Activation of Vascular Endothelial Growth Factor Gene Transcription by Hypoxia-Inducible Factor 1

• DOI: 10.1128/mcb.16.9.4604
• Publication Date: 2015-10-09T00:25:47Z
• Authors: Jo A. Forsythe; Bing-Hua Jiang; Narayan V. Iyer; Faton Agani; Sandra W. Leung; Robert D. Koos; Gregg L. Semenza
• Keywords: Response element; Transcription; Sp1 transcription factor

Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia.Neovascularization stimulated by VEGF occurs several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth.Hypoxia-inducible 1 (HIF-1) a heterodimeric basic helix-loop-helix protein that activates transcription the human erythropoietin gene hypoxic cells.Here we demonstrate involvement HIF-1 activation transcription.VEGF 5-flanking sequences mediated transcriptional reporter expression Hep3B cells.A 47-bp sequence located 985 939 bp 5 initiation site hypoxia-inducible directed simian virus 40 promoter element was otherwise minimally responsive hypoxia.When reporters containing sequences, context native heterologous promoter, were cotransfected with vectors encoding HIF-1␣ HIF-1␤ (ARNT [aryl hydrocarbon receptor nuclear translocator]), much greater both nonhypoxic than transfected alone.A binding demonstrated response element, 3-bp substitution eliminated ability bind activate and/or recombinant HIF-1.Cotransfection an vector dominant negative form inhibited dose-dependent manner.VEGF mRNA not mutant do express (ARNT) subunit.These findings implicate cells.