USP10 Regulates p53 Localization and Stability by Deubiquitinating p53

By Jian Yuan, K. Luo, Lizhi Zhang, John C. Cheville, Zhenkun Lou. Cell, 2010

603 citations recorded by the source corpus.

Summary p53 stability and localization 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. Following 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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/7b61a6213fb41b340fb837b0c7eaaf85bb537dcf

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In Molecular Biology

1. D. Komander
2. M. Rapé
3. Wenyi Wei
4. Lei Chen
5. T. Meng
6. Junying Yuan
7. Ping Wang
8. Lu Deng

In Oncology

1. M. Rapé
2. D. Komander
3. Junying Yuan

Citations in the corpus

• The ubiquitin code. (2012, background): “Given the importance of E2s in determining know about physiological E2-E3 pairs.”
• Beclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13 (2011, methodology): “Regulation of p53 via Vps34 Complexes and Deubiquitination Since USP10 is known as a deubiquitinating protease of p53 (Yuan et al., 2010), inhibition of USP10 by spautin-1 may promote the degradation of p53.”
• The role of ubiquitination in tumorigenesis and targeted drug discovery (2020, background): “2c).(122) In addition to ubiquitination, p53 can also undergo other ubiquitination-like modifications, such as neddylation and SUMOylation.”