Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate

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 NH2-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 NH2-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.

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

“…These results suggested that acetylation of Lys-317 negatively regulates p53 apoptotic activity. Studies using a p53 K320Q mutant, which mimics constitutive acetylation, support this conclusion (16). Recently Lys-320 of human p53 was shown to be subject to ubiquitylation by E4F1 or neddylation by FBXO11 (17,18).…”

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

“…Covalent modifications of p53 may change target gene preference by imposing conformational changes in p53 that recognize different p53-responsive elements. In this regard, K373 and K382 are necessary for binding of p53 to low-affinity proapoptotic promoters (Knights et al, 2006). Chromatin immunoprecipitation studies show that HIPK2 is necessary in vivo for efficient p300/ p53 corecruitment onto apoptotic promoters of p53AIP1 and Puma.…”

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

“…In this case, low p53 levels in the cytoplasm are unlikely to induce mitochondrial membrane permeabilization, and low p53 levels in the nucleus could titrate p53 binding to chromatin, to restrict its interaction with only those promoters to which it has the highest affinity. Under these conditions, a cell proliferation arrest could be favored in most tissues because p53 apparently binds the promoter of the p21 gene (a major determinant of proliferation arrest) much more efficiently than promoters of many pro-apoptotic genes (Knights et al, 2006). A nonexclusive possibility is that variations in p53 levels may affect its interaction with other proteins proposed to promote cell cycle arrest (e.g.…”