MDMX inhibits the p300/CBP-mediated acetylation of p53.
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.
Sabbatini
Peter
P
Research Institute, University of California, School of Medicine, San Francisco, California 94080, USA.
McCormick
Frank
F
D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases