C. Rodriguez et al., Functional cloning of the proto-oncogene brain factor-1 (BF-1) as a smad-binding antagonist of transforming growth factor-beta signaling, J BIOL CHEM, 276(32), 2001, pp. 30224-30230
Using the plasminogen activator inhibitor (PAI) promoter to drive the expre
ssion of a reporter gene (mouse CD2), we devised a system to clone negative
regulators of the transforming growth factor-beta (TGF-beta) signaling pat
hway. We infected a TGF-beta -responsive cell line (MvLu1) with a retrovira
l cDNA library, selecting by fluorescence-activated cell sorter single cell
s displaying low PAI promoter activity in response to TGF-beta. Using this
strategy we cloned the proto-oncogene brain factor-1 (BF-1). BF-1 represses
the PAI promoter in part by associating with both unphosphorylated Smad3 (
in the cytoplasm) and phosphorylated Smad3 (in the nucleus), thus preventin
g its binding to DNA BF-1 also associates with Smad1, -2, and -4, the Smad
MH2 domain binds to BF-1, and the C-terminal segment of BF-1 is uniquely an
d solely required for binding to Smads. Further, BF-1 represses another TGF
-beta -induced promoter (p15), it upregulates a TGF-beta -repressed promote
r (Cyclin A), and it reverses the growth arrest caused by TGF-beta. Our res
ults suggest that BF-1 is a general inhibitor of TGF-beta signaling and as
such may play a key role during brain development.