Cho Jinhong, Park Jinyoung, Shin Sang Chul, Jang Mihue, Kim Jae-Hong, Kim Eunice EunKyeong, Song Eun Joo
Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea.
Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul 02841, Korea.
Cancers (Basel). 2020 May 1;12(5):1137. doi: 10.3390/cancers12051137.
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.
p53会在诸如DNA损伤、氧化应激尤其是核糖体应激等细胞应激反应中被激活。尽管已经描述了E3连接酶和去泛素化酶（DUBs）对p53的调控作用，但与核糖体应激相关的DUB的细胞作用尚未得到充分研究。在本研究中，我们报告泛素特异性蛋白酶47（USP47）作为p53的重要调节因子发挥作用。我们发现，小鼠双微体2同源物（MDM2）使核糖体蛋白S2（RPS2）泛素化，而USP47可使其去泛素化。在正常条件下，USP47抑制RPS2与MDM2之间的相互作用，从而减轻RPS2介导的对MDM2的抑制作用。然而，USP47的解离会导致RPS2与MDM2结合，这是抑制MDM2所必需的，从而在核糖体应激下诱导p53水平上调。最后，我们表明，USP47的缺失会诱导p53表达，因此会抑制癌细胞系和小鼠异种移植模型中的细胞增殖、集落形成及肿瘤进展。这些发现表明，USP47可能是癌症的一个潜在治疗靶点。
