The p53--Mdm2--HAUSP complex is involved in p53 stabilization by HAUSP.
The ubiquitin-specific protease HAUSP is a critical component of the p53-Mdm2 pathway by acting as a specific deubiquitinase for both p53 and Mdm2. Recent structural studies have indicated that p53 and Mdm2 bind to the N-terminal TRAF-like domain of HAUSP in a mutually exclusive manner. To understand the mechanism of HAUSP-mediated effects, we have created a p53 mutant that lacks HAUSP binding based on the crystal structure analysis. Indeed, this mutant p53 protein can be degraded by Mdm2 but fails to interact with HAUSP both in vitro and in vivo. Surprisingly, however, we have found that direct interaction between HAUSP and p53 is not absolutely required for it to antagonize efficiently Mdm2-mediated ubiquitination of p53 and that HAUSP is capable of enzymatically functioning in trans on p53 by using Mdm2 as a bridge. Further, we show that a trimeric protein complex containing p53, Mdm2 and HAUSP can exist in vivo, despite mutually exclusive binding, with Mdm2 serving as a binding mediator for p53 and HAUSP. These findings reveal the complication of HAUSP-mediated effects in the p53-Mdm2 interplay. It also has important implications for the development of novel chemotherapeutic compounds aimed at blocking this protein-protein interaction.
Brooks
C L
CL
1Department of Pathology, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Li
M
M
Hu
M
M
Shi
Y
Y
Gu
W
W
D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D000076084:Ubiquitin-Specific Peptidase 7
D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7