Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Cell. 2010 Feb 5;140(3):384-96. doi: 10.1016/j.cell.2009.12.032. Epub 2010 Jan 21.
Stability and localization of p53 is essential for its tumor suppressor function. Ubiquitination by the E3 ubiquitin ligase Mdm2 is the major regulatory mechanism of p53, which induces p53 nuclear export and degradation. However, it is unclear whether ubiquitinated cytoplasmic p53 can be recycled. Here, we report that USP10, a cytoplasmic ubiquitin-specific protease, deubiquitinates p53, reversing Mdm2-induced p53 nuclear export and degradation. After DNA damage, USP10 is stabilized, and a fraction of USP10 translocates to the nucleus to activate p53. The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337. Finally, USP10 suppresses tumor cell growth in cells with wild-type p53, with USP10 expression downregulated in a high percentage of clear cell carcinomas, known to have few p53 mutations. These findings reveal USP10 to be a novel regulator of p53, providing an alternative mechanism of p53 inhibition in cancers with wild-type p53.
p53 的稳定性和定位对于其肿瘤抑制功能至关重要。E3 泛素连接酶 Mdm2 对 p53 的泛素化是其主要的调节机制，可诱导 p53 的核输出和降解。然而，尚不清楚是否可使泛素化的细胞质 p53 循环利用。本文报道了一种细胞质泛素特异性蛋白酶 USP10，它可使 p53 去泛素化，逆转 Mdm2 诱导的 p53 核输出和降解。在 DNA 损伤后，USP10 稳定，一部分 USP10 易位到细胞核以激活 p53。USP10 的易位和稳定受 ATM 介导的 USP10 的 Thr42 和 Ser337 磷酸化调节。最后，USP10 抑制具有野生型 p53 的肿瘤细胞生长，在已知 p53 突变较少的透明细胞癌中，USP10 的表达有很大比例下调。这些发现揭示了 USP10 是 p53 的一种新型调节剂，为具有野生型 p53 的癌症中 p53 抑制提供了一种替代机制。
