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首页> 外文期刊>Molecular and Cellular Biology >Chromatin-Bound p53 Anchors Activated Smads and the mSin3A Corepressor To Confer Transforming Growth Factor β-Mediated Transcription Repression
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Chromatin-Bound p53 Anchors Activated Smads and the mSin3A Corepressor To Confer Transforming Growth Factor β-Mediated Transcription Repression

机译：染色质结合的p53锚激活的Smads和mSin3A的corepressor赋予转化生长因子β介导的转录抑制。

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In hepatic cells, Smad and SnoN proteins converge with p53 to repress transcription of AFP, an oncodevelopmental tumor marker aberrantly reactivated in hepatoma cells. Using p53- and SnoN-depleted hepatoma cell clones, we define a mechanism for repression mediated by this novel transcriptional partnership. We find that p53 anchors activated Smads and the corepressor mSin3A to the AFP distal promoter. Sequential chromatin immunoprecipitation analyses and molecular modeling indicate that p53 and Smad proteins simultaneously occupy overlapping p53 and Smad regulatory elements to establish repression of AFP transcription. In addition to its well-known function in antagonizing transforming growth factor β (TGF-β) responses, we find that SnoN actively participates in AFP repression by positively regulating mSin3A protein levels. We propose that activation of TGF-β signaling restores a dynamic interplay between p53 and TGF-β effectors that cooperate to effectively target mSin3A to tumor marker AFP and reestablish transcription repression.
机译：在肝细胞中，Smad和SnoN蛋白与p53融合以抑制 AFP 的转录，AFP是在肝癌细胞中异常激活的癌变肿瘤标记。使用p53和SnoN耗竭的肝癌细胞克隆，我们定义了一种由这种新型转录伴侣介导的抑制机制。我们发现p53锚激活了Smads和mSin3A到 AFP 远端启动子。顺序染色质免疫沉淀分析和分子建模表明，p53和Smad蛋白同时占据重叠的p53和Smad调控元件，从而建立对 AFP 转录的抑制。除了其在拮抗转化生长因子β（TGF-β）应答中的众所周知的功能外，我们还发现SnoN通过积极调节mSin3A蛋白水平积极参与 AFP 抑制。我们建议激活TGF-β信号恢复p53和TGF-β效应子之间的动态相互作用，这些效应子可以有效地将mSin3A靶向肿瘤标志物 AFP 并重新建立转录抑制。

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