Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression
Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression
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DOI：
10.1038/sj.emboj.7601167
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发表时间：
2006-06-07
期刊：
影响因子：
11.4
通讯作者：
Xu, Yang
中科院分区：
文献类型：
--
作者：
Chao, Connie;Herr, Deron;Xu, Yang
小鼠p53在DNA损伤后在Ser 18和Ser 23处磷酸化。为了确定这两个磷酸化事件是否在激活p53反应中具有协同作用，我们同时将Ser 18/23突变为Ala突变引入小鼠内源性p53位点。虽然在暴露于IR的p53（S18 A）和p53（S23 A）胸腺细胞中观察到凋亡的部分缺陷，但在p53（S18/23 A）胸腺细胞中p53依赖性凋亡基本上被消除，表明这两个事件在激活p53依赖性凋亡中具有关键和协同作用。此外，p53（S18/23 A）而不是p53（S18 A）可以完全挽救由大量p53依赖性神经元凋亡引起的Xrcc 4（-/-）小鼠的胚胎致死性。然而，某些p53依赖的功能，包括G（1）/S检查点和细胞衰老，在p53（S18/23 A）细胞中部分保留。虽然p53（S18 A）小鼠不容易患癌症，但p53（S18/23 A）小鼠发生了与p53（S23 A）和p53（-/-）小鼠不同的恶性肿瘤谱。有趣的是，Xrcc 4（-/-）p53（S18/23 A）小鼠没有像在Xrcc 4（-/-）p53（-/-）动物中均匀发展的pro-B细胞淋巴瘤那样发展肿瘤，但表现出加速老化的典型发育缺陷。因此，Ser 18和Ser 23磷酸化对于p53依赖性抑制肿瘤发生在某些生理环境中是重要的。
Mouse p53 is phosphorylated at Ser18 and Ser23 after DNA damage. To determine whether these two phosphorylation events have synergistic functions in activating p53 responses, we simultaneously introduced Ser18/23 to Ala mutations into the endogenous p53 locus in mice. While partial defects in apoptosis are observed in p53(S18A) and p53(S23A) thymocytes exposed to IR, p53- dependent apoptosis is essentially abolished in p53(S18/23A) thymocytes, indicating that these two events have critical and synergistic roles in activating p53- dependent apoptosis. In addition, p53(S18/23A), but not p53(S18A) could completely rescue embryonic lethality of Xrcc4(-/-) mice that is caused by massive p53- dependent neuronal apoptosis. However, certain p53- dependent functions, including G(1)/S checkpoint and cellular senescence, are partially retained in p53(S18/23A) cells. While p53(S18A) mice are not cancer prone, p53(S18/23A) mice developed a spectrum of malignancies distinct from p53(S23A) and p53(-/-) mice. Interestingly, Xrcc4(-/-) p53(S18/23A) mice fail to develop tumors like the pro-B cell lymphomas uniformly developed in Xrcc4(-/-) p53(-/-) animals, but exhibit developmental defects typical of accelerated ageing. Therefore, Ser18 and Ser23 phosphorylation is important for p53- dependent suppression of tumorigenesis in certain physiological context.