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dc.contributor.authorMilanini, Julie-
dc.contributor.authorViñals Canals, Francesc-
dc.contributor.authorPouysségur, Jacques-
dc.contributor.authorPages, Gilles-
dc.description.abstractVascular Endothelial Growth Factor (VEGF) is a potent mitogen for vascular endothelial cells that has been implicated in tumor neovascularization. We show that, in hamster fibroblasts (CCL39 cells), VEGF mRNAs are expressed at low levels in serum-deprived or exponentially growing cells, whereas it is rapidly induced after stimulation of quiescent cells with serum. CCL39 derivatives, transformed with Polyoma virus or with active members of the p42/p44 mitogen-activated protein (MAP) kinase pathway, Gly/Val point mutant of Ras at position 12 (Ras-Val12), MKK1 in which Ser218 and Ser222 were mutated to Asp (MKK1-SS/DD)), express very high levels of VEGF mRNA. To analyze the contribution of the p42/p44MAP kinase in this induction, we used the CCL39-derived cell line (Raf-1:ER) expressing an estradiol-activable Raf-1. We show a time and an estradiol dose-dependent up-regulation of VEGF mRNA clearly detectable after 2 h of stimulation. The induction of VEGF mRNA in response to conditioned activation of Raf-1 is reverted by an inhibitor of MKK1, PD 098059, highlighting a specific role for the p42/p44 MAP kinase pathway in VEGF expression. Interestingly, hypoxia has an additive effect on VEGF induction in CCL39 cells stimulated by serum or in Raf-1:ER cells stimulated by estradiol. In contrast to VEGF, the isoforms VEGF-B and VEGF-C are poorly regulated by growth and oncogenic factors. We have identified a GC-rich region of the VEGF promoter between -88 and -66 base pairs which contains all the elements responsible of its up-regulation by constitutive active Ras or MKK1-SS/DD. By mutation of the putative binding sites and electrophoretic mobility supershift experiments, we showed that the GC-rich region constitutively binds Sp1 and AP-2 transcription factors. Furthermore, following activation of the p42/p44 MAP kinase module, the binding of Sp1 and AP-2 is increased in the complexes formed in this region of the promoter. Altogether, these data suggest that hypoxia and p42/p44 MAP kinase independently play a key role in the regulation of the VEGF expression.-
dc.format.extent8 p.-
dc.publisherAmerican Society for Biochemistry and Molecular Biology-
dc.relation.isformatofReproducció del document publicat a:
dc.relation.ispartofJournal of Biological Chemistry, 1998, vol. 273, num. 29, p. 18165-18172-
dc.rights(c) American Society for Biochemistry and Molecular Biology, 1998-
dc.subject.classificationProteïnes quinases-
dc.subject.classificationFactor de creixement de l'endoteli vascular-
dc.subject.classificationTranscripció genètica-
dc.subject.otherProtein kinases-
dc.subject.otherVascular endothelial growth factors-
dc.subject.otherGenetic transcription-
dc.titlep42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts-
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)

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