Analysis of ku80-mutant mice and cells with deficient levels of p53
Analysis of ku80-mutant mice and cells with deficient levels of p53
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DOI：
10.1128/mcb.20.11.3772-3780.2000
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发表时间：
2000-06-01
影响因子：
5.3
通讯作者：
Hasty, P
中科院分区：
文献类型：
--
作者：
Lim, DS;Vogel, H;Hasty, P
Ku 80的缺乏导致对电离辐射的敏感性增加、淋巴细胞发育缺陷、年龄相关表型的早发和过早复制性衰老。在这里，我们研究p53对ku 80突变小鼠和细胞表型的作用。降低p53的水平增加了ku 80（-/-）小鼠的癌症发病率。约20%的ku 80（-/-）p53（+/-）小鼠在40周时发展为广谱癌症，所有ku 80（-/-）p53（-/-）小鼠在16周时发展为前B细胞淋巴瘤。降低p53的水平通过使ku 80（-/-）细胞能够自发永生化来拯救ku 80（-/-）细胞群体免于复制性衰老。由于p53突变，双突变细胞的G（1）/S检查点受损，并且由于Ku 80突变，双突变细胞对γ射线和活性氧超敏感。这些数据表明，复制性衰老是由p53依赖性细胞周期对ku 80（-/-）细胞中受损DNA的反应引起的，并且p53对于防止ku 80（-/-）小鼠中的前B细胞淋巴瘤的极早期发作是必不可少的。
Absence of Ku80 results in increased sensitivity to ionizing radiation, defective lymphocyte development, early onset of an age-related phenotype, and premature replicative senescence. Here we investigate the role of p53 on the phenotype of ku80-mutant mice and cells. Reducing levels,of p53 increased the cancer incidence for ku80(-/-) mice. About 20% of ku80(-/-) p53(+/-) mice developed a broad spectrum of cancer by 40 weeks and all ku80(-/-) p53(-/-) mice developed pro-B-cell lymphoma by 16 weeks. Reducing levels of p53 rescued populations of ku80(-/-) cells from replicative senescence by enabling spontaneous immortalization. The double-mutant cells are impaired for the G(1)/S checkpoint due to the p53 mutation and are hypersensitive to gamma-radiation and reactive oxygen species due to the Ku80 mutation. These data show that replicative senescence is caused by a p53-dependent cell cycle response to damaged DNA in ku80(-/-) cells and that p53 is essential for preventing very early onset of pro-B-cell lymphoma in ku80(-/-) mice.