BF-1 interferes with transforming growth factor beta signaling by associating with Smad partners.
The winged-helix (WH) BF-1 gene, which encodes brain factor 1 (BF-1) (also known as foxg1), is essential for the proliferation of the progenitor cells of the cerebral cortex. Here we show that BF-1-deficient telencephalic progenitor cells are more apt to leave the cell cycle in response to transforming growth factor ... beta (TGF-beta) and activin. We found that ectopic expression of BF-1 in vitro inhibits TGF-beta mediated growth inhibition and transcriptional activation. Surprisingly, we found that the ability of BF-1 to function as a TGF-beta antagonist does not require its DNA binding activity. Therefore, we investigated whether BF-1 can inhibit Smad-dependent transcriptional responses by interacting with Smads or Smad binding partners. We found that BF-1 does not interact with Smads. Because the identities of the Smad partners mediating growth inhibition by TGF-beta are not clearly established, we examined a model reporter system which is known to be activated by activin and TGF-beta through Smads and the WH factor FAST-2. We demonstrate that BF-1 associates with FAST-2. This interaction is dependent on the same region of protein which mediates its ability to interfere with the antiproliferative activity of TGF-beta and with TGF-beta-dependent transcriptional activation. Furthermore, the interaction of FAST-2 with BF-1 is mediated by the same domain which is required for FAST-2 to interact with Smad2. We propose a model in which BF-1 interferes with transcriptional responses to TGF-beta by interacting with FAST-2 or with other DNA binding proteins which function as Smad2 partners and which have a common mode of interaction with Smad2.
Mesh Terms:
Activins, Animals, COS Cells, Cell Division, Cell Line, DNA-Binding Proteins, Dose-Response Relationship, Drug, Forkhead Transcription Factors, Immunoblotting, Inhibins, Luciferases, Mice, Mice, Inbred C57BL, Mink, Models, Biological, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Smad2 Protein, Trans-Activators, Transcription Factors, Transcriptional Activation, Transforming Growth Factor beta, beta-Galactosidase
Activins, Animals, COS Cells, Cell Division, Cell Line, DNA-Binding Proteins, Dose-Response Relationship, Drug, Forkhead Transcription Factors, Immunoblotting, Inhibins, Luciferases, Mice, Mice, Inbred C57BL, Mink, Models, Biological, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Smad2 Protein, Trans-Activators, Transcription Factors, Transcriptional Activation, Transforming Growth Factor beta, beta-Galactosidase
Mol. Cell. Biol.
Date: Sep. 01, 2000
PubMed ID: 10938097
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