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MDMX inhibits the p300/CBP-mediated acetylation of p53
Peter Sabbatini1, Frank McCormick
1Research Institute, University of California, School of Medicine, San Francisco, California 94080, USA.
Abstract:
The p300/CBP-mediated acetylation of p53 significantly potentiates p53-mediated transactivation and growth inhibition. MDM2 inhibits the acetylation of p53 by p300/CBP through a mechanism that requires a stable p53-MDM2 interaction and that is sensitive to the deacetylase inhibitor, TSA. MDMX is an MDM2-like protein that shares with MDM2 the ability to interact with p53 and, in turn, inhibit p53-mediated transcription. It was therefore of interest to determine if MDMX could also inhibit the acetylation of p53 by p300/CBP. We demonstrate that MDMX dramatically inhibits the acetylation of p53 induced by both endogenous and ectopically expressed p300/CBP. We also demonstrate that the p53-binding domain of MDMX is required for the MDMX-mediated inhibition of p53 acetylation. Our results indicate that MDMX shares with MDM2 the ability to regulate a potentially important post-translational modification of p53. These results may have important biologic implications with respect to the MDMX-mediated regulation of p53 activity during development.
Insights
MDMX protein inhibits the acetylation of p53, a crucial step for p53 activity. This finding reveals a new regulatory mechanism for p53, impacting its role in cell growth and development.
Area of Science:
- Molecular Biology
- Cellular Biology
- Cancer Research
Background:
- p53 acetylation by p300/CBP enhances its tumor-suppressive functions.
- MDM2 inhibits p53 acetylation, regulating p53 activity.
- MDMX, an MDM2-like protein, interacts with p53 and inhibits transcription.
Purpose of the Study:
- To investigate whether MDMX can inhibit p53 acetylation by p300/CBP.
- To understand the role of MDMX in regulating p53 post-translational modifications.
Main Methods:
- Co-immunoprecipitation assays to study protein interactions.
- Western blotting to detect p53 acetylation.
- Experiments using endogenous and ectopically expressed proteins.
Main Results:
- MDMX significantly inhibits p53 acetylation induced by both endogenous and exogenous p300/CBP.
- The p53-binding domain of MDMX is essential for this inhibitory effect.
- MDMX regulates p53 acetylation, similar to MDM2.
Conclusions:
- MDMX shares with MDM2 the ability to regulate p53 acetylation.
- This regulation of p53 post-translational modification by MDMX has potential biological implications for p53 activity during development.