Abstract
Transforming growth factor-beta (TGF-beta) is the prototypical member of a family of growth factors that play important roles in normal development and human diseases. We identified the gene for fibroblast growth factor-binding protein 1 (FGF-BP1) as being significantly repressed following TGF-beta treatment. FGF-BP1 is an extracellular matrix bound protein that enhances fibroblast growth factor (FGF) signaling. We demonstrate here that TGF-beta signaling significantly represses FGF-BP1 expression in mesenchymal and neural crest cells undergoing in vitro smooth muscle differentiation. Analysis of the downstream signaling pathways shows that Smad2/3 are crucial for efficient FGF-BP1 repression by TGF-beta. Furthermore, we identified a novel element in the region from -785 to -782 bp of the FGF-BP1 promoter, which represents a known binding site for Hypermethylation in Cancer-1 (Hic-1), necessary for repression of FGF-BP1 by TGF-beta. These data define the molecular mechanism of transcriptional repression of an important target of TGF-beta signaling during angiogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Binding Sites
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Cell Differentiation
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DNA Methylation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Extracellular Matrix Proteins / physiology*
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / metabolism
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Gene Silencing / physiology*
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Humans
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Kruppel-Like Transcription Factors
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Muscle, Smooth / cytology
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Muscle, Smooth / metabolism
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Promoter Regions, Genetic / physiology*
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Receptor, Fibroblast Growth Factor, Type 1 / genetics
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Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
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Smad2 Protein / genetics
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Smad2 Protein / metabolism
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transforming Growth Factor beta / physiology*
Substances
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DNA-Binding Proteins
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Extracellular Matrix Proteins
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HIC1 protein, human
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Kruppel-Like Transcription Factors
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Smad2 Protein
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Smad3 Protein
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Transcription Factors
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Transforming Growth Factor beta
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betaIG-H3 protein
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Fibroblast Growth Factors
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Receptor, Fibroblast Growth Factor, Type 1