Abstract
The angiogenic effects of vascular endothelial growth factor are mediated predominantly by the FLK-1/KDR receptor. An understanding of the transcriptional control mechanisms underlying flk-1/KDR expression should provide insight into the molecular basis of angiogenesis. In this study, we show that transforming growth factor-beta(1) (TGF-beta(1)) down-regulates expression of the endogenous flk-1/KDR gene in endothelial cells. In transient transfection assays, this effect was mapped to a palindromic GATA site in the 5'-untranslated region. In electrophoretic mobility shift assays, the palindromic GATA site was shown to bind to two molecules of GATA protein. Moreover, DNA-GATA interactions were inhibited by TGF-beta(1). Finally, in cotransfection assays, transactivation of the flk-1/KDR promoter by GATA-1 or GATA-2 was attenuated in TGF-beta(1)-treated cells. Taken together, these results suggest that the TGF-beta-1-mediated inhibition of the flk-1/KDR gene is mediated by a 5'-untranslated region palindromic GATA site.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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5' Untranslated Regions
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Animals
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Cattle
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Cell Line
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Cells, Cultured
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Consensus Sequence
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DNA / metabolism
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DNA Footprinting
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DNA-Binding Proteins / metabolism*
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Down-Regulation
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism*
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GATA2 Transcription Factor
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Humans
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Promoter Regions, Genetic
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RNA, Messenger / metabolism
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Receptor Protein-Tyrosine Kinases / genetics*
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Receptors, Growth Factor / genetics*
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Receptors, Vascular Endothelial Growth Factor
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Transcription Factors / metabolism*
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Transcriptional Activation / drug effects
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta1
Substances
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5' Untranslated Regions
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DNA-Binding Proteins
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GATA2 Transcription Factor
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GATA2 protein, human
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RNA, Messenger
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Receptors, Growth Factor
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TGFB1 protein, human
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Transcription Factors
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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DNA
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor