Stevenson Lauren F, Sparks Alison, Allende-Vega Nerea, Xirodimas Dimitris P, Lane David P, Saville Mark K
CR-UK Cell Transformation Research Group, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
EMBO J. 2007 Feb 21;26(4):976-86. doi: 10.1038/sj.emboj.7601567. Epub 2007 Feb 8.
Mdm2 is an E3 ubiquitin ligase that promotes its own ubiquitination and also ubiquitination of the p53 tumour suppressor. In a bacterial two-hybrid screen, using Mdm2 as bait, we identified an Mdm2-interacting peptide that bears sequence similarity to the deubiquitinating enzyme USP2a. We have established that full-length USP2a associates with Mdm2 in cells where it can deubiquitinate Mdm2 while demonstrating no deubiquitinating activity towards p53. Ectopic expression of USP2a causes accumulation of Mdm2 in a dose-dependent manner and consequently promotes Mdm2-mediated p53 degradation. This differs from the behaviour of HAUSP, which deubiquitinates p53 in addition to Mdm2 and thus protects p53 from Mdm2-mediated degradation. We further demonstrate that suppression of endogenous USP2a destabilises Mdm2 and causes accumulation of p53 protein and activation of p53. Our data identify the deubiquitinating enzyme USP2a as a novel regulator of the p53 pathway that acts through its ability to selectively target Mdm2.
Mdm2是一种E3泛素连接酶，它能促进自身的泛素化以及肿瘤抑制因子p53的泛素化。在一项细菌双杂交筛选中，我们以Mdm2为诱饵，鉴定出了一个与去泛素化酶USP2a具有序列相似性的Mdm2相互作用肽段。我们已经证实，全长USP2a在细胞中与Mdm2结合，它能够使Mdm2去泛素化，而对p53没有去泛素化活性。USP2a的异位表达会以剂量依赖的方式导致Mdm积累，从而促进Mdm2介导的p53降解。这与HAUSP的行为不同，HAUSP除了能使Mdm2去泛素化外，还能使p53去泛素化，从而保护p53不被Mdm2介导的降解。我们进一步证明，内源性USP2a的抑制会使Mdm2不稳定，导致p53蛋白积累和p53激活。我们的数据表明，去泛素化酶USP2a是p53通路的一种新型调节因子，它通过选择性靶向Mdm2发挥作用。
