has revealed a dramatic lethal effect in early embryogenesis, suggesting a very tight regulation of this gene. This commentary reviews the mechanisms whereby VEGF mRNA is controlled within the tumor environment by hypoxia and the MAP kinase signaling cascades. Using hamster fibroblasts as a cellular model, we demonstrated that the Ras-mediated activation 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 complexes are recruited. At low O2 tension, the stabilized and nuclear hypoxia inducible factor-1α (HIF-1α) 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 (p38MAPK and JNK), contribute to the increased expression of this angiogenic growth and survival factor by stabilizing the VEGF mRNA.
221 citations
TL;DR: It is demonstrated that p42/p44 MAP kinases play a pivotal role in angiogenesis by exerting a determinant action at three levels, and a model which suggests an autoregulatory feedback mechanism controlling HIF-1 alpha and therefore Hif-1-dependent gene expression is proposed.
198 citations
TL;DR: A major role of stress-activated protein kinases in the post-transcriptional regulation of VEGF is demonstrated, mediated through an AU-rich region of the 3′-UTR contained within a stable hairpin structure.
188 citations
TL;DR: Results suggest that the HIF-1α736isoform modulates gene expression upon hypoxia, a small isoform that can compete with the endogenous and transfected full-length Hif-1 α and 3-fold less active than the C-terminal transactivation domain.
107 citations