Copyright © 2004, European Society of Cardiology
Transcriptional regulation of the Vascular Endothelial Growth Factor gene–a concert of activating factors*
Institute of Signaling, Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, 33 avenue de Valombrose, 06189 Nice cedex 2, France
* Corresponding author. Tel.: +33 492 03 12 31; fax: +33 492 03 12 35. Email address: gpages{at}unice.fr
The vascular endothelial growth factor A (VEGF-A) is essential during embryonic development as inactivation of only one allele of its gene results in embryonic lethality. Up-regulation of VEGF under physiological situations allows for adaptation to hypoxic stress, to transient inflammatory processes, and to wounding. Its expression also increases all along the process of neovascularization of solid and hematological tumors. The object of this article is to focus on the transcriptional regulation of its gene. The major cis-acting sequences and trans-activating factors will be described as well as the physiological and pathological situations leading to the intervention of such sequences and factors. We will also focus on two transcription factors essential to VEGF gene transcription: the hypoxia-inducible factor-1, which is responsible for its increased by hypoxia, as well as Sp1, which is implicated in the response to various extracellular stimuli.
KEYWORDS VEGF; Transcription; Promoter; Sp1; HIF
Abbreviations: Abl, abelson • AP-2, activating protein 2 • EGF, epidermal growth factor • Egr 1, early gene response protein • FGF, fibroblast growth factor • HGF, hepatocyte growth factor • HIF, hypoxia inducible factor • IGF, insulin-like growth factor • IL, interleukin • PDGF, platelet derived growth factor • PDK-1, phospholipid dependent kinase • PKC, protein kinase C • Sp1, specificity protein 1 • STAT, signal transducer and activator of transcription • TGF, transforming growth factor • TPA, 12-O-tetradecanoylphorbol-13-acetate • VEGF, vascular endothelial growth factor • VHL, von Hippel Lindau
* During the completion of our manuscript, Chang et al. have demonstrated that the NFAT transcription factor binds to a site at –2400 of the VEGF promoter region (GGAAA). NFAT inhibits the VEGF promoter activity in the myocardium. This repression is essential to mediate a transformation of myocardial cells into mesenchymal cells. Chang CP, Neilson JR, Bayle JH, Gestwicki JE, Kuo A, Stankunas K, et al. A field of myocardial-endothelial NFAT signaling underlies heart valve morphogenesis. Cell 2004;118:649–63.
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