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首页> 外文期刊>Molecular and Cellular Biology >Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II
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Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II

机译：p53突变体通过抑制II型TGF-β受体的表达来减弱SMAD依赖性转化生长因子β1（TGF-β1）的信号通路

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Both transforming growth factor beta (TGF-β) and p53 have been shown to control normal cell growth. Acquired mutations either in the TGF-β signaling pathway or in the p53 protein were shown to induce malignant transformation. Recently, cross talk between wild-type p53 and the TGF-β pathway was observed. The notion that mutant p53 interferes with the wild-type p53-induced pathway and acts by a “gain-of-function” mechanism prompted us to investigate the effect of mutant p53 on the TGF-β-induced pathway. In this study, we show that cells expressing mutant p53 lost their sensitivity to TGF-β1, as observed by less cell migration and a reduction in wound healing. We found that mutant p53 attenuates TGF-β1 signaling. This was exhibited by a reduction in SMAD2/3 phosphorylation and an inhibition of both the formation of SMAD2/SMAD4 complexes and the translocation of SMAD4 to the cell nucleus. Furthermore, we found that mutant p53 attenuates the TGF-β1-induced transcription activity of SMAD2/3 proteins. In searching for the mechanism that underlies this attenuation, we found that mutant p53 reduces the expression of TGF-β receptor type II. These data provide important insights into the molecular mechanisms that underlie mutant p53 “gain of function” pertaining to the TGF-β signaling pathway.
机译：转化生长因子β（TGF-β）和p53均显示可控制正常细胞生长。 TGF-β信号通路或p53蛋白中的获得性突变均显示诱导恶性转化。近来，观察到野生型p53和TGF-β途径之间的串扰。突变体p53干扰野生型p53诱导的途径并通过“功能获得”机制起作用的观念促使我们研究突变体p53对TGF-β诱导的途径的影响。在这项研究中，我们发现表达突变型p53的细胞丧失了对TGF-β1的敏感性，这是通过较少的细胞迁移和伤口愈合减少所观察到的。我们发现突变体p53减弱了TGF-β1信号传导。这通过减少SMAD2 / 3的磷酸化和抑制SMAD2 / SMAD4复合物的形成以及SMAD4向细胞核的转运来表现。此外，我们发现突变体p53减弱了TGF-β1诱导的SMAD2 / 3蛋白的转录活性。在寻找引起这种衰减的机制时，我们发现突变体p53降低了II型TGF-β受体的表达。这些数据提供了对与TGF-β信号通路有关的突变体p53“功能获得”基础的分子机制的重要见解。

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