Chao Connie, Hergenhahn Manfred, Kaeser Matthias D, Wu Zhiqun, Saito Shin'ichi, Iggo Richard, Hollstein Monica, Appella Ettore, Xu Yang
Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0322, USA.
J Biol Chem. 2003 Oct 17;278(42):41028-33. doi: 10.1074/jbc.M306938200. Epub 2003 Aug 8.
Phosphorylation of mouse p53 at Ser18 occurs after DNA damage. To determine the physiological roles of this phosphorylation event in p53-dependent DNA damage responses, a Ser18 to Ala missense mutation was introduced into the germline of mice. Thymocytes and fibroblasts from the knock-in mice show reduced transactivation of many p53 target genes following DNA damage. p53 protein stabilization and DNA binding are similar in knock-in and wild type mice, but C-terminal acetylation was defective, consistent with a role for Ser18 in the recruitment of transcriptional co-activators. The apoptotic response of knock-in thymocytes to ionizing radiation is intermediate between that of wild type and p53 null thymocytes. Despite impaired transcriptional and apoptotic responses, the knock-in mice are not prone to spontaneous tumorigenesis. This indicates that neither phosphorylation of p53 on Ser18 by ATM nor a full transcriptional response is essential to prevent spontaneous tumor formation in mice.
小鼠p53的丝氨酸18位点磷酸化发生在DNA损伤之后。为了确定这一磷酸化事件在p53依赖性DNA损伤反应中的生理作用，将丝氨酸18突变为丙氨酸的错义突变引入小鼠种系。敲入小鼠的胸腺细胞和成纤维细胞在DNA损伤后显示出许多p53靶基因的转录激活减少。敲入小鼠和野生型小鼠的p53蛋白稳定性和DNA结合相似，但C末端乙酰化存在缺陷，这与丝氨酸18在招募转录共激活因子中的作用一致。敲入胸腺细胞对电离辐射的凋亡反应介于野生型和p53基因敲除胸腺细胞之间。尽管转录和凋亡反应受损，但敲入小鼠不易发生自发肿瘤形成。这表明，ATM介导的p53丝氨酸18位点磷酸化以及完整的转录反应对于预防小鼠自发肿瘤形成都不是必需的。
