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Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization

Abstract

The p53 tumour suppressor is a short-lived protein that is maintained at low levels in normal cells by Mdm2-mediated ubiquitination and subsequent proteolysis1,2,3. Stabilization of p53 is crucial for its tumour suppressor function1,2,3,4,5. However, the precise mechanism by which ubiquitinated p53 levels are regulated in vivo is not completely understood. By mass spectrometry of affinity-purified p53-associated factors, we have identified herpesvirus-associated ubiquitin-specific protease6 (HAUSP) as a novel p53-interacting protein. HAUSP strongly stabilizes p53 even in the presence of excess Mdm2, and also induces p53-dependent cell growth repression and apoptosis. Significantly, HAUSP has an intrinsic enzymatic activity that specifically deubiquitinates p53 both in vitro and in vivo. In contrast, expression of a catalytically inactive point mutant of HAUSP in cells increases the levels of p53 ubiquitination and destabilizes p53. These findings reveal an important mechanism by which p53 can be stabilized by direct deubiquitination and also imply that HAUSP might function as a tumour suppressor in vivo through the stabilization of p53.

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Figure 1: Purification of HAUSP, and interactions between p53 and HAUSP.
Figure 2: HAUSP interacts with and stabilizes p53 in vivo.
Figure 3: Effects of HAUSP on p53-mediated cell growth repression (a) and apoptosis (b).
Figure 4: Deubiquitination of p53 by HAUSP both in vivo and in vitro.
Figure 5: The dominant-negative effects of HAUSP-cs in human cells.

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Acknowledgements

We thank R. Baer, R. Dalla-Favera, B. Tycko and T. Ludwig for critical discussions; we also thank many colleges in the field for providing antibodies, cell lines and plasmids, and other members of W.G.’s laboratory for sharing unpublished data and critical comments. This work was supported in part by grants from Avon Foundation, the Stewart Trust, the Irma T. Hirschl Trust and NIH/NCI to W.G., who is also a Leukemia and Lymphoma Society Scholar.

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Correspondence to Wei Gu.

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Li, M., Chen, D., Shiloh, A. et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416, 648–653 (2002). https://doi.org/10.1038/nature737

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