Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity
Open Access
- 1 March 2012
- journal article
- Published by SAGE Publications in Genes & Cancer
- Vol. 3 (3-4), 240-248
- https://doi.org/10.1177/1947601912455199
Abstract
MDM2 oncogenic protein is the principal cellular antagonist of the p53 tumor suppresser gene. p53 activity needs exquisite control to elicit appropriate responses to differential cellular stress conditions. p53 becomes stabilized and active upon various types of stresses. However, too much p53 is not beneficial to cells and causes lethality. At the steady state, p53 activity needs to be leashed for cell survival. Early studies suggested that the MDM2 oncoprotein negatively regulates p53 activity through the induction of p53 protein degradation. MDM2 serves as an E3 ubiquitin ligase of p53; it catalyzes polyubiquitination and subsequently induces proteasome degradation to downregulate p53 protein level. However, the mechanism by which MDM2 represses p53 is not a single mode. Emerging evidence reveals another cellular location of MDM2-p53 interaction. MDM2 is recruited to chromatin, specifically the p53 responsive promoter regions, in a p53 dependent manner. MDM2 is proposed to directly inhibit p53 transactivity at chromatin. This article provides an overview of the mechanism by which p53 is repressed by MDM2 in both ubiquitination dependent and ubiquitination independent pathways.Keywords
This publication has 83 references indexed in Scilit:
- MDM2 and MDMX in Cancer and DevelopmentCurrent topics in developmental biology, 2011
- Phosphorylation by Casein Kinase I Promotes the Turnover of the Mdm2 Oncoprotein via the SCFβ-TRCP Ubiquitin LigaseCancer Cell, 2010
- Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathwayOncogene, 2010
- Mdm2 facilitates the association of p53 with the proteasomeProceedings of the National Academy of Sciences of the United States of America, 2010
- CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53Proceedings of the National Academy of Sciences of the United States of America, 2009
- RING Domain E3 Ubiquitin LigasesAnnual Review of Biochemistry, 2009
- Structural Basis for Cooperative Transcription Factor Binding to the CBP CoactivatorJournal of Molecular Biology, 2006
- 14-3-3σ Positively Regulates p53 and Suppresses Tumor GrowthMolecular and Cellular Biology, 2003
- Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53.Molecular and Cellular Biology, 1993
- p53, a transformation-related cellular-encoded protein, can be used as a biochemical marker for the detection of primary mouse tumor cells.Proceedings of the National Academy of Sciences of the United States of America, 1983