Abstract
Arising from: Li, M. et al. Nature 416, 648–653 (2002) Ubiquitination of p53 is the principal mechanism through which p53 concentrations in the cell are regulated1,2 in order to maintain its effects on tumori-genesis and normal cell growth. The protein HAUSP (also known as USP7) is a ubiquitin-specific protease (deubiquitinase)3,4 that has been shown by Li et al. to bind to p53 (ref. 5); in overexpression experiments, Li et al. showed that p53 could be stabilized as a result of deubiquitination by HAUSP and suggested that HAUSP may thereby act as a tumour suppressor5,6. Here we use a different approach to investigate the relationship between HAUSP and p53 stability, in which we disrupt the HAUSP gene in human cells by targeted homologous recombination. Instead of the expected increase in ubiquitinated p53 and destabilization of p53, we find that disruption of HAUSP results in the opposite phenotype, leading to stabilization and functional activation of p53 in our system. It may be that HAUSP can deubiquitinate other proteins such as MDM2, another regulator of p53, and that the balance between the deubiquitination of the different targets of HAUSP determines the steady-state level of p53.
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(Under a licensing agreement between Genzyme Corporation, CalBioChem and the Johns Hopkins University, K.W K. and B.V. are entitled to a share of royalty received by the university on sales of p53-related and p21-related products described in this communication. The university and these investigators also own Genzyme Corporation stock, which is subject to certain restrictions under university policy. K.W.K. is a paid consultant to, and receives research funding from, Genzyme. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.)
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Cummins, J., Rago, C., Kohli, M. et al. Disruption of HAUSP gene stabilizes p53. Nature 428, 1–2 (2004). https://doi.org/10.1038/nature02501
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DOI: https://doi.org/10.1038/nature02501
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