Dou C, Lee J, Liu B, Liu F, Massague J, Xuan S, Lai E
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Mol Cell Biol. 2000 Sep;20(17):6201-11. doi: 10.1128/MCB.20.17.6201-6211.2000.
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.
翼状螺旋（WH）BF-1基因编码脑因子1（BF-1）（也称为foxg1），对大脑皮质祖细胞的增殖至关重要。在此我们表明，缺乏BF-1的端脑祖细胞更易于响应转化生长因子β（TGF-β）和激活素而离开细胞周期。我们发现在体外BF-1的异位表达抑制TGF-β介导的生长抑制和转录激活。令人惊讶的是，我们发现BF-1作为TGF-β拮抗剂发挥作用的能力并不需要其DNA结合活性。因此，我们研究了BF-1是否可通过与Smads或Smad结合伴侣相互作用来抑制Smad依赖的转录反应。我们发现BF-1不与Smads相互作用。由于介导TGF-β生长抑制作用的Smad伴侣的身份尚未明确确定，我们检测了一种模型报告系统，已知该系统可通过Smads和WH因子FAST-2被激活素和TGF-β激活。我们证明BF-1与FAST-2相关联。这种相互作用依赖于蛋白质的同一区域，该区域介导其干扰TGF-β抗增殖活性以及TGF-β依赖的转录激活的能力。此外，FAST-2与BF-1的相互作用由FAST-2与Smad2相互作用所需的同一结构域介导。我们提出了一个模型，其中BF-1通过与FAST-2或与其他作为Smad2伴侣并与Smad2具有共同相互作用模式的DNA结合蛋白相互作用来干扰对TGF-β的转录反应。
