Deficiencies in mouse Myh and Ogg1 result in tumor predisposition and G to T mutations in codon 12 of the K-Ras oncogene in lung tumors
Deficiencies in mouse Myh and Ogg1 result in tumor predisposition and G to T mutations in codon 12 of the K-Ras oncogene in lung tumors
复制标题
DOI：
10.1158/0008-5472.can-03-3834
复制
发表时间：
2004-05-01
期刊：
影响因子：
11.2
通讯作者：
Miller, JH
中科院分区：
文献类型：
--
作者：
Xie, YL;Yang, HJ;Miller, JH
DNA 氧化损伤是由正常细胞代谢的氧化副产物不可避免地持续产生的。 DNA 损伤修复基因 muff 和 mutM 可防止大肠杆菌中活性氧引起的 G 到 T 突变，但哺乳动物对应基因 Myh 和 Ogg1 的缺陷是否直接参与肿瘤发生仍存在争议。在这里，我们证明 Myh 和 Ogg1 的缺陷使 65.7% 的小鼠易患肿瘤，主要是肺癌和卵巢肿瘤以及淋巴瘤。值得注意的是，随后的分析在 75% 的肺肿瘤中发现了 K-ras 癌基因的激活热点（密码子 12）处的 G 到 T 突变，但在其邻近的正常组织中没有发现突变。此外，恶性肺部肿瘤随着Msh2（一种也参与氧化DNA损伤修复的错配修复基因）的组合杂合性而增加。因此，DNA 氧化损伤似乎在肿瘤发生中起因果作用，并且 K-ras 的密码子 12 可能是肺肿瘤发生中的重要下游靶标。需要多种氧化修复基因来防止突变和肿瘤形成。这里描述的小鼠为研究肿瘤发生中氧化 DNA 损伤的机制以及研究预防或治疗方法提供了一个有价值的模型。
Oxidative DNA damage is unavoidably and continuously generated by oxidant byproducts of normal cellular metabolism. The DNA damage repair genes, muff and mutM, prevent G to T mutations caused by reactive oxygen species in Escherichia coli, but it has remained debatable whether deficiencies in their mammalian counterparts, Myh and Ogg1, are directly involved in tumorigenesis. Here, we demonstrate that deficiencies in Myh and Ogg1 predispose 65.7% of mice to tumors, predominantly lung and ovarian tumors, and lymphomas. Remarkably, subsequent analyses identified G to T mutations in 75% of the lung tumors at an activating hot spot, codon 12, of the K-ras oncogene, but none in their adjacent normal tissues. Moreover, malignant lung tumors were increased with combined heterozygosity of Msh2, a mismatch repair gene involved in oxidative DNA damage repair as well. Thus, oxidative DNA damage appears to play a causal role in tumorigenesis, and codon 12 of K-ras is likely to be an important downstream target in lung tumorigenesis. The multiple oxidative repair genes are required to prevent mutagenesis and tumor formation. The mice described here provide a valuable model for studying the mechanisms of oxidative DNA damage in tumorigenesis and investigating preventive or therapeutic approaches.