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.
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
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Dou
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Lee
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Liu
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Liu
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Massague
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Xuan
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Lai
D028341:Activins; D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors; D015151:Immunoblotting; D007265:Inhibins / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008907:Mink; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001616:beta-Galactosidase / Q000378:metabolism
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C489562:Foxd1 protein, mouse; C491117:Foxh1 protein, mouse; D009419:Nerve Tissue Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D028341:Activins; D007265:Inhibins; D008156:Luciferases; D001616:beta-Galactosidase