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首页> 美国卫生研究院文献>Molecular and Cellular Biology >Nuclear Factor YY1 Inhibits Transforming Growth Factor β- and Bone Morphogenetic Protein-Induced Cell Differentiation
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Nuclear Factor YY1 Inhibits Transforming Growth Factor β- and Bone Morphogenetic Protein-Induced Cell Differentiation

机译：核因子YY1抑制转化生长因子β-和骨形态发生蛋白诱导的细胞分化

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摘要

Smad proteins transduce transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signals that regulate cell growth and differentiation. We have identified YY1, a transcription factor that positively or negatively regulates transcription of many genes, as a novel Smad-interacting protein. YY1 represses the induction of immediate-early genes to TGF-β and BMP, such as the plasminogen activator inhibitor 1 gene (PAI-1) and the inhibitor of differentiation/inhibitor of DNA binding 1 gene (Id-1). YY1 inhibits binding of Smads to their cognate DNA elements in vitro and blocks Smad recruitment to the Smad-binding element-rich region of the PAI-1 promoter in vivo. YY1 interacts with the conserved N-terminal Mad homology 1 domain of Smad4 and to a lesser extent with Smad1, Smad2, and Smad3. The YY1 zinc finger domain mediates the association with Smads and is necessary for the repressive effect of YY1 on Smad transcriptional activity. Moreover, downregulation of endogenous YY1 by antisense and small interfering RNA strategies results in enhanced transcriptional responses to TGF-β or BMP. Ectopic expression of YY1 inhibits, while knockdown of endogenous YY1 enhances, TGF-β- and BMP-induced cell differentiation. In contrast, overexpression or knockdown of YY1 does not affect growth inhibition induced by TGF-β or BMP. Accordingly, YY1 does not interfere with the regulation of immediate-early genes involved in the TGF-β growth-inhibitory response, the cell cycle inhibitors p15 and p21, and the proto-oncogene c-myc. In conclusion, YY1 represses Smad transcriptional activities in a gene-specific manner and thus regulates cell differentiation induced by TGF-β superfamily pathways.
机译：Smad蛋白转导调节细胞生长和分化的转化生长因子β（TGF-β）和骨形态发生蛋白（BMP）信号。我们已经确定，YY1是一种正向或负向调节许多基因转录的转录因子，是一种新型的Smad相互作用蛋白。 YY1抑制了对TGF-β和BMP的早期基因的诱导，例如纤溶酶原激活物抑制剂1基因（PAI-1）和DNA结合1基因的分化/抑制剂（Id-1）。 YY1在体外抑制Smads与其同源DNA元素的结合，并在体内阻止Smad募集到PAI-1启动子的Smad结合元素丰富的区域。 YY1与Smad4的保守N末端Mad同源1域相互作用，并在较小程度上与Smad1，Smad2和Smad3相互作用。 YY1锌指结构域介导与Smads的缔合，并且是YY1对Smad转录活性的抑制作用所必需的。此外，内源性YY1通过反义和小的干扰RNA策略下调导致对TGF-β或BMP的转录反应增强。 YY1的异位表达受到抑制，而内源性YY1的敲低则增强了TGF-β-和BMP诱导的细胞分化。相反，YY1的过表达或敲低并不影响TGF-β或BMP诱导的生长抑制。因此，YY1不干扰涉及TGF-β生长抑制反应的即早基因，细胞周期抑制剂p15和p21以及原癌基因c-myc的调节。总之，YY1以基因特异性方式抑制Smad转录活性，从而调节TGF-β超家族途径诱导的细胞分化。

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