@article{3b23d306e96c4c8cb77cd87f3833f05f,
title = "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 proteolysis. Stabilization of p53 is crucial for its tumour suppressor function. 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 protease (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.",
author = "Muyang Li and Delln Chen and Ariel Shiloh and Jlanyuan Luo and Nikolaev, {Anatoly Y.} and Jun Qin and Wei Gu",
note = "Funding Information: M.R. devised and carried out the RNAi screen and performed microarray and luciferase analysis. P.M. did the in vivo fly work under supervision of B.M.-P. A.P. did some of the targeted RNAi treatments and was intellectually involved throughout the project. M.R. and R.A.B.E. co-wrote the paper. We thank members of Hoffmann and Ezekowitz laboratories for discussions. We also thank M. Sackal for help with northern blots, J. Couget and M. Tahiliani for help with Affymetrix microrrays. M. Krieger provided the S2 cell cDNA library. This work was supported by grants from the National Institutes of Health (R.A.B.E.), the Foundation for Pediatric Research (M.R.), the Finnish Medical Foundation (M.R.), Maud Kuistila Foundation (M.R.), l{\textquoteright}A.R.C. (P.M.) and American Cancer Society (A.P.). Funding Information: 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.{\textquoteright}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.",
year = "2002",
month = apr,
day = "11",
doi = "10.1038/nature737",
language = "English (US)",
volume = "416",
pages = "648--653",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6881",
}