p53 is an important tumor suppressor that is mutated in more than 50% of human cancers. A major function of p53 is to activate the expression of its target genes, such as p21 and PUMA in response to cellular stress, thereby regulating cell cycle progression and apoptosis. p53 activity is mainly regulated by posttranslational modifications, such as ubiquitination, sumoylation, phosphorylation, acetylation, and methylation. Among them, Mdm2-induced ubiquitination of p53 induces p53 nuclear export and degradation, which is a major cellular mechanism that regulates p53 activity. However, the process of reversing ubiquitination of p53, i.e. deubiquitination, is not well understood. We have found that the ubiquitin-specific protease USP10 deubiquitinates p53 in vitro and in cells. USP10 is required for the stabilization p53 in both unstressed cells and cells subjected to DNA damage. USP10 predominately localizes in the cytoplasm in unstressed cells. In response to DNA damage, USP10 is stabilized and translocates into the nucleus following DNA damage, and ATM-dependent phosphorylated of USP10 is important for USP10 translocation and stabilization. Furthermore, we found that USP10 suppresses tumor cell growth in cells with wild-type p53, while promoting tumor cell growth in cells with mutant p53. Finally, we found loss of USP10 expression in high percentage of renal cell carcinoma cases. Based on these preliminary results, we hypothesize that USP10 is an important regulator of p53, and USP10 suppresses tumorigenesis through p53. Therefore, it is important to further investigate the regulation of the USP10-p53 pathway in cells and in model systems. We propose the following Specific Aims: 1. Study the regulation of USP10-p53 pathway by Ras and G3BP1. G3BP1 (Ras- GTPase-activating protein SH3-domain-binding protein), a downstream effector of Ras, has previously been shown to inhibit USP10 in vitro. We hypothesize that the Ras-G3BP1 pathway regulates p53 stability through USP10, and will test this hypothesis in this aim. 2. Study the regulation of USP10 by the DNA damage response pathway. USP10 predominately localizes in the cytoplasm of unstressed cells. However, following DNA damage, USP10 translocates to the nucleus and becomes stabilized following DNA damage, which contributes to p53 activation. We have shown that ATM-dependent phosphorylation of USP10 is required for USP10 stabilization and translocation, however the mechanisms underlying these events are not entirely clear. We found that USP10 is also sumoylated in a phosphorylation-dependent manner, suggesting that USP10 sumoylation might be important for USP10 stabilization and translocation. We will study the functional significance and regulation of USP10 sumoylation in this aim. 3. Examine the role of USP10 in tumorigenesis. Since USP10 positively regulates p53, we hypothesize that USP10 functions as a tumor suppressor. Consistent with this hypothesis, USP10 can suppress cancer cell growth in p53-dependent manner and USP10 expression is downregulated in high percentage of renal cell carcinoma samples. We will examine the role of USP10 in tumorigenesis in vivo using USP10 knockout mice as a model system. In summary, these studies will reveal novel mechanisms of p53 regulation and tumor suppression. They will also lay the base for future molecular intervention for cancer therapy.

Public Health Relevance

p53 is a critical tumor suppressor that is mutated in more than 50% of human cancers. Ubiquitination of p53 is a major regulatory mechanism of p53, however, the deubiquitination of p53 is unclear. We will investigate the regulation of p53 by a novel p53 deubiquitinase USP10, which will provide important insights into the molecular mechanism of p53 regulation and tumor suppression.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Deng, Min; Yang, Xu; Qin, Bo et al. (2016) Deubiquitination and Activation of AMPK by USP10. Mol Cell 61:614-24
Zhang, Haoxing; Liu, Hailong; Chen, Yali et al. (2016) A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice. Nat Commun 7:10201
Liu, Tongzheng; Fang, Yuan; Zhang, Haoxing et al. (2016) HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy. Cancer Res 76:572-81
Evans, Debra L; Zhang, Haoxing; Ham, Hyoungjun et al. (2016) MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication. Cell Cycle 15:95-105
Oi, N; Yuan, J; Malakhova, M et al. (2015) Resveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1. Oncogene 34:2660-71
Qin, Bo; Minter-Dykhouse, Katherine; Yu, Jia et al. (2015) DBC1 functions as a tumor suppressor by regulating p53 stability. Cell Rep 10:1324-34
Luo, Kuntian; Deng, Min; Li, Yunhui et al. (2015) CDK-mediated RNF4 phosphorylation regulates homologous recombination in S-phase. Nucleic Acids Res 43:5465-75
Kim, Jung Jin; Lee, Seung Baek; Jang, Jinsung et al. (2015) WSB1 promotes tumor metastasis by inducing pVHL degradation. Genes Dev 29:2244-57
Lee, Seung Baek; Kim, Jung Jin; Nam, Hyun-Ja et al. (2015) Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1. Mol Cell 60:21-34
Lin, Yi-Hui; Yuan, Jian; Pei, Huadong et al. (2015) KAP1 Deacetylation by SIRT1 Promotes Non-Homologous End-Joining Repair. PLoS One 10:e0123935

Showing the most recent 10 out of 21 publications