Sadot E, Geiger B, Oren M, Ben-Ze'ev A
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Mol Cell Biol. 2001 Oct;21(20):6768-81. doi: 10.1128/MCB.21.20.6768-6781.2001.
beta-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 beta-catenin in the nucleus, where it activates the transcription of target genes. Abnormal accumulation of beta-catenin is characteristic of various types of cancer and is caused by mutations either in the adenomatous polyposis coli protein, which regulates beta-catenin degradation, or in the beta-catenin molecule itself. Aberrant accumulation of beta-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 beta-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 beta-catenin level was accompanied by inhibition of its transactivation potential. The inhibitory effect of p53 on beta-catenin is apparently mediated by the ubiquitin-proteasome system and requires an active glycogen synthase kinase 3beta (GSK3beta). Mutations in the N terminus of beta-catenin which compromise its degradation by the proteasomes, overexpression of dominant-negative DeltaF-beta-TrCP, or inhibition of GSKbeta activity all rendered beta-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 beta-catenin.
β-连环蛋白是一种细胞质蛋白，它通过将钙黏着蛋白与肌动蛋白细胞骨架结合，参与细胞间黏附连接的组装。此外，它是Wnt信号通路的关键组成部分。该通路的激活会触发β-连环蛋白在细胞核内积累，在细胞核中它会激活靶基因的转录。β-连环蛋白的异常积累是各类癌症的特征，其由调节β-连环蛋白降解的腺瘤性息肉病大肠杆菌蛋白或β-连环蛋白分子本身的突变引起。肿瘤中β-连环蛋白的异常积累通常与p53肿瘤抑制因子的突变失活有关。在此我们表明，通过转染或DNA损伤使野生型p53过表达，可下调人和小鼠细胞中的β-连环蛋白。转录无活性的p53，包括常见的肿瘤相关p53突变体，无法产生这种效果。β-连环蛋白水平的降低伴随着其反式激活潜能的抑制。p53对β-连环蛋白的抑制作用显然是由泛素-蛋白酶体系统介导的，并且需要活性糖原合酶激酶3β（GSK3β）。β-连环蛋白N端的突变会损害其被蛋白酶体降解的能力，显性负性DeltaF-β-TrCP的过表达或GSKβ活性的抑制都会使β-连环蛋白对p53的下调产生抗性。这些发现支持了这样一种观点，即在由β-连环蛋白过度积累驱动的癌症中，野生型p53表达缺失会存在选择性压力。
