DNA double-strand breaks, p53, and apoptosis during lymphomagenesis in scid/scid mice.
DNA double-strand breaks, p53, and apoptosis during lymphomagenesis in scid/scid mice.
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发表时间：
1998-07
期刊：
影响因子：
11.2
通讯作者：
K. Gurley;K. Vo;C. Kemp
中科院分区：
文献类型：
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作者：
K. Gurley;K. Vo;C. Kemp
p53的肿瘤抑制表型被认为是由于其响应于DNA损伤和由此产生的细胞周期停滞或凋亡而积累。scid/scid小鼠由于DNA依赖性蛋白激酶（DNAPK）的突变而在DNA双链断裂修复中有缺陷。用γ射线或N-乙基-N-亚硝基脲治疗scid/scid小鼠，T细胞淋巴瘤的发病率约为86%，而野生型小鼠的发病率低于6%。在scid/scid小鼠中，其他肿瘤类型的发生率没有增加，这表明在这些小鼠中未修复的DNA双链断裂类型不是强致癌性的。为了确定DNAPK和p53突变是否相互作用，我们检查了两种基因缺陷的小鼠。scid/scid p53-/-和scid/scid p53+/-小鼠自发发生淋巴瘤的潜伏期比单独缺陷的小鼠短。在scid/scid p53 +/-小鼠的100%肿瘤中观察到野生型p53等位基因的丢失，表明对p53的强选择性。相反，在scid/scid p53+/+小鼠的淋巴瘤中，p53没有被灭活。将这些荷瘤小鼠暴露于γ射线导致所有肿瘤中p53蛋白积累和高水平的细胞凋亡，而在scid/scid p53+/-小鼠的肿瘤中没有观察到。因此，肿瘤发生的分子途径存在分歧。当p53在生殖细胞系中是杂合子时，发生野生型等位基因的丢失，并且肿瘤变得抗凋亡。当p53在生殖细胞系中为野生型时，p53未失活，并且肿瘤保持高度凋亡敏感性。
The tumor-suppressing phenotype of p53 is thought to be due to its accumulation in response to DNA damage and resultant cell cycle arrest or apoptosis. scid/scid mice are defective in DNA double-strand break repair due to a mutation in DNA-dependent protein kinase (DNAPK). Treatment of scid/scid mice with gamma radiation or N-ethyl-N-nitrosourea resulted in approximately 86% incidence of T-cell lymphomas, compared with <6% in wild-type mice. The incidence of other tumor types was not increased in scid/scid mice, suggesting that the types of DNA double-strand break that are unrepaired in these mice are not strongly carcinogenic. To determine whether mutations in DNAPK and p53 interact, we examined mice deficient in both genes. Both scid/scid p53-/- and scid/scid p53+/- mice spontaneously developed lymphomas at shorter latency than did mice with either defect alone. Loss of the wild-type p53 allele was observed in 100% of tumors from scid/scid p53 +/- mice, indicating strong selection against p53. In contrast, p53 was not inactivated in lymphomas from scid/scid p53+/+ mice. Exposure of these tumor-bearing mice to gamma radiation resulted in p53 protein accumulation and high levels of apoptosis in all tumors that were not observed in tumors from scid/scid p53+/- mice. Thus, there was a bifurcation of molecular pathways to tumorigenesis. When p53 was heterozygous in the germ line, loss of the wild-type allele occurred, and the tumors became apoptosis resistant. When p53 was wild type in the germ line, p53 was not inactivated, and the tumors remained highly apoptosis sensitive.