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

Muyang Li, Delln Chen, Ariel L. Shiloh, Jlanyuan Luo, Anatoly Y. Nikolaev, Jun Qin, Wei Gu

Research output: Contribution to journalArticle

650 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)648-653
Number of pages6
JournalNature
Volume416
Issue number6881
DOIs
StatePublished - Apr 11 2002
Externally publishedYes

Fingerprint

Ubiquitin-Specific Proteases
Herpesviridae
Ubiquitination
Neoplasms
Proteolysis
Mass Spectrometry
Proteins
Apoptosis
Growth

ASJC Scopus subject areas

  • General

Cite this

Li, M., Chen, D., Shiloh, A. L., Luo, J., Nikolaev, A. Y., Qin, J., & Gu, W. (2002). Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature, 416(6881), 648-653. https://doi.org/10.1038/nature737

Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. / Li, Muyang; Chen, Delln; Shiloh, Ariel L.; Luo, Jlanyuan; Nikolaev, Anatoly Y.; Qin, Jun; Gu, Wei.

In: Nature, Vol. 416, No. 6881, 11.04.2002, p. 648-653.

Research output: Contribution to journalArticle

Li, M, Chen, D, Shiloh, AL, Luo, J, Nikolaev, AY, Qin, J & Gu, W 2002, 'Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization', Nature, vol. 416, no. 6881, pp. 648-653. https://doi.org/10.1038/nature737
Li, Muyang ; Chen, Delln ; Shiloh, Ariel L. ; Luo, Jlanyuan ; Nikolaev, Anatoly Y. ; Qin, Jun ; Gu, Wei. / Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. In: Nature. 2002 ; Vol. 416, No. 6881. pp. 648-653.
@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 Shiloh, {Ariel L.} and Jlanyuan Luo and Nikolaev, {Anatoly Y.} and Jun Qin and Wei Gu",
year = "2002",
month = "4",
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",

}

TY - JOUR

T1 - Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization

AU - Li, Muyang

AU - Chen, Delln

AU - Shiloh, Ariel L.

AU - Luo, Jlanyuan

AU - Nikolaev, Anatoly Y.

AU - Qin, Jun

AU - Gu, Wei

PY - 2002/4/11

Y1 - 2002/4/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037061508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037061508&partnerID=8YFLogxK

U2 - 10.1038/nature737

DO - 10.1038/nature737

M3 - Article

VL - 416

SP - 648

EP - 653

JO - Nature

JF - Nature

SN - 0028-0836

IS - 6881

ER -