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

机译：BF-1通过与Smad Partners关联干扰转化生长因子β信号传导

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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 β (TGF-β) and activin. We found that ectopic expression of BF-1 in vitro inhibits TGF-β mediated growth inhibition and transcriptional activation. Surprisingly, we found that the ability of BF-1 to function as a TGF-β 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-β are not clearly established, we examined a model reporter system which is known to be activated by activin and TGF-β 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-β and with TGF-β-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-β 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.
机译：翼状螺旋（WH）BF-1基因编码脑因子1（BF-1）（也称为foxg1），对于大脑皮质祖细胞的增殖至关重要。在这里，我们表明缺乏BF-1的端脑祖细胞更容易离开细胞周期，以响应转化生长因子β（TGF-β）和激活素。我们发现BF-1的异位表达在体外抑制TGF-β介导的生长抑制和转录激活。出人意料的是，我们发现BF-1充当TGF-β拮抗剂的能力不需要其DNA结合活性。因此，我们调查了BF-1是否可以通过与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。由于尚未明确确定介导TGF-β抑制生长的Smad伴侣的身份，因此我们检查了一个模型报告系统，该系统已知通过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。这种相互作用取决于蛋白质的同一区域，该区域介导其干扰TGF-β的抗增殖活性和TGF-β依赖性转录激活的能力。此外，FAST-2与BF-1的相互作用是由FAST-2与Smad2相互作用所需的同一域介导的。我们提出了一种模型，其中BF-1通过与FAST-2或与其他具有Smad2伴侣功能并与Smad2相互作用的DNA结合蛋白相互作用来干扰对TGF-β的转录反应。

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