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Molecular and Cellular Biology, September 2000, p. 6201-6211, Vol. 20, No. 17
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

BF-1 Interferes with Transforming Growth Factor beta  Signaling by Associating with Smad Partners

Changlin Dou,1 Jun Lee,1 Bo Liu,1 Fang Liu,1,dagger Joan Massague,1,2 Shouhong Xuan,1,Dagger and Eseng Lai1,*

Cell Biology Program, Memorial Sloan-Kettering Cancer Center,1 and Howard Hughes Medical Institute,2 New York, New York 10021

Received 24 January 2000/Returned for modification 10 March 2000/Accepted 30 May 2000

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.

* Corresponding author. Mailing address: Box 83, 1275 York Ave., New York, NY 10021. Phone: (212) 639-2556. Fax: (212) 717-3053. E-mail: e-lai{at}ski.mskcc.org.

dagger Present address: Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854.

Dagger Present address: Columbia University, New York, NY 10016.

Molecular and Cellular Biology, September 2000, p. 6201-6211, Vol. 20, No. 17
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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