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USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.

ABSTRACT: Tumour suppressor p53 levels in the cell are tightly regulated by controlled degradation through ubiquitin ligases including Mdm2, COP1, Pirh2, and ARF-BP1. The ubiquitination process is reversible via deubiquitinating enzymes, such as ubiquitin-specific peptidases (USPs). In this study, we identified ubiquitin-specific peptidase 4 (USP4) as an important regulator of p53. USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels. Usp4 knockout mice are viable and developmentally normal, but showed enhanced apoptosis in thymus and spleen in response to ionizing radiation. Compared with wild-type mouse embryonic fibroblasts (MEFs), Usp4-/- MEFs exhibited retarded growth, premature cellular senescence, resistance to oncogenic transformation, and hyperactive DNA damage checkpoints, consistent with upregulated levels and activity of p53 in the absence of USP4. Finally, we showed that USP4 is overexpressed in several types of human cancer, suggesting that USP4 is a potential oncogene.

SUBMITTER: Zhang X

PROVIDER: S-EPMC3117646 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.

Zhang Xinna X Berger Franklin G FG Yang Jianhua J Lu Xiongbin X

The EMBO journal 20110426 11

Tumour suppressor p53 levels in the cell are tightly regulated by controlled degradation through ubiquitin ligases including Mdm2, COP1, Pirh2, and ARF-BP1. The ubiquitination process is reversible via deubiquitinating enzymes, such as ubiquitin-specific peptidases (USPs). In this study, we identified ubiquitin-specific peptidase 4 (USP4) as an important regulator of p53. USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of ...[more]

PMID: 21522127

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Project description:BackgroundUSP4, USP15 and USP11 are paralogous deubiquitinating enzymes as evidenced by structural organization and sequence similarity. Based on known interactions and substrates it would appear that they have partially redundant roles in pathways vital to cell proliferation, development and innate immunity, and elevated expression of all three has been reported in various human malignancies. The nature and order of duplication events that gave rise to these extant genes has not been determined, nor has their functional redundancy been established experimentally at the organismal level.MethodsWe have employed phylogenetic and syntenic reconstruction methods to determine the chronology of the duplication events that generated the three paralogs and have performed genetic crosses to evaluate redundancy in mice.ResultsOur analyses indicate that USP4 and USP15 arose from whole genome duplication prior to the emergence of jawed vertebrates. Despite having lower sequence identity USP11 was generated later in vertebrate evolution by small-scale duplication of the USP4-encoding region. While USP11 was subsequently lost in many vertebrate species, all available genomes retain a functional copy of either USP4 or USP15, and through genetic crosses of mice with inactivating mutations we have confirmed that viability is contingent on a functional copy of USP4 or USP15. Loss of ubiquitin-exchange regulation, constitutive skipping of the seventh exon and neural-specific expression patterns are derived states of USP11. Post-translational modification sites differ between USP4, USP15 and USP11 throughout evolution.ConclusionsIn isolation sequence alignments can generate erroneous USP gene phylogenies. Through a combination of methodologies the gene duplication events that gave rise to USP4, USP15, and USP11 have been established. Although it operates in the same molecular pathways as the other USPs, the rapid divergence of the more recently generated USP11 enzyme precludes its functional interchangeability with USP4 and USP15. Given their multiplicity of substrates the emergence (and in some cases subsequent loss) of these USP paralogs would be expected to alter the dynamics of the networks in which they are embedded.

Project description:BackgroundP53 pathway inactivation plays an important role in the process of breast cancer tumorigenesis. Post-translational protein modification abnormalities have been confirmed to be an important mechanism underlying inactivation of p53. Numerous deubiquitinating enzymes are aberrantly expressed in breast cancer, and a few deubiquitination enzymes can deubiquitinate and stabilize p53. Here, we report that ovarian tumor (OTU) deubiquitinase 3 (OTUD3) is a deubiquitylase of p53 in breast carcinoma (BC).MethodsCorrelations between the mRNA expression levels of OTUD3, TP53 and PTEN and the prognosis of BC were assessed with the Kaplan-Meier Plotter tool. OTUD3 protein expression in 80 pairs of specimens in our cohort was examined by immunohistochemistry and western blotting. The relationship among OTUD3, p53, and p21 proteins was analyzed. Half-life analysis and ubiquitylation assay were performed to elucidate the molecular mechanism by which OTUD3 stabilizes p53. The interaction between OTUD3 and p53 in BC cells was verified by a co-immunoprecipitation assay and GST pulldown experiments. MTS assay for proliferation detection, detection of apoptosis induced by cisplatin and colony formation assay were employed to investigate the functional effects of OTUD3 on breast cancer cells.ResultsOTUD3 downregulation is correlated with a poor prognosis in BC patients. OTUD3 expression is decreased in breast cancer tissues and not associated with the histological grade. OTUD3 also inhibits cell proliferation and clone formation and increases the sensitivity of BC cells to apoptosis induced by chemotherapy drugs. Reduced OTUD3 expression accompanied by decreased p53 abundance is correlated with human breast cancer progression. Ectopic expression of wild-type OTUD3, but not its catalytically inactive mutant, stabilizes and activates p53. Mechanistically, OTUD3 interacts directly with p53 through the amino-terminal OTU region. Finally, OTUD3 protects p53 from murine double minute 2 (Mdm2)-mediated ubiquitination and degradation, enabling the deubiquitination of p53 in BC cells.ConclusionsIn summary, we found that OTUD3 may be a potential therapeutic target for restoring p53 function in breast cancer cells and suggest that the OTUD3-p53 signaling axis may play a critical role in tumor suppression.

Dataset Information

USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.

Publications

USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.

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