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.
Kobet
E
E
Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA.
Zeng
X
X
Zhu
Y
Y
Keller
D
D
Lu
H
H
D000107:Acetylation; D000123:Acetyltransferases / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000302:isolation & purification / Q000378:metabolism*; D002457:Cell Extracts; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005720:Gamma Rays; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000302:isolation & purification / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D014466:Ultraviolet Rays; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D002457:Cell Extracts; D004247:DNA; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse