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The ubiquitin-specific protease USP47 is a novel β-TRCP interactor regulating cell survival

Oncogene volume 29, pages 1384–1393 (2010)Cite this article

Abstract

Ubiquitin-specific proteases (USPs) are a subclass of cysteine proteases that catalyze the removal of ubiquitin (either monomeric or chains) from substrates, thus counteracting the activity of E3 ubiquitin ligases. Although the importance of USPs in a multitude of processes, from hereditary cancer to neurodegeneration, is well established, our knowledge on their mode of regulation, substrate specificity and biological function is quite limited. In this study we identify USP47 as a novel interactor of the E3 ubiquitin ligase, Skp1/Cul1/F-box protein β-transducin repeat-containing protein (SCFβ-Trcp). We found that both β-Trcp1 and β-Trcp2 bind specifically to USP47, and point mutations in the β-Trcp WD-repeat region completely abolished USP47 binding, indicating an E3-substrate-type interaction. However, unlike canonical β-Trcp substrates, USP47 protein levels were neither affected by silencing of β-Trcp nor modulated in a variety of processes, such as cell-cycle progression, DNA damage checkpoint responses or tumor necrosis factor (TNF) pathway activation. Notably, genetic or siRNA-mediated depletion of USP47 induced accumulation of Cdc25A, decreased cell survival and augmented the cytotoxic effects of anticancer drugs. In conclusion, we showed that USP47, a novel β-Trcp interactor, regulates cell growth and survival, potentially providing a novel target for anticancer therapies.

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Acknowledgements

This work has been supported by grants from EU EPISTEM (LSHB-CT-019067), ‘Alleanza contro il Cancro’ (ACC12/6), MIUR/PRIN (RBIP06LCA9_0023), AIRC (2008-2010_33-08), ISS ‘Program Italia-USA’ N526D5, Italian Human ProteomeNet RBRN07BMCT_007 and Telethon to GM; and grants from the National Institutes of Health (R01-GM57587, R37-CA76584 and R21-CA125173) and Multiple Myeloma Research Foundation to MP. Research described in this article was also supported in part by Philip Morris USA Inc. and Philip Morris International to GM. JRS was supported by the American Cancer Society—Mr and Mrs William G Campbell Postdoctoral Fellowship in Memory of Carolyn Cabott. MP is an Investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Experimental Medicine and Biochemical Sciences, IDI IRCCS Biochemistry Laboratory, University of Rome ‘Tor Vergata’, Rome, Italy

    A Peschiaroli & G Melino

  2. Department of Pathology, NYU Cancer Institute, New York University School of Medicine, New York, NY, USA

    J R Skaar & M Pagano

  3. Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, USA

    M Pagano

  4. Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK

    G Melino

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  1. A Peschiaroli
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  4. G Melino
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Correspondence to G Melino.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Peschiaroli, A., Skaar, J., Pagano, M. et al. The ubiquitin-specific protease USP47 is a novel β-TRCP interactor regulating cell survival. Oncogene 29, 1384–1393 (2010). https://doi.org/10.1038/onc.2009.430

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