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.

Updates on p53: modulation of p53 degradation as a therapeutic approach

“…Deubiquitinating enzymes (DUBs) have been established as yet another critical modulator of p53 stability, the most notable example being HAUSP (herpesvirus-associated ubiquitin-specific protease), which has been shown to deubiquitinate p53, Mdm2 and Mdm4 in a concentration-dependent manner (Li et al, 2002;Meulmeester et al, 2005). More recently, USP2a (ubiquitin-specific protease 2a) has been identified as a novel DUB that selectively targets Mdm2, unlike HAUSP, and thereby offers another potential approach of therapeutic intervention to reactivate WT p53 (Stevenson et al, 2007).…”

Body language: the function of PML nuclear bodies in apoptosis regulation

“…137,138 This significant accumulation of factors involved in p53 regulation raises the assumption that PMLNBs form supramolecular scaffolds that establish a peculiar molecular microenvironment enabling efficient post-translational modification of a fraction of p53. Similar to most PML-NB components, p53 is not a constitutive resident and its recruitment to PML-NBs is mediated by all PML isoforms, 16 but only interaction with PML IV regulates p53 activity.…”

“…52 Recently, the deubiquitinating enzyme HAUSP, which colocalises with PML-NBs, 137 was found to stabilise p53 and to activate its proapoptotic activity. 138 Whether HAUSP can exert its function in PML-NBs remains to be studied.…”

MdmX is a substrate for the deubiquitinating enzyme USP2a

“…HAUSP can deubiquitinate p53, Mdm2 and MdmX and overexpression of HAUSP prevents p53 degradation. However, the balance of activity of endogenous HAUSP is such that its knockdown or knockout results in destabilization of Mdm2 and MdmX and stabilization of p53 (Li et al, 2002(Li et al, , 2004Cummins et al, 2004;Meulmeester et al, 2005). We have previously shown that USP2a can deubiquitinate Mdm2 without reversing Mdm2-mediated p53 ubiquitination (Stevenson et al, 2007).…”