MDM2 is the most important negative regulator of tumor suppressor p53. Both RING finger domain and acidic domain of MDM2 contribute to the ubiquitination of p53. The crosstalk between ubiquitination and acetylation of p53 prompts us to examine whether acidic domain is essential for MDM2 to regulate the acetylation of p53. We find that the acidic domain of MDM2 is necessary to inhibit p300-mediated acetylation of p53 as well as to mediate the deacetylation of p53. Our results indicate that acidic domain of MDM2 Provides essential information for acetyltransferase p300 and deacetylase HDAC1 and is indispensable for MDM2 to negatively regulate the acetylation of p53. (C) 2008 Elsevier Inc. All rights reserved.