p53 acetylation is crucial for its transcription-independent proapoptotic functions.
Acetylation of p53 at carboxyl-terminal lysine residues enhances its transcriptional activity associated with cell cycle arrest and apoptosis. Here we demonstrate that p53 acetylation at Lys-320/Lys-373/Lys-382 is also required for its transcription-independent functions in BAX activation, reactive oxygen species production, and apoptosis in response to the histone deacetylase inhibitors (HDACi) suberoylanilide hydroxamic acid and LAQ824. Knock-out of p53 markedly reduced HDACi-induced apoptosis. Unexpectedly, expression of transactivation-deficient p53 variants sensitized p53-null cells to HDACi-mediated BAX-dependent apoptosis, whereas knockdown of endogenous mutant p53 in cancer cells reduced HDACi-mediated cytotoxicity. Evaluation of the mechanisms controlling this response led to the discovery of a novel interaction between p53 and Ku70. The association between these two proteins was acetylation-independent, but acetylation of p53 could prevent and disrupt the Ku70-BAX complex and enhance apoptosis. These results suggest a new mechanism of acetylated p53 transcription-independent regulation of apoptosis.
Yamaguchi
Hirohito
H
Department of Pharmacology and Pennsylvania State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Woods
Nicholas T
NT
Piluso
Landon G
LG
Lee
Heng-Huan
HH
Chen
Jiandong
J
Bhalla
Kapil N
KN
Monteiro
Alvaro
A
Liu
Xuan
X
Hung
Mien-Chie
MC
Wang
Hong-Gang
HG
D034961:Antigens, Nuclear / Q000096:biosynthesis; D017209:Apoptosis; D002453:Cell Cycle; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D000072200:Ku Autoantigen; D008239:Lysine / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013347:Subcellular Fractions; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D005982:Glutathione Transferase; D006655:Histone Deacetylases; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D008239:Lysine