Acetylation-dependent regulation of MDM2 E3 ligase activity dictates its oncogenic function

Sci Signal. 2017 Feb 14;10(466):eaai8026. doi: 10.1126/scisignal.aai8026.


Abnormal activation of the oncogenic E3 ubiquitin ligase murine double minute 2 (MDM2) is frequently observed in human cancers. By ubiquitinating the tumor suppressor p53 protein, which leads to its proteasome-mediated destruction, MDM2 limits the tumor-suppressing activity of p53. On the other hand, by ubiquitinating itself, MDM2 targets itself for destruction and promotes the p53 tumor suppressor pathway, a process that can be antagonized by the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP). We investigated the regulation of MDM2 substrate specificity and found that acetyltransferase p300-mediated acetylation and stabilization of MDM2 are molecular switches that block self-ubiquitination, thereby shifting its E3 ligase activity toward p53. In vitro and in cancer cell lines, p300-mediated acetylation of MDM2 on Lys182 and Lys185 enabled HAUSP to bind, presumably deubiquitinate, and stabilize MDM2. This acetylation within the nuclear localization signal domain decreased its interaction with the acidic domain, subsequently increased the interaction between the acidic domain and RING domain in MDM2, enabled the binding of HAUSP to the acidic domain in MDM2, and shifted MDM2 activity from autoubiquitination to p53 ubiquitination. However, upon genotoxic stress through exposure to etoposide, the deacetylase sirtuin 1 (SIRT1) deacetylated MDM2 at Lys182 and Lys185, thereby promoting self-ubiquitination and less ubiquitination and subsequent degradation of p53, thus increasing p53-dependent apoptosis. Therefore, this study indicates that dynamic acetylation is a molecular switch in the regulation of MDM2 substrate specificity, revealing further insight into the posttranslational regulation of the MDM2/p53 cell survival axis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • Acetylation
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Lysine / genetics
  • Lysine / metabolism
  • MCF-7 Cells
  • Oncogenes*
  • Protein Binding
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • RNA Interference
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Specific Peptidase 7 / metabolism
  • Ubiquitination
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*


  • Tumor Suppressor Protein p53
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Proto-Oncogene Proteins c-mdm2
  • Ubiquitin-Specific Peptidase 7
  • SIRT1 protein, human
  • Sirtuin 1
  • Lysine