PMID:12464608

Citation	Elvert, G, Kappel, A, Heidenreich, R, Englmeier, U, Lanz, S, Acker, T, Rauter, M, Plate, K, Sieweke, M, Breier, G and Flamme, I (2003) Cooperative interaction of hypoxia-inducible factor-2alpha (HIF-2alpha ) and Ets-1 in the transcriptional activation of vascular endothelial growth factor receptor-2 (Flk-1). J. Biol. Chem. 278:7520-30
Abstract	Interactions between Ets family members and a variety of other transcription factors serve important functions during development and differentiation processes, e.g. in the hematopoietic system. Here we show that the endothelial basic helix-loop-helix PAS domain transcription factor, hypoxia-inducible factor-2alpha (HIF-2alpha) (but not its close relative HIF-1alpha), cooperates with Ets-1 in activating transcription of the vascular endothelial growth factor receptor-2 (VEGF-2) gene (Flk-1). The receptor tyrosine kinase Flk-1 is indispensable for angiogenesis, and its expression is closely regulated during development. Consistent with the hypothesis that HIF-2alpha controls the expression of Flk-1 in vivo, we show here that HIF-2alpha and Flk-1 are co-regulated in postnatal mouse brain capillaries. A tandem HIF-2alpha/Ets binding site was identified within the Flk-1 promoter that acted as a strong enhancer element. Based on the analysis of transgenic mouse embryos, these motifs are essential for endothelial cell-specific reporter gene expression. A single HIF-2alpha/Ets element conferred strong cooperative induction by HIF-2alpha and Ets-1 when fused to a heterologous promoter and was most active in endothelial cells. The physical interaction of HIF-2alpha with Ets-1 was demonstrated and localized to the HIF-2alpha carboxyl terminus and the autoinhibitory exon VII domain of Ets-1, respectively. The deletion of the DNA binding and carboxyl-terminal transactivation domains of HIF-2alpha, respectively, created dominant negative mutants that suppressed transactivation by the wild type protein and failed to synergize with Ets-1. These results suggest that the interaction between HIF-2alpha and endothelial Ets factors is required for the full transcriptional activation of Flk-1 in endothelial cells and may therefore represent a future target for the manipulation of angiogenesis.
Links	PubMed Online version:10.1074/jbc.M211298200
Keywords	Age Factors; Amino Acid Motifs; Animals; Basic Helix-Loop-Helix Transcription Factors; Binding Sites; Blotting, Western; Cell Differentiation; Cell Division; Cell Line; Cell Nucleus/metabolism; Dose-Response Relationship, Drug; Embryo, Mammalian/metabolism; Endothelium/cytology; Endothelium/metabolism; Exons; Gene Deletion; Gene Expression Regulation, Developmental; Genes, Reporter; Genetic Vectors; Glutathione Transferase/metabolism; Humans; Immunohistochemistry; In Situ Hybridization; Luciferases/metabolism; Mice; Mice, Transgenic; Mutagenesis, Site-Directed; Neovascularization, Pathologic; Plasmids/metabolism; Promoter Regions, Genetic; Protein Binding; Protein Biosynthesis; Protein Structure, Tertiary; Proto-Oncogene Protein c-ets-1; Proto-Oncogene Proteins/chemistry; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-ets; RNA, Messenger/metabolism; Recombinant Fusion Proteins/metabolism; Time Factors; Trans-Activators/chemistry; Trans-Activators/metabolism; Transcription Factors/chemistry; Transcription Factors/metabolism; Transfection; Transgenes; Vascular Endothelial Growth Factor Receptor-2/genetics; Vascular Endothelial Growth Factor Receptor-2/metabolism
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