TY - JOUR
T1 - USP10 Regulates p53 Localization and Stability by Deubiquitinating p53
AU - Yuan, Jian
AU - Luo, Kuntian
AU - Zhang, Lizhi
AU - Cheville, John C.
AU - Lou, Zhenkun
N1 - Funding Information:
We thank Bert Vogelstein (Johns Hopkins University), Thomas Roberts (Dana-Farber Cancer Institute and Harvard Medical School), Peter Howley (National Cancer Institute), and Tyler Jacks (MIT Center for Cancer Research) for providing reagents used in this study. This work was supported in part by grants from the Richard Schulze Family Foundation and Research Grant and the National Institutes of Health (CA130996).
PY - 2010/2/5
Y1 - 2010/2/5
N2 - 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.
AB - 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.
KW - HUMDISEASE
KW - PROTEINS
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=75749132016&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=75749132016&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2009.12.032
DO - 10.1016/j.cell.2009.12.032
M3 - Article
C2 - 20096447
AN - SCOPUS:75749132016
SN - 0092-8674
VL - 140
SP - 384
EP - 396
JO - Cell
JF - Cell
IS - 3
ER -