Mechanism of fibroblast growth factor-binding protein 1 repression by TGF-beta.
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.
Briones
Victorino R
VR
Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20057, USA.
Chen
Shiyou
S
Riegel
Anna Tate
AT
Lechleider
Robert J
RJ
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000099222:betaIG-H3 Protein
D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D005346:Fibroblast Growth Factors; D051741:Kruppel-Like Transcription Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051899:Smad2 Protein; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C499808:HIC1 protein, human