USP10 Regulates p53 Localization and Stability by Deubiquitinating p53

• Published in: Cell Vol. 140; no. 3; pp. 384 - 396
• Main Authors: Yuan, Jian, Luo, Kuntian, Zhang, Lizhi, Cheville, John C., Lou, Zhenkun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.02.2010
• Subjects: Active Transport, Cell Nucleus; Ataxia Telangiectasia Mutated Proteins; Carcinoma, Renal Cell - metabolism; Cell Cycle Proteins - metabolism; Cell Line; DNA Repair; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; HUMDISEASE; Kidney Neoplasms - metabolism; Protein Stability; Protein-Serine-Threonine Kinases - metabolism; PROTEINS; SIGNALING; Tumor Suppressor Protein p53 - analysis; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism; Ubiquitin Thiolesterase - metabolism; Ubiquitination; PROTEINS; HUMDISEASE; SIGNALING
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2009.12.032

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. [Display omitted] ► USP10 is a deubiquitinase specific for p53 and counteracts Mdm2 ► Upon DNA damage, USP10 translocates to the nucleus and stabilizes p53 ► USP10 translocation requires ATM-mediated phosphorylation ► USP10 acts as a tumor suppressor in cells with wild-type p53