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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2003-2-24
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Basic Helix-Loop-Helix...,
http://linkedlifedata.com/resource/pubmed/chemical/ETS1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Ets1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione Transferase,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Protein c-ets-1,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-ets,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factor...,
http://linkedlifedata.com/resource/pubmed/chemical/endothelial PAS domain-containing...
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0021-9258
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pubmed:author |
pubmed-author:BreierGeorgG,
pubmed-author:CookeJ TJT,
pubmed-author:ElvertGerdG,
pubmed-author:EnglmeierUrsulaU,
pubmed-author:FlammeIngoI,
pubmed-author:HeidenreichReginaR,
pubmed-author:KappelAndreasA,
pubmed-author:LanzStephanS,
pubmed-author:PlateKarlK,
pubmed-author:RauterManuelM,
pubmed-author:SiewekeMichaelM
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pubmed:issnType |
Print
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pubmed:day |
28
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
7520-30
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12464608-Age Factors,
pubmed-meshheading:12464608-Amino Acid Motifs,
pubmed-meshheading:12464608-Animals,
pubmed-meshheading:12464608-Basic Helix-Loop-Helix Transcription Factors,
pubmed-meshheading:12464608-Binding Sites,
pubmed-meshheading:12464608-Blotting, Western,
pubmed-meshheading:12464608-Cell Differentiation,
pubmed-meshheading:12464608-Cell Division,
pubmed-meshheading:12464608-Cell Line,
pubmed-meshheading:12464608-Cell Nucleus,
pubmed-meshheading:12464608-Dose-Response Relationship, Drug,
pubmed-meshheading:12464608-Embryo, Mammalian,
pubmed-meshheading:12464608-Endothelium,
pubmed-meshheading:12464608-Exons,
pubmed-meshheading:12464608-Gene Deletion,
pubmed-meshheading:12464608-Gene Expression Regulation, Developmental,
pubmed-meshheading:12464608-Genes, Reporter,
pubmed-meshheading:12464608-Genetic Vectors,
pubmed-meshheading:12464608-Glutathione Transferase,
pubmed-meshheading:12464608-Humans,
pubmed-meshheading:12464608-Immunohistochemistry,
pubmed-meshheading:12464608-In Situ Hybridization,
pubmed-meshheading:12464608-Luciferases,
pubmed-meshheading:12464608-Mice,
pubmed-meshheading:12464608-Mice, Transgenic,
pubmed-meshheading:12464608-Mutagenesis, Site-Directed,
pubmed-meshheading:12464608-Neovascularization, Pathologic,
pubmed-meshheading:12464608-Plasmids,
pubmed-meshheading:12464608-Promoter Regions, Genetic,
pubmed-meshheading:12464608-Protein Binding,
pubmed-meshheading:12464608-Protein Biosynthesis,
pubmed-meshheading:12464608-Protein Structure, Tertiary,
pubmed-meshheading:12464608-Proto-Oncogene Protein c-ets-1,
pubmed-meshheading:12464608-Proto-Oncogene Proteins,
pubmed-meshheading:12464608-Proto-Oncogene Proteins c-ets,
pubmed-meshheading:12464608-RNA, Messenger,
pubmed-meshheading:12464608-Recombinant Fusion Proteins,
pubmed-meshheading:12464608-Time Factors,
pubmed-meshheading:12464608-Trans-Activators,
pubmed-meshheading:12464608-Transcription Factors,
pubmed-meshheading:12464608-Transfection,
pubmed-meshheading:12464608-Transgenes,
pubmed-meshheading:12464608-Vascular Endothelial Growth Factor Receptor-2
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pubmed:year |
2003
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pubmed:articleTitle |
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).
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pubmed:affiliation |
Zentrum für Molekulare Medizin der Universität zu Köln, Joseph-Stelzmann-Strasse 9, 50931 Köln, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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