Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1

Xiao Xin Sun, Kishore B. Challagundla, Mu Shui Dai

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

The ubiquitin (Ub)-proteasome system plays a pivotal role in the regulation of p53 protein stability and activity. p53 is ubiquitinated and destabilized by MDM2 and several other Ub E3s, whereas it is deubiquitinated and stabilized by Ub-specific protease (USP)7 and USP10. Here we show that the ovarian tumour domain-containing Ub aldehyde-binding protein 1 (Otub1) is a novel p53 regulator. Otub1 directly suppresses MDM2-mediated p53 ubiquitination in cells and in vitro. Overexpression of Otub1 drastically stabilizes and activates p53, leading to apoptosis and marked inhibition of cell proliferation in a p53-dependent manner. These effects are independent of its catalytic activity but require residue Asp88. Mutation of Asp88 to Ala (Otub1 D88A) abolishes activity of Otub1 to suppress p53 ubiquitination. Further, wild-type Otub1 and its catalytic mutant (Otub1 C 91S), but not Otub1 D88A, bind to the MDM2 cognate E2, UbcH5, and suppress its Ub-conjugating activity in vitro. Overexpression of Otub1 D88A or ablation of endogenous Otub1 by siRNA markedly impaired p53 stabilization and activation in response to DNA damage. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity.

Original languageEnglish (US)
Pages (from-to)576-592
Number of pages17
JournalEMBO Journal
Volume31
Issue number3
DOIs
StatePublished - Feb 1 2012

Fingerprint

Ubiquitin
Ubiquitination
Enzymes
Ubiquitin-Specific Proteases
Protein Stability
Cell proliferation
Proteasome Endopeptidase Complex
Ablation
Small Interfering RNA
DNA Damage
Tumors
Catalyst activity
Carrier Proteins
Stabilization
Chemical activation
Cell Proliferation
Apoptosis
Mutation
DNA
Deubiquitinating Enzymes

Keywords

  • MDM2
  • Otub1
  • deubiquitinating enzyme
  • p53
  • ubiquitination

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1. / Sun, Xiao Xin; Challagundla, Kishore B.; Dai, Mu Shui.

In: EMBO Journal, Vol. 31, No. 3, 01.02.2012, p. 576-592.

Research output: Contribution to journalArticle

@article{a7aaa309c6904af1bae671508d949e4d,
title = "Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1",
abstract = "The ubiquitin (Ub)-proteasome system plays a pivotal role in the regulation of p53 protein stability and activity. p53 is ubiquitinated and destabilized by MDM2 and several other Ub E3s, whereas it is deubiquitinated and stabilized by Ub-specific protease (USP)7 and USP10. Here we show that the ovarian tumour domain-containing Ub aldehyde-binding protein 1 (Otub1) is a novel p53 regulator. Otub1 directly suppresses MDM2-mediated p53 ubiquitination in cells and in vitro. Overexpression of Otub1 drastically stabilizes and activates p53, leading to apoptosis and marked inhibition of cell proliferation in a p53-dependent manner. These effects are independent of its catalytic activity but require residue Asp88. Mutation of Asp88 to Ala (Otub1 D88A) abolishes activity of Otub1 to suppress p53 ubiquitination. Further, wild-type Otub1 and its catalytic mutant (Otub1 C 91S), but not Otub1 D88A, bind to the MDM2 cognate E2, UbcH5, and suppress its Ub-conjugating activity in vitro. Overexpression of Otub1 D88A or ablation of endogenous Otub1 by siRNA markedly impaired p53 stabilization and activation in response to DNA damage. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity.",
keywords = "MDM2, Otub1, deubiquitinating enzyme, p53, ubiquitination",
author = "Sun, {Xiao Xin} and Challagundla, {Kishore B.} and Dai, {Mu Shui}",
year = "2012",
month = "2",
day = "1",
doi = "10.1038/emboj.2011.434",
language = "English (US)",
volume = "31",
pages = "576--592",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1

AU - Sun, Xiao Xin

AU - Challagundla, Kishore B.

AU - Dai, Mu Shui

PY - 2012/2/1

Y1 - 2012/2/1

N2 - The ubiquitin (Ub)-proteasome system plays a pivotal role in the regulation of p53 protein stability and activity. p53 is ubiquitinated and destabilized by MDM2 and several other Ub E3s, whereas it is deubiquitinated and stabilized by Ub-specific protease (USP)7 and USP10. Here we show that the ovarian tumour domain-containing Ub aldehyde-binding protein 1 (Otub1) is a novel p53 regulator. Otub1 directly suppresses MDM2-mediated p53 ubiquitination in cells and in vitro. Overexpression of Otub1 drastically stabilizes and activates p53, leading to apoptosis and marked inhibition of cell proliferation in a p53-dependent manner. These effects are independent of its catalytic activity but require residue Asp88. Mutation of Asp88 to Ala (Otub1 D88A) abolishes activity of Otub1 to suppress p53 ubiquitination. Further, wild-type Otub1 and its catalytic mutant (Otub1 C 91S), but not Otub1 D88A, bind to the MDM2 cognate E2, UbcH5, and suppress its Ub-conjugating activity in vitro. Overexpression of Otub1 D88A or ablation of endogenous Otub1 by siRNA markedly impaired p53 stabilization and activation in response to DNA damage. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity.

AB - The ubiquitin (Ub)-proteasome system plays a pivotal role in the regulation of p53 protein stability and activity. p53 is ubiquitinated and destabilized by MDM2 and several other Ub E3s, whereas it is deubiquitinated and stabilized by Ub-specific protease (USP)7 and USP10. Here we show that the ovarian tumour domain-containing Ub aldehyde-binding protein 1 (Otub1) is a novel p53 regulator. Otub1 directly suppresses MDM2-mediated p53 ubiquitination in cells and in vitro. Overexpression of Otub1 drastically stabilizes and activates p53, leading to apoptosis and marked inhibition of cell proliferation in a p53-dependent manner. These effects are independent of its catalytic activity but require residue Asp88. Mutation of Asp88 to Ala (Otub1 D88A) abolishes activity of Otub1 to suppress p53 ubiquitination. Further, wild-type Otub1 and its catalytic mutant (Otub1 C 91S), but not Otub1 D88A, bind to the MDM2 cognate E2, UbcH5, and suppress its Ub-conjugating activity in vitro. Overexpression of Otub1 D88A or ablation of endogenous Otub1 by siRNA markedly impaired p53 stabilization and activation in response to DNA damage. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity.

KW - MDM2

KW - Otub1

KW - deubiquitinating enzyme

KW - p53

KW - ubiquitination

UR - http://www.scopus.com/inward/record.url?scp=84856415004&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856415004&partnerID=8YFLogxK

U2 - 10.1038/emboj.2011.434

DO - 10.1038/emboj.2011.434

M3 - Article

C2 - 22124327

AN - SCOPUS:84856415004

VL - 31

SP - 576

EP - 592

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 3

ER -