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. (c) 2006 Elsevier Inc. All rights reserved.