Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate.
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.
Knights
Chad D
CD
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Catania
Jason
J
Di Giovanni
Simone
S
Muratoglu
Selen
S
Perez
Ricardo
R
Swartzbeck
Amber
A
Quong
Andrew A
AA
Zhang
Xiaojing
X
Beerman
Terry
T
Pestell
Richard G
RG
Avantaggiati
Maria Laura
ML
D000107:Acetylation; D000595:Amino Acid Sequence / Q000502:physiology; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D018816:Genes, cdc / Q000502:physiology; D006801:Humans; D008239:Lysine / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000502:physiology; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D008239:Lysine