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USP10 regulates p53 localization and stability by deubiquitinating p53.

Cell | Feb 5, 2010

http://www.ncbi.nlm.nih.gov/pubmed/20096447

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.

Pubmed ID: 20096447 RIS Download

Mesh terms: Active Transport, Cell Nucleus | Ataxia Telangiectasia Mutated Proteins | Carcinoma, Renal Cell | Cell Cycle Proteins | Cell Line | DNA Repair | DNA-Binding Proteins | Gene Expression Regulation, Neoplastic | HCT116 Cells | Humans | Kidney Neoplasms | Protein Stability | Protein-Serine-Threonine Kinases | Tumor Suppressor Protein p53 | Tumor Suppressor Proteins | Ubiquitin Thiolesterase | Ubiquitination

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Associated grants

  • Agency: NCI NIH HHS, Id: CA130996
  • Agency: NCI NIH HHS, Id: R01 CA130996
  • Agency: NCI NIH HHS, Id: R01 CA130996-02
  • Agency: NCI NIH HHS, Id: R01 CA148940

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