Acetylation of mouse p53 at lysine 317 negatively regulates p53 apoptotic activities after DNA damage.
Posttranslational modifications of p53, including phosphorylation and acetylation, play important roles in regulating p53 stability and activity. Mouse p53 is acetylated at lysine 317 by PCAF and at multiple lysine residues at the extreme carboxyl terminus by CBP/p300 in response to genotoxic and some nongenotoxic stresses. To determine the physiological roles of p53 acetylation at lysine 317, we introduced a Lys317-to-Arg (K317R) missense mutation into the endogenous p53 gene of mice. p53 protein accumulates to normal levels in p53(K317R) mouse embryonic fibroblasts (MEFs) and thymocytes after DNA damage. While p53-dependent gene expression is largely normal in p53(K317R) MEFs after various types of DNA damage, increased p53-dependent apoptosis was observed in p53(K317R) thymocytes, epithelial cells from the small intestine, and cells from the retina after ionizing radiation (IR) as well as in E1A/Ras-expressing MEFs after doxorubicin treatment. Consistent with these findings, p53-dependent expression of several proapoptotic genes was significantly increased in p53(K317R) thymocytes after IR. These findings demonstrate that acetylation at lysine 317 negatively regulates p53 apoptotic activities after DNA damage.
Chao
Connie
C
Section of Molecular Biology, Division of Biological Sciences, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
Wu
Zhiqun
Z
Mazur
Sharlyn J
SJ
Borges
Helena
H
Rossi
Matteo
M
Lin
Tongxiang
T
Wang
Jean Y J
JY
Anderson
Carl W
CW
Appella
Ettore
E
Xu
Yang
Y
D000107:Acetylation; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D007421:Intestine, Small / Q000166:cytology / Q000528:radiation effects; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D046228:Microarray Analysis; D050505:Mutant Proteins / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D011839:Radiation, Ionizing; D012160:Retina / Q000166:cytology / Q000528:radiation effects; D013816:Thermodynamics; D013950:Thymus Gland / Q000166:cytology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53; D015689:Oncogene Protein p21(ras); D008239:Lysine