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Acetylation directs MDM2 activity
As a tumor suppressor, the transcription factor p53 promotes cell death when cellular and genomic integrity is compromised. The ubiquitin E3 ligase MDM2 marks p53 and itself for degradation and is thus a critical regulatory node controlling cell death and survival. Nihira et al. explored what dictated autoubiquitination versus p53-targeted activity by MDM2 and found that acetylation at two lysine residues in its nuclear localization sequence changed intermolecular interactions. When acetylated, an increased interaction with a deubiquitinase stabilized this E3 ubiquitin ligase and enabled greater activity toward p53. Deacetylation of these sites in response to genotoxic stress promoted more MDM2 autoubiquitination, thereby increasing p53 stability and promoting cell death. Thus, acetylation in this motif of MDM2 contributes to the cell’s decision between survival and death.
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.