MdmX is a substrate for the deubiquitinating enzyme USP2a

Allende-Vega, N; Sparks, A; Lane, D P; Saville, M K

doi:10.1038/onc.2009.330

Cited by 103Ubiquitin and proteasome pathwaysCancer-related Molecular PathwaysTGF-β signaling in diseases

MdmX is a substrate for the deubiquitinating enzyme USP2a

Allende-Vega, N, Sparks, A, Lane, D P, Saville, M K·2010·Oncogene

DOI 10.1038/onc.2009.330

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Abstract

It has previously been shown that ubiquitin-specific protease 2a (USP2a) is a regulator of the Mdm2/p53 pathway. USP2a binds to Mdm2 and can deubiquitinate Mdm2 without reversing Mdm2-mediated p53 ubiquitination. Overexpression of USP2a causes accumulation of Mdm2 and promotes p53 degradation. We now show that MdmX is also a substrate for USP2a. MdmX associates with USP2a independently of Mdm2. Ectopic expression of wild-type USP2a but not a catalytic mutant prevents Mdm2-mediated degradation of MdmX. This correlates with the ability of wild-type USP2a to deubiquitinate MdmX. siRNA-mediated knockdown of USP2a in NTERA-2 testicular embryonal carcinoma cells and MCF7 breast cancer cells causes destabilization of MdmX and results in a decrease in MdmX protein levels, showing that endogenous USP2a participates in the regulation of MdmX stability. The therapeutic drug, cisplatin decreases MdmX protein expression. USP2a mRNA and protein levels were also reduced after cisplatin exposure. The magnitude and time course of USP2a downregulation suggests that the reduction in USP2a levels could contribute to the decrease in MdmX expression following treatment with cisplatin. Knockdown of USP2a increases the sensitivity of NTERA-2 cells to cisplatin, raising the possibility that suppression of USP2a in combination with cisplatin may be an approach for cancer therapy.

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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 [47]

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The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2
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Authors: Allende-Vega, N., Sparks, A., Lane, D. P., & Saville, M. K.
Affiliations: University of Dundee (GB)
Corresponding author: Saville, M K
ORCID: Allende-Vega, N
Lane, D P
Saville, M K
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2009-10-19
Volume: 29
Issue: 3
Pages: 432-441
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/onc.2009.330
OpenAlex: W2117646314
Cited by: 100
References: 56
Citations by year: 2026: 3 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 8 · 2016: 6 · 2015: 8 · 2014: 11 · 2013: 9 · 2012: 11
FWCI: 2.81
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (publishedVersion)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (publishedVersion)
Funders: Cancer Research UK
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: MDMX, deubiquitination, MDM2, p53, protein stability, cisplatin, MDM2-p53 pathway, NTERA-2 cells, MCF-7 cells, combination cancer therapy
MeSH terms: Antineoplastic Agents, Cisplatin, Humans, Mutation, Nuclear Proteins, Endopeptidases, Protein Binding, Proto-Oncogene Proteins, Substrate Specificity, Transfection, Blotting, Western, Down-Regulation, Cell Cycle Proteins, Reverse Transcriptase Polymerase Chain Reaction, Catalytic Domain, RNA Interference, Ubiquitin Thiolesterase, Cell Line, Tumor, Immunoprecipitation, Proto-Oncogene Proteins c-mdm2, Ubiquitination

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MdmX is a substrate for the deubiquitinating enzyme USP2a

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