The ubiquitin-specific protease USP47 is a novel beta-TRCP interactor regulating cell survival.
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 beta-transducin repeat-containing protein (SCF(beta-Trcp)). We found that both beta-Trcp1 and beta-Trcp2 bind specifically to USP47, and point mutations in the beta-Trcp WD-repeat region completely abolished USP47 binding, indicating an E3-substrate-type interaction. However, unlike canonical beta-Trcp substrates, USP47 protein levels were neither affected by silencing of beta-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 beta-Trcp interactor, regulates cell growth and survival, potentially providing a novel target for anticancer therapies.
Peschiaroli
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IDI IRCCS Biochemistry Laboratory, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.
Skaar
J R
JR
Pagano
M
M
Melino
G
G
D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D057056:Cysteine Proteases / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015293:Transducin; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; D057056:Cysteine Proteases; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases; D015293:Transducin