Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice
Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice
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DOI：
10.1158/0008-5472.can-05-2980
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发表时间：
2005-12-15
期刊：
影响因子：
11.2
通讯作者：
Vijg, J
中科院分区：
文献类型：
--
作者：
Busuttil, RA;Garcia, AM;Vijg, J
活性氧被认为是哺乳动物癌症和衰老的原因。缺乏抗氧化酶铜锌超氧化物歧化酶（Sod1）的小鼠寿命缩短，肝癌发病率升高。为了验证此类小鼠的癌症倾向表型是由于加速的自发突变积累所致的假设，我们将这些突变体与含有中性 lacZ 突变报告基因的小鼠进行了杂交。 2个月大时，杂交动物肝脏中的lacZ突变频率已经是同龄同窝对照动物的两倍。这种突变频率的差异在 6 个月大时增加到 3 倍以上，此后不再增加。 Sod1 缺失小鼠肝脏突变谱的表征主要表明 GC-to-TA 转换和 GC-to-AT 转换，这是氧化应激的标志性突变。肝脏中突变积累的加速伴随着凋亡细胞频率的增加，如 6 月龄和 12 月龄时末端脱氧核糖核苷酸转移酶介导的 dUTP 缺口末端标记和 caspase 3 染色细胞的增加所表明的。在肾脏中，不早于 6 个月时发现突变频率比对照组高出约 2.5 倍。在大脑或脾脏中没有观察到突变积累增加。这些结果支持了这样的假设：氧化应激是哺乳动物癌症的重要致病因素。
Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice deficient for the antioxidant enzyme CuZn-superoxide dismutase (Sod1) have a decreased life span and an elevated incidence of liver cancer. To test the hypothesis that the cancer-prone phenotype in such mice is due to accelerated spontaneous mutation accumulation, we crossed these mutants with mice harboring a neutral lacZ mutation reporter gene. At 2 months of age, the lacZ mutation frequency in the liver of the hybrid animals was already twice as high as in littermate controls of the same age. This difference in mutation frequency increased to > 3-fold at 6 months of age, after which it did not increase any further. Characterization of the mutation spectra in liver of the Sod1-null mice indicated mainly GC-to-TA transversions and GC-to-AT transitions, signature mutations of oxidative stress. The accelerated mutation accumulation in liver was accompanied by an increased frequency of apoptotic cells, as indicated by an increase in both terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling- and caspase 3-stained cells at 6 and 12 months of age. In kidney, an elevated mutation frequency above controls of similar to 2.5-fold was found not earlier than at 6 months. No increased mutation accumulation was observed in brain or spleen. These results support the hypothesis, that oxidative stress is an important causal factor of cancer in mammals.