The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2
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Mdm2 is an E3 ubiquitin ligase that promotes its own ubiquitination and also ubiquitination of the p53 tumour suppressor. In a bacterial two-hybrid screen, using Mdm2 as bait, we identified an Mdm2-interacting peptide that bears sequence similarity to the deubiquitinating enzyme USP2a. We have established that full-length USP2a associates with Mdm2 in cells where it can deubiquitinate Mdm2 while demonstrating no deubiquitinating activity towards p53. Ectopic expression of USP2a causes accumulation of Mdm2 in a dose-dependent manner and consequently promotes Mdm2-mediated p53 degradation. This differs from the behaviour of HAUSP, which deubiquitinates p53 in addition to Mdm2 and thus protects p53 from Mdm2-mediated degradation. We further demonstrate that suppression of endogenous USP2a destabilises Mdm2 and causes accumulation of p53 protein and activation of p53. Our data identify the deubiquitinating enzyme USP2a as a novel regulator of the p53 pathway that acts through its ability to selectively target Mdm2.
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Usp2a has been reported to deubiquitylate both Mdm2 and Mdmx and lead to p53 destabilization.
“More recently a second DUB, Usp2a, has been reported to deubiquitylate both Mdm2 and Mdmx [47,48] and lead to p53 destabilization.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [48]
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- Authors
- Stevenson, L. F., Sparks, A., Allende‐Vega, N., Xirodimas, D. P., Lane, D. P., & Saville, M. K.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Saville, Mark K
- Venue
- The EMBO Journal
- Published
- 2007-02-08
- Volume
- 26
- Issue
- 4
- Pages
- 976-986
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1852834
- OpenAlex
- W2143460288
- Cited by
- 280
- References
- 57
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 7 · 2023: 13 · 2022: 17 · 2021: 18 · 2020: 22 · 2019: 12 · 2018: 13 · 2017: 10 · 2016: 16 · 2015: 16 · 2014: 25 · 2013: 14 · 2012: 19
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Cancer Research UK (A6613)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- MDM2, p53, deubiquitination, p53 degradation, E3 ubiquitin ligase, USP7, protein stability
- MeSH terms
- Amino Acid Sequence, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Molecular Sequence Data, Endopeptidases, Peptides, Blotting, Western, Signal Transduction, Tumor Suppressor Protein p53, Two-Hybrid System Techniques, Ubiquitin, RNA Interference, Ubiquitin Thiolesterase, Cell Line, Tumor, Immunoprecipitation, Green Fluorescent Proteins, Proto-Oncogene Proteins c-mdm2
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