Dataset Information

Ubiquitin-specific cysteine protease 2a (USP2a) regulates the stability of Aurora-A.

ABSTRACT: The ubiquitin/proteasome pathway plays critical roles in virtually all aspects of cell biology. Enzymes of the ubiquitin pathway add (ligases) or remove (deubiquitinases) ubiquitin tags to or from their target proteins in a selective fashion. USP2a is a member of a subfamily of deubiquitinases, called ubiquitin-specific cysteine proteases (USPs). Although USP2a has been reported to be a bona fide oncogene that regulates the stability of MDM2, MDMX, and FAS, it is likely that there are other unidentified substrates for USP2a. In this study, we show that USP2a mediates mitotic progression by regulating the stability of Aurora-A. Through cell-based screening of a USP siRNA library, we discovered that knockdown of USP2a reduced the protein levels of Aurora-A. USP2a interacts with Aurora-A directly in vitro and in vivo. In addition, Aurora-A is a substrate for USP2a in vitro and in vivo. Our study provides a novel mechanism for the role of USP2a in mediating the stability of Aurora-A.

SUBMITTER: Shi Y

PROVIDER: S-EPMC3234721 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Ubiquitin-specific cysteine protease 2a (USP2a) regulates the stability of Aurora-A.

Shi Yan Y Solomon Larry R LR Pereda-Lopez Ana A Giranda Vincent L VL Luo Yan Y Johnson Eric F EF Shoemaker Alexander R AR Leverson Joel J Liu Xuesong X

The Journal of biological chemistry 20110902 45

The ubiquitin/proteasome pathway plays critical roles in virtually all aspects of cell biology. Enzymes of the ubiquitin pathway add (ligases) or remove (deubiquitinases) ubiquitin tags to or from their target proteins in a selective fashion. USP2a is a member of a subfamily of deubiquitinases, called ubiquitin-specific cysteine proteases (USPs). Although USP2a has been reported to be a bona fide oncogene that regulates the stability of MDM2, MDMX, and FAS, it is likely that there are other unid ...[more]

PMID: 21890637

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Project description:Deubiquitinase (DUB) dysregulation is closely associated with multiple diseases, including tumors. In this study, we used data from The Cancer Genome Atlas and Gene Expression Omnibus databases to analyze the expression of 51 ubiquitin-specific proteases (USPs) in gastric cancer (GC) tissues and adjacent non-neoplastic tissues. The Kaplan-Meier Plotter database was used to analyze the association of the differentially expressed USPs with the overall survival of patients with GC. The results showed that five USPs (USP5, USP10, USP13, USP21, and USP35) were highly expressed in GC tissues and were associated with poor prognosis in patients with GC. Because the epithelial-mesenchymal transition enables epithelial cells to acquire mesenchymal features and contributes to poor prognosis, we investigated whether these USPs had regulatory effects on the key epithelial-mesenchymal transition transcription factor Snail1. Our results showed that USP35 exhibited the most significant regulation on Snail1. Overexpression of USP35 increased and its knockdown decreased Snail1 protein levels. Mechanistically, USP35 interacted with Snail1 and removed its polyubiquitinated chain, thereby increasing its stability. Furthermore, USP35 promoted the invasion and migration of GC cells depending on its DUB activity. USP35 knockdown exhibited the opposite effect. Snail1 depletion partially abrogated the biological effects of USP35. Experiments using nude mouse tail vein injections indicated that wild-type USP35, but not the catalytically inactive USP35-C450A mutant, dramatically enhanced cell colonization and tumorigenesis in the lungs of mice. In addition, USP35 positively correlated with Snail1 expression in clinical GC tissues. Helicobacter pylori infection increased USP35 and Snail1 expression levels. Altogether, we found that USP35 can deubiquitinate Snail1 and increase its expression, thereby contributing to the malignant progression of GC. Therefore, USP35 may serve as a viable target for GC treatment.

Dataset Information

Ubiquitin-specific cysteine protease 2a (USP2a) regulates the stability of Aurora-A.

Publications

Ubiquitin-specific cysteine protease 2a (USP2a) regulates the stability of Aurora-A.

Similar Datasets

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