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p53 transcriptional activity is essential for p53‐dependent apoptosis following DNA damage
Author(s) -
Chao Connie,
Saito Shin'ichi,
Kang Jian,
Anderson Carl W.,
Appella Ettore,
Xu Yang
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.18.4967
Subject(s) - biology , dna damage , psychological repression , apoptosis , dna , microbiology and biotechnology , acetylation , transcription (linguistics) , homologous recombination , histone , mutant , dna repair , transcription factor , cell cycle , cell cycle checkpoint , genetics , gene expression , gene , linguistics , philosophy
p53‐mediated transcription activity is essential for cell cycle arrest, but its importance for apoptosis remains controversial. To address this question, we employed homologous recombination and LoxP/Cre‐mediated deletion to produce mutant murine embryonic stem (ES) cells that express p53 with Gln and Ser in place of Leu25 and Trp26, respectively. p53 Gln25Ser26 was stable but did not accumulate after DNA damage; the expression of p21/Waf1 and PERP was not induced, and p53‐dependent repression of MAP4 expression was abolished. Therefore, p53 Gln25Ser26 is completely deficient in transcriptional activation and repression activities. After DNA damage by UV radiation, p53 Gln25Ser26 was phosphorylated at Ser18 but was not acetylated at C‐terminal sites, and its DNA binding activity did not increase, further supporting a role for p53 acetylation in the activation of sequence‐specific DNA binding activity. Most importantly, p53 Gln25Ser26 mouse thymocytes and ES cells, like p53 −/− cells, did not undergo DNA damage‐induced apoptosis. We conclude that the transcriptional activities of p53 are required for p53‐dependent apoptosis.