Abstract
Acetylation of multiple lysine residues in the p53 plays critical roles in the protein stability and transcriptional activity of p53. To better understand how p53 acetylation is regulated, we generated a number of p53 mutants and examined acetylation of each mutant in transfected cells. We found that p53 mutants that are defective in tetramer formation are also defective in C-terminal lysine residue acetylation. Consistently, we found that several cancer-derived p53 mutants that bear mutations in the tetramerization domain cannot form oligomers and are defective in C-terminal lysine acetylation, and these mutants are inactive in p21 transactivation. We demonstrated that the acetyltransferase p300 interacts with and promotes acetylation of wild-type p53 but not with any of the artificially generated or human cancer-derived p53 mutants that are defective in oligomerization. These results, combined with a computer-aided crystal structure analysis, suggest a model in which p53 oligomerization precedes its acetylation by providing docking sites for acetyltransferases.
Highlights
The tumor suppressor p53 is a critical mediator of the cellular stress response, maintaining genomic integrity and preventing oncogenic transformation by inducing both cell cycle arrest and apoptotic cell death [1]
We found that p53 mutants that are defective in tetramer formation are defective in C-terminal lysine residue acetylation
Nuclear-confined p53 NES Mutant Is Defective in Lys-382 Acetylation—p53 shuttles between the nucleus and cytoplasm via its bipartite nuclear localization signal (NLS) [24] and its nuclear export signal (NES) [20, 25] sequences
Summary
The tumor suppressor p53 is a critical mediator of the cellular stress response, maintaining genomic integrity and preventing oncogenic transformation by inducing both cell cycle arrest and apoptotic cell death [1]. Our data indicate that the acetyltransferase p300 interacts with and promotes acetylation of wild-type p53, but not with any of the artificially generated or human cancer derived p53 mutants that are defective in oligomerization.
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