TSPYL5 suppresses p53 levels and function by physical interaction with USP7
TSPYL5 suppresses p53 levels and function by physical interaction with USP7
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DOI：
10.1038/ncb2142
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发表时间：
2011-01-01
影响因子：
21.3
通讯作者：
Bernards, Rene
中科院分区：
文献类型：
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作者：
Epping, Mirjam T.;Meijer, Lars A. T.;Bernards, Rene
我们之前曾报道过一种基因表达特征，它是乳腺癌临床预后不良的有力预测因子(1)。在这个表达谱中的70个基因中，有一个功能未知的基因：TSPYL5 （TSPY-like 5，也称为KIAA1750）。TSPYL5位于染色体8q22的一个小区域内，该区域在乳腺癌中经常被扩增，这表明TSPYL5在乳腺癌发生中具有因果作用（2,3）。在这里，我们报告高TSPYL5表达是乳腺癌预后不良的独立标志物。质谱分析显示，TSPYL5与泛素特异性蛋白酶7 （USP7，也称为疱疹病毒相关泛素特异性蛋白酶；HAUSP）相互作用。USP7是p53肿瘤抑制因子的去泛素化酶(4)，TSPYL5降低USP7对p53的活性，导致p53泛素化增加。我们证明TSPYL5降低p53蛋白水平并抑制p53靶基因的激活。此外，TSPYL5的表达覆盖了p53依赖的增殖抑制和癌基因诱导的衰老，并在多种基于细胞的实验中促进了致癌转化。我们的数据表明，通过与USP7的相互作用，TSPYL5是p53功能的抑制因子。
We have previously reported a gene expression signature that is a powerful predictor of poor clinical outcome in breast cancer(1). Among the seventy genes in this expression profile is a gene of unknown function: TSPYL5 (TSPY-like 5, also known as KIAA1750). TSPYL5 is located within a small region at chromosome 8q22 that is frequently amplified in breast cancer, which suggests that TSPYL5 has a causal role in breast oncogenesis(2,3). Here, we report that high TSPYL5 expression is an independent marker of poor outcome in breast cancer. Mass spectrometric analysis revealed that TSPYL5 interacts with ubiquitin-specific protease 7 (USP7; also known as herpesvirus-associated ubiquitin-specific protease; HAUSP). USP7 is the deubiquitylase for the p53 tumour suppressor(4) and TSPYL5 reduces the activity of USP7 towards p53, resulting in increased p53 ubiquitylation. We demonstrate that TSPYL5 reduces p53 protein levels and inhibits activation of p53-target genes. Furthermore, expression of TSPYL5 overrides p53-dependent proliferation arrest and oncogene-induced senescence, and contributes to oncogenic transformation in multiple cell-based assays. Our data identify TSPYL5 as a suppressor of p53 function through its interaction with USP7.