Abstract
Transforming growth factor-beta (TGF-beta) increases expression of endothelial nitric oxide synthase (eNOS), although the precise mechanism by which it does so is unclear. We report that Smad2, a transcription factor activated by TGF-beta, mediates TGF-beta induction of eNOS in endothelial cells. TGF-beta induces Smad2 translocation from cytoplasm to nucleus, where it directly interacts with a specific region of the eNOS promoter. Overexpression of Smad2 increases basal levels of eNOS, and further increases TGF-beta stimulation of eNOS expression. Ectopic expression of Smurf, an antagonizer of Smad2, decreases Smad2 expression and blocks TGF-beta induction of eNOS. Because Smad2 can interact with a variety of transcription factors, coactivators, and corepressors, Smad2 may thus act as an integrator of multiple signals in the regulation of eNOS expression.
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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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / physiology
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Animals
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Cattle
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism*
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / physiology
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Humans
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Ligases / biosynthesis
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Ligases / genetics
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Ligases / pharmacology
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Nitric Oxide Synthase / biosynthesis*
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type III
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / physiology
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Protein Binding / drug effects
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RNA, Messenger / metabolism
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Signal Transduction / physiology
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Smad2 Protein
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcriptional Activation / drug effects
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Transcriptional Activation / physiology
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Transfection
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / pharmacology*
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Ubiquitin-Protein Ligases
Substances
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DNA-Binding Proteins
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RNA, Messenger
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SMAD2 protein, human
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Smad2 Protein
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Trans-Activators
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Transforming Growth Factor beta
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NOS3 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type III
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Ubiquitin-Protein Ligases
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Ligases