The acetylase activity of p300 is dispensable for MDM2 stabilization.
It has been shown that p300 binds to MDM2 and leads to down-regulation of the p53 function. However, it remains unclear whether the acetylase activity of p300 is necessary for regulating MDM2 stability. In this study, we address this issue. First, p300 did not acetylate MDM2 in solution and in cells. Second, overexpression of p300 in cells increased the level of the MDM2 protein but not its mRNA. Similarly, the acetylase-defective p300 AT2 mutant stabilized the MDM2 protein as well. Consistently, the deacetylase inhibitor, trichostatin A, did not significantly affect the half-life of the endogenous MDM2 protein, whereas p300 enhanced the half-life of MDM2. Finally, both wild type and acetylase-defective mutant p300 proteins associated with MDM2 in nuclear body-like structures where MDM2 might be protected from proteasomal degradation. Thus, these results suggest that p300 appears to stabilize MDM2 by retaining this protein in a specific nuclear structure rather than by acetylating it.
Zeng
Shelya X
SX
Department of Biochemistry and Molecular Biology and the Molecular Medicine Division, Oregon Health and Science University, Portland, Oregon 97239, USA.
Jin
Yetao
Y
Kuninger
David T
DT
Rotwein
Peter
P
Lu
Hua
H
D000107:Acetylation; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D050881:E1A-Associated p300 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015534:Trans-Activators; D003513:Cycloheximide; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2