Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1
Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1
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DOI：
10.1074/jbc.m414305200
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发表时间：
2005-06-24
影响因子：
4.8
通讯作者：
Derynck, R
中科院分区：
文献类型：
--
作者：
Alliston, T;Ko, TC;Derynck, R
Smad是转化生长因子(TGF)- β、激活素和骨形态发生蛋白（BMP）信号传导的关键效应因子，调节基因表达，并与调节Smad活性的共激活因子和共抑制因子相互作用。辅抑制因子Evi-1通过抑制tgf - β / smad3介导的转录发挥其致癌作用，从而阻断tgf - β诱导的生长停滞。由于Evi-1与高度保守的Smad3的MH2结构域相互作用，我们研究了Evi-1与Smad1和Smad2的物理和功能相互作用，分别是BMP和激活素信号的下游靶点。与Smad3类似，Evi-1通过Smad1和Smad2与受体激活的转录相互作用并抑制其转录。此外，Evi-1抑制BMP/Smad1-和激活素/ smad2介导的内源性爪蟾基因表达，提示Evi-1抑制BMP和激活素信号在脊椎动物胚胎发生中的作用。Evi-1还抑制tgf - β家族配体诱导内源性Smad7表达。在这些研究过程中，我们观察到即使Smad与DNA的结合保持不变，Evi-1也会抑制Smad的转激活。因此，我们探索了Evi-1抑制tgf - β家族诱导转录的机制。Evi-1的抑制不是由于Smad与DNA或creb结合蛋白结合的位移，而是由于Smad3和creb结合蛋白将Evi-1募集到DNA上。在tgf - β刺激后，Evi-1和相关的辅助抑制因子CtBP被募集到内源性Smad7启动子中。Evi-1在启动子上的募集减少了tgf - β诱导的组蛋白乙酰化，这与它对Smad7基因表达的抑制一致。通过这种方式，Evi-1作为一般的Smad协抑制因子抑制tgf - β、激活素和bmp诱导的转录。
Smads, key effectors of transforming growth factor ( TGF)-beta, activin, and bone morphogenetic protein (BMP) signaling, regulate gene expression and interact with coactivators and corepressors that modulate Smad activity. The corepressor Evi-1 exerts its oncogenic effects by repressing TGF-beta/Smad3-mediated transcription, thereby blocking TGF-beta-induced growth arrest. Because Evi-1 interacts with the highly conserved MH2 domain of Smad3, we investigated the physical and functional interaction of Evi-1 with Smad1 and Smad2, downstream targets of BMP and activin signaling, respectively. Evi-1 interacted with and repressed the receptor-activated transcription through Smad1 and Smad2, similarly to Smad3. In addition, Evi-1 repressed BMP/Smad1- and activin/Smad2-mediated induction of endogenous Xenopus gene expression, suggesting a role of repression of BMP and activin signals by Evi-1 in vertebrate embryogenesis. Evi-1 also repressed the induction of endogenous Smad7 expression by TGF-beta family ligands. In the course of these studies, we observed Evi-1 repression of Smad transactivation even when Smad binding to DNA was kept constant. We therefore explored the mechanism of Evi-1 repression of TGF-beta family-inducible transcription. Evi-1 repression did not result from displacement of Smad binding to DNA or to CREB-binding protein but from the recruitment of Evi-1 by Smad3 and CREB-binding protein to DNA. Following TGF-beta stimulation, Evi-1 and the associated corepressor CtBP were recruited to the endogenous Smad7 promoter. Evi-1 recruitment to the promoter decreased TGF-beta-induced histone acetylation, coincident with its repression of Smad7 gene expression. In this way, Evi-1 acts as a general Smad corepressor to inhibit TGF-beta-, activin-, and BMP-inducible transcription.