Abstract
Smooth muscle cells switch between differentiated and proliferative phenotypes in response to extracellular cues, but the transcriptional mechanisms that confer such phenotypic plasticity remain unclear. Serum response factor (SRF) activates genes involved in smooth muscle differentiation and proliferation by recruiting muscle-restricted cofactors, such as the transcriptional coactivator myocardin, and ternary complex factors (TCFs) of the ETS-domain family, respectively. Here we show that growth signals repress smooth muscle genes by triggering the displacement of myocardin from SRF by Elk-1, a TCF that acts as a myogenic repressor. The opposing influences of myocardin and Elk-1 on smooth muscle gene expression are mediated by structurally related SRF-binding motifs that compete for a common docking site on SRF. A mutant smooth muscle promoter, retaining responsiveness to myocardin and SRF but defective in TCF binding, directs ectopic transcription in the embryonic heart, demonstrating a role for TCFs in suppression of smooth muscle gene expression in vivo. We conclude that growth and developmental signals modulate smooth muscle gene expression by regulating the association of SRF with antagonistic cofactors.
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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Amino Acid Sequence
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Animals
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Base Sequence
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Binding, Competitive
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Cell Line
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DNA-Binding Proteins*
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Gene Expression Regulation* / drug effects
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Macromolecular Substances
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Muscle, Smooth / drug effects
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Muscle, Smooth / metabolism*
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Mutation
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Myocardium / metabolism
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphorylation / drug effects
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Platelet-Derived Growth Factor / pharmacology
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Rats
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Repressor Proteins / chemistry
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Response Elements / genetics
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Serum Response Factor / antagonists & inhibitors
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Serum Response Factor / metabolism*
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Trans-Activators / chemistry
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors*
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Transgenes / genetics
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ets-Domain Protein Elk-1
Substances
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DNA-Binding Proteins
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Elk1 protein, mouse
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Elk1 protein, rat
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Macromolecular Substances
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Nuclear Proteins
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins
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Repressor Proteins
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Serum Response Factor
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Trans-Activators
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Transcription Factors
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ets-Domain Protein Elk-1
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myocardin