Division of Endocrinology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
PLoS One. 2011;6(9):e24813. doi: 10.1371/journal.pone.0024813. Epub 2011 Sep 27.
Phosphorylation at murine Serine 18 (human Serine 15) is a critical regulatory process for the tumor suppressor function of p53. p53Ser18 residue is a substrate for ataxia-telangiectasia mutated (ATM) and ATM-related (ATR) protein kinases. Studies of mice with a germ-line mutation that replaces Ser18 with Ala (p53(S18A) mice) have demonstrated that loss of phosphorylation of p53Ser18 leads to the development of tumors, including lymphomas, fibrosarcomas, leukemia and leiomyosarcomas. The predominant lymphoma is B-cell lymphoma, which is in contrast to the lymphomas observed in Atm(-/-) animals. This observation and the fact that multiple kinases phosphorylate p53Ser18 suggest Atm-independent tumor suppressive functions of p53Ser18. Therefore, in order to examine p53Ser18 function in relationship to ATM, we analyzed the lifespan and tumorigenesis of mice with combined mutations in p53Ser18 and Atm. Surprisingly, we observed no cooperation in survival and tumorigenesis in compound p53(S18A) and Atm(-/-) animals. However, we observed embryonic lethality in the compound mutant animals. In addition, the homozygous p53Ser18 mutant allele impacted the weight of Atm(-/-) animals. These studies examine the genetic interaction of p53Ser18 and Atm in vivo. Furthermore, these studies demonstrate a role of p53Ser18 in regulating embryonic survival and motor coordination.
丝氨酸 18 位点（人类为丝氨酸 15 位点）的磷酸化是肿瘤抑制因子 p53 发挥功能的关键调节过程。p53 的丝氨酸 18 残基是共济失调毛细血管扩张突变（ATM）和 ATM 相关（ATR）蛋白激酶的底物。研究用一个替代丝氨酸 18 为丙氨酸的基因敲入突变（p53(S18A)）的小鼠发现，p53 丝氨酸 18 磷酸化缺失会导致肿瘤的发生，包括淋巴瘤、纤维肉瘤、白血病和平滑肌肉瘤。主要的淋巴瘤为 B 细胞淋巴瘤，这与 Atm(-/-)动物中观察到的淋巴瘤不同。这一观察结果以及多个激酶磷酸化 p53 丝氨酸 18 的事实表明，p53 丝氨酸 18 具有 ATM 非依赖性的肿瘤抑制功能。因此，为了研究 p53 丝氨酸 18 在与 ATM 相关的功能，我们分析了同时存在 p53 丝氨酸 18 和 Atm 突变的小鼠的寿命和肿瘤发生情况。令人惊讶的是，我们在复合 p53(S18A)和 Atm(-/-)动物中没有观察到生存和肿瘤发生的协同作用。然而，我们观察到复合突变动物存在胚胎致死性。此外，p53 丝氨酸 18 纯合突变等位基因影响了 Atm(-/-)动物的体重。这些研究在体内研究了 p53 丝氨酸 18 和 Atm 的遗传相互作用。此外，这些研究表明 p53 丝氨酸 18 在调节胚胎存活和运动协调方面发挥了作用。
