The gene encoding the transcription factor p53 is frequently mutated in tumors. In unstressed cells, p53 abundance is kept low through Mdm2-mediated polyubiquitination, which triggers nuclear export of p53 and its subsequent proteasomal degradation in the cytoplasm (see commentary by Jochemsen and Shiloh). DNA damage attenuates polyubiquitination of p53, thereby enabling the p53-dependent transcription of genes encoding factors that promote apoptosis. Ubiquitin E3 ligases such as Mdm2 are opposed by deubiquitinases (DUBs). Yuan et al. found that ubiquitin-specific peptidase 10 (USP10) directly interacted with p53. Overexpression of full-length USP10 increased the abundance of p53 and two of its target genes, p21 and Bax, and decreased the ubiquitination of p53. In contrast, expression of a short hairpin RNA (shRNA) directed against USP10 decreased p53 abundance and increased its ubiquitination. In vitro assays confirmed that USP10 deubiquitinated p53. Immunofluorescence and subcellular fractionation assays indicated that USP10 localized to the cytoplasm; furthermore, USP10 coimmunoprecipitated only with the cytoplasmic, and not the nuclear, pool of p53. USP10 promoted p53 transcriptional activity and p53-dependent decreases in proliferation and foci formation in soft agar by cancer cells. Irradiation induced phosphorylation of USP10 at Thr42 and Ser337 by ataxia telangiectasia mutated (ATM), a phosphorylation event that triggered nuclear translocation of USP10. Cells stably expressing a USP10 shRNA underwent apoptosis after irradiation when reconstituted with wild-type USP10 but not a mutant that could not be phosphorylated by ATM. USP10 abundance was decreased in renal cell carcinoma cell lines with wild-type p53 (such as the CAKI-1 and CAKI-2 lines) but increased in those with mutant p53 (such as the 786-O line). USP10 reconstitution decreased foci formation in CAKI-1 and CAKI-2 cells, but in 786-O cells, the same effect required knockdown of USP10. Thus, the authors suggest that manipulating the abundance of USP10 as a therapeutic approach would depend on whether the tumor contained wild-type or mutant p53.
J. Yuan, K. Luo, L. Zhang, J. C. Cheville, Z. Lou, USP10 regulates p53 localization and stability by deubiquitinating p53. Cell 140, 384–396 (2010). [PubMed]
A. G. Jochemsen, Y. Shiloh, USP10: Friend and foe. Cell 140, 308–310 (2010). [PubMed]