Abstract
p53 is activated in response to cellular stresses such as DNA damage, oxidative stress, and especially ribosomal stress. Although the regulations of p53 by E3 ligase and deubiquitinating enzymes (DUBs) have been described, the cellular roles of DUB associated with ribosomal stress have not been well studied. In this study, we report that Ubiquitin Specific Protease 47 (USP47) functions as an important regulator of p53. We show that ubiquitinated ribosomal protein S2 (RPS2) by Mouse double minute 2 homolog (MDM2) is deubiquitinated by USP47. USP47 inhibits the interaction between RPS2 and MDM2 thereby alleviating RPS2-mediated suppression of MDM2 under normal conditions. However, dissociation of USP47 leads to RPS2 binding to MDM2, which is required for the suppression of MDM2, consequently inducing up-regulation of the p53 level under ribosomal stress. Finally, we show that depletion of USP47 induces p53 and therefore inhibits cell proliferation, colony formation, and tumor progression in cancer cell lines and a mouse xenograft model. These findings suggest that USP47 could be a potential therapeutic target for cancer.
Highlights
The tumor suppressor p53 acts as a key regulator of apoptosis and cell cycle control
Consistent with these results, we found that endogenous ribosomal protein S2 (RPS2) interacted with endogenous Ubiquitin Specific Protease 47 (USP47) in cells (Figure 1b)
Through the deubiquitination of RPS2, USP47 regulates the interaction between RPS2 and Mouse double minute 2 homolog (MDM2), and USP47 functions as an important
Summary
The tumor suppressor p53 acts as a key regulator of apoptosis and cell cycle control. Mutation or dysregulation of p53 can promote tumorigenesis and is highly correlated with poor prognosis of cancer. Various cellular stresses such as oxidative stress, DNA damage, and mitotic catastrophe trigger activation of p53, which in turn functions as a transcription factor, inducing its target genes related to apoptosis, cell growth arrest, and senescence [1,2]. The level of p53 is maintained at low levels by MDM2-mediated ubiquitination and degradation through the ubiquitin-proteasome system. The level of p53 is increased via the inhibition of MDM2 [4]
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