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J. Cell Biol. 173 (4): 533-544

Copyright © 2006 by the Rockefeller University Press.

Article

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

Chad D. Knights1, Jason Catania1, Simone Di Giovanni1, Selen Muratoglu2, Ricardo Perez1, Amber Swartzbeck1, Andrew A. Quong3, Xiaojing Zhang4, Terry Beerman4, Richard G. Pestell3, , and Maria Laura Avantaggiati1

1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057
2 Department of Pathology, Center for Vascular and Inflammatory Disease, University of Maryland, Baltimore, MD 21201
3 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
4 Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, NY 14203

Correspondence to Maria Laura Avantaggiati: ma364{at}georgetown.edu

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.

C.D. Knights and J. Catania contributed equally to this paper.

Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; CPI, cyclopropylpyrroloindole; EMSA, electrophoretic mobility shift assay; PCAF, p300/CBP-associated factor; WT, wild-type.

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