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

A. Peschiaroli, J. R. Skaar, M. Pagano, G. Melino

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 (SCF Β-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.

Original languageEnglish
Pages (from-to)1384-1393
Number of pages10
JournalOncogene
Volume29
Issue number9
DOIs
Publication statusPublished - Mar 2010

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Ubiquitin-Specific Proteases
Ubiquitin-Protein Ligases
Cell Survival
F-Box Proteins
Transducin
Cysteine Proteases
Ubiquitin
Substrate Specificity
Point Mutation
Small Interfering RNA
DNA Damage
Cell Cycle
Proteins
Tumor Necrosis Factor-alpha
Growth
Pharmaceutical Preparations
Neoplasms
Therapeutics

Keywords

  • Β-Trcp
  • Degradation
  • F-box proteins
  • Ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

The ubiquitin-specific protease USP47 is a novel Β-TRCP interactor regulating cell survival. / Peschiaroli, A.; Skaar, J. R.; Pagano, M.; Melino, G.

In: Oncogene, Vol. 29, No. 9, 03.2010, p. 1384-1393.

Research output: Contribution to journalArticle

Peschiaroli, A. ; Skaar, J. R. ; Pagano, M. ; Melino, G. / The ubiquitin-specific protease USP47 is a novel Β-TRCP interactor regulating cell survival. In: Oncogene. 2010 ; Vol. 29, No. 9. pp. 1384-1393.
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