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J Cell Biol ; 173(4): 533-44, 2006 May 22.
Article in English | MEDLINE | ID: mdl-16717128

ABSTRACT

The activity of the p53 gene product is regulated by a plethora of posttranslational modifications. An open question is whether such posttranslational changes act redundantly or dependently upon one another. We show that a functional interference between specific acetylated and phosphorylated residues of p53 influences cell fate. Acetylation of lysine 320 (K320) prevents phosphorylation of crucial serines in the NH(2)-terminal region of p53; only allows activation of genes containing high-affinity p53 binding sites, such as p21/WAF; and promotes cell survival after DNA damage. In contrast, acetylation of K373 leads to hyperphosphorylation of p53 NH(2)-terminal residues and enhances the interaction with promoters for which p53 possesses low DNA binding affinity, such as those contained in proapoptotic genes, leading to cell death. Further, acetylation of each of these two lysine clusters differentially regulates the interaction of p53 with coactivators and corepressors and produces distinct gene-expression profiles. By analogy with the "histone code" hypothesis, we propose that the multiple biological activities of p53 are orchestrated and deciphered by different "p53 cassettes," each containing combination patterns of posttranslational modifications and protein-protein interactions.


Subject(s)
Cell Cycle/genetics , Gene Expression Regulation/genetics , Protein Processing, Post-Translational/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Acetylation , Amino Acid Sequence/physiology , Apoptosis/genetics , Binding Sites/genetics , Cell Line, Tumor , Cell Survival/genetics , Cell Transformation, Neoplastic/genetics , Genes, cdc/physiology , Humans , Lysine/metabolism , Phosphorylation , Promoter Regions, Genetic/genetics , Protein Binding/genetics , Protein Structure, Tertiary/physiology , Regulatory Elements, Transcriptional/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , Tumor Suppressor Protein p53/chemistry
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