Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23
Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23
复制标题
DOI：
10.1038/sj.emboj.7600363
复制
发表时间：
2004-09-15
期刊：
影响因子：
11.4
通讯作者：
Jacks, T
中科院分区：
文献类型：
--
作者：
MacPherson, D;Kim, JH;Jacks, T
P53肿瘤抑制因子Ser 20（鼠Ser 23）的磷酸化被认为是破坏p53与其负调节因子MDM 2相互作用并使p53稳定的关键。为了确定Ser 23对p53体内功能的重要性，我们产生了一种小鼠，其中内源性p53基因座被靶向以丙氨酸取代Ser 23。我们发现，在Ser 23突变小鼠产生的小鼠胚胎成纤维细胞中，Ser 23突变并没有显着降低IR诱导的p53蛋白稳定性或p53依赖性细胞周期阻滞。然而，在Ser 23突变的胸腺细胞和发育中的小脑，p53稳定IR后下降，并观察到抗凋亡。纯合子Ser 23突变动物的寿命缩短，但没有发生p53-/-小鼠特有的胸腺淋巴瘤或肉瘤。相反，Ser 23突变动物在1至2年内死亡，肿瘤最常见的是B细胞谱系。这些数据支持Ser 20/23磷酸化在p53稳定、凋亡和肿瘤抑制中的重要作用。
Phosphorylation of the p53 tumor suppressor at Ser20 ( murine Ser23) has been proposed to be critical for disrupting p53 interaction with its negative regulator, MDM2, and allowing p53 stabilization. To determine the importance of Ser23 for the function of p53 in vivo, we generated a mouse in which the endogenous p53 locus was targeted to replace Ser23 with alanine. We show that, in mouse embryonic fibroblasts generated from Ser23 mutant mice, Ser23 mutation did not dramatically reduce IR-induced p53 protein stabilization or p53-dependent cell cycle arrest. However, in Ser23 mutant thymocytes and in the developing cerebellum, p53 stabilization following IR was decreased and resistance to apoptosis was observed. Homozygous Ser23 mutant animals had a reduced lifespan, but did not develop thymic lymphomas or sarcomas that are characteristic of p53-/- mice. Instead, Ser23 mutant animals died between 1 and 2 years with tumors that were most commonly of B-cell lineage. These data support an important role for Ser20/23 phosphorylation in p53 stabilization, apoptosis and tumor suppression.