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Down-Regulation of β-Catenin by Activated p53

机译：活化的p53对β-catenin的下调

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β-Catenin is a cytoplasmic protein that participates in the assembly of cell-cell adherens junctions by binding cadherins to the actin cytoskeleton. In addition, it is a key component of the Wnt signaling pathway. Activation of this pathway triggers the accumulation of β-catenin in the nucleus, where it activates the transcription of target genes. Abnormal accumulation of β-catenin is characteristic of various types of cancer and is caused by mutations either in the adenomatous polyposis coli protein, which regulates β-catenin degradation, or in the β-catenin molecule itself. Aberrant accumulation of β-catenin in tumors is often associated with mutational inactivation of the p53 tumor suppressor. Here we show that overexpression of wild-type p53, by either transfection or DNA damage, down-regulates β-catenin in human and mouse cells. This effect was not obtained with transcriptionally inactive p53, including a common tumor-associated p53 mutant. The reduction in β-catenin level was accompanied by inhibition of its transactivation potential. The inhibitory effect of p53 on β-catenin is apparently mediated by the ubiquitin-proteasome system and requires an active glycogen synthase kinase 3β (GSK3β). Mutations in the N terminus of β-catenin which compromise its degradation by the proteasomes, overexpression of dominant-negative ΔF-β-TrCP, or inhibition of GSKβ activity all rendered β-catenin resistant to down-regulation by p53. These findings support the notion that there will be a selective pressure for the loss of wild-type p53 expression in cancers that are driven by excessive accumulation of β-catenin.
机译：β-Catenin是一种细胞质蛋白，通过将钙黏着蛋白与肌动蛋白细胞骨架结合而参与细胞间粘附连接的组装。此外，它是Wnt信号通路的关键组成部分。该途径的激活触发β-连环蛋白在细胞核中的积累，并在此激活靶基因的转录。 β-catenin的异常蓄积是各种类型癌症的特征，并且是由调节β-catenin降解的腺瘤性息肉病大肠菌蛋白质或β-catenin分子本身的突变引起的。 β-catenin在肿瘤中的异常积累通常与p53肿瘤抑制因子的突变失活有关。在这里，我们表明通过转染或DNA损伤导致野生型p53的过表达下调人和小鼠细胞中的β-catenin。使用转录失活的p53（包括常见的肿瘤相关性p53突变体）无法获得这种效果。 β-catenin水平的降低伴随着其反式激活潜能的抑制。 p53对β-catenin的抑制作用显然是由泛素-蛋白酶体系统介导的，需要活性糖原合酶激酶3β（GSK3β）。 β-cateninN末端的突变会影响其被蛋白酶体降解，显性负性ΔF-β-TrCP的过表达或GSKβ活性的抑制，这些都使β-catenin抵抗p53的下调。这些发现支持以下观点：由于β-catenin的过度积累，在癌症中野生型p53表达的丧失将受到选择压力。

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