MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins.
p300 acetylates and activates the tumor suppressor p53 after DNA damage. Here, we show that MDM2, a negative-feedback regulator of p53, inhibited p300-mediated p53 acetylation by complexing with these two proteins. First, we purified a p300-MDM2-p53 protein complex from HeLa nuclear extracts, which was inactive in p53 acetylation, but active ... in histone acetylation. Also, wild-type, but not N-terminally deleted, MDM2 inhibited p53 acetylation by p300 in vitro and in vivo. This inhibition was specific for p53, because MDM2 did not affect acetylation of histones or the C terminus of p73 by p300. Consequently, wild-type, but not the mutant, MDM2 repressed the p300-stimulated sequence-specific DNA-binding and transcriptional activities of p53. These results demonstrate that an additional mechanism of p53 inactivation by MDM2 is to inhibit p53 acetylation by p300.
Mesh Terms:
Acetylation, Acetyltransferases, Animals, Cell Cycle Proteins, Cell Extracts, Cell Nucleus, DNA, Gamma Rays, HeLa Cells, Histone Acetyltransferases, Humans, Male, Mice, Nuclear Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Ultraviolet Rays, p300-CBP Transcription Factors
Acetylation, Acetyltransferases, Animals, Cell Cycle Proteins, Cell Extracts, Cell Nucleus, DNA, Gamma Rays, HeLa Cells, Histone Acetyltransferases, Humans, Male, Mice, Nuclear Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Ultraviolet Rays, p300-CBP Transcription Factors
Proc. Natl. Acad. Sci. U.S.A.
Date: Nov. 07, 2000
PubMed ID: 11070080
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