Activation of the K-ras protooncogene in lung tumors from rats and mice chronically exposed to tetranitromethane.
Activation of the K-ras protooncogene in lung tumors from rats and mice chronically exposed to tetranitromethane.
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长期暴露于四硝基甲烷的大鼠和小鼠肺部肿瘤中 K-ras 原癌基因的激活。
作者：
S. Stowers;P. Glover;S. Reynolds;L. Boone;R. Maronpot;M. Anderson
在长期吸入四硝基甲烷（一种用于多种工业过程的高挥发性化合物）的Fischer 344大鼠和C57 BL/6 X C3 H F1小鼠的肺肿瘤中检测到显性转化基因。大鼠肺肿瘤分为腺癌、鳞状细胞癌（表皮样癌）或腺鳞癌。小鼠肺肿瘤被分类为乳头状腺癌或腺瘤。在这两个物种中，肿瘤在形态上与人类的肺肿瘤相似。使用NIH/3 T3小鼠成纤维细胞的转染试验在74%（14/19）的大鼠肺肿瘤和100%（4/4）的小鼠肺肿瘤中检测到转化基因。Southern杂交分析表明，转化基因是一个激活的K-ras原癌基因在这两个物种。通过对K-ras基因第一外显子的克隆和序列测定，比较了正常人DNA和肿瘤DNA转化的两种细胞系DNA中K-ras基因第一外显子的差异。实验结果表明，两种转染DNA中K-ras癌基因第12位密码子第2位碱基均存在GC → AT的转换。寡核苷酸杂交表明，所有的大鼠和小鼠转染有这种激活病变。然后测试另外的肿瘤DNA中是否存在具有GC----AT转换的突变等位基因。所有测试的大鼠肿瘤和所有测试的小鼠肿瘤都存在这种突变。使用第12密码子周围的正常寡核苷酸序列的杂交表明，正常等位基因也存在于大多数肿瘤中，这表明正常等位基因的丢失不是肿瘤形成所必需的。一个大鼠肺肿瘤没有正常等位基因存在，可能表明这个肿瘤可能已经在一个更先进的阶段比其他肿瘤。这是第一项检测啮齿动物肿瘤中激活的原癌基因的研究，这些肿瘤是在模拟人类在工作场所接触化学物质的条件下诱导的。四硝基甲烷可能通过激活K-ras癌基因和刺激细胞增殖来发挥其致癌作用。
Dominant transforming genes were detected in lung tumors from Fischer 344 rats and C57BL/6 X C3H F1 mice chronically exposed by inhalation to tetranitromethane, a highly volatile compound used in several industrial processes. The rat lung neoplasms were classified as adenocarcinomas, squamous cell carcinomas (epidermoid carcinomas), or adenosquamous carcinomas. The mouse lung tumors were classified as papillary adenocarcinomas or adenomas. In both species, the tumors were morphologically similar to lung tumors in humans. The transfection assay using NIH/3T3 mouse fibroblasts detected transforming genes in 74% (14 of 19) of the rat lung tumors and in 100% (4 of 4) of the mouse lung tumors. Southern blot analysis indicated that transforming gene was an activated K-ras protooncogene in both species. The first exon of the K-ras gene in normal DNA and in DNA from two cell lines transformed by tumor DNA was compared by cloning and sequencing the gene. Experiments showed that there was a GC----AT transition in the second base of the 12th codon of the K-ras oncogene in the two transfectant DNAs. Oligonucleotide hybridization indicated that all of the rat and mouse transfectants had this activating lesion. Additional tumor DNA was then tested for the presence of a mutated allele with the GC----AT transition. All of the rat tumors tested and all of the mouse tumors tested had this mutation present. Hybridization using the normal oligonucleotide sequence around the 12th codon indicated that the normal allele was also present in the majority of the tumors, suggesting that the loss of normal allele is not necessary for the development of neoplasia. One rat lung tumor had no normal allele present, possibly suggesting that this tumor could have been in a more advanced stage than the other tumors. This is the first study to detect activated protooncogenes in rodent tumors induced under conditions which mimic human exposure to a chemical in the workplace. Tetranitromethane may exert its carcinogenic action by both activation of the K-ras oncogene and stimulation of cell proliferation by its irritant properties.
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致癌物诱导的胸腺淋巴瘤小鼠 N-ras 基因的分离、表征和染色体分配。
DOI：
10.1126/science.6089339
发表时间：
1984
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Guerrero,I;Villasante,A;D'Eustachio,P;Pellicer,A
通讯作者：
Pellicer,A
影响因子：
11.2
作者：
C. Griffin;S. Baylin
通讯作者：
C. Griffin;S. Baylin
DOI：
10.1073/pnas.83.16.5825
发表时间：
1986-08
影响因子：
11.1
作者：
R. Wiseman;S. Stowers;E. Miller;M. Anderson;J. Miller
通讯作者：
R. Wiseman;S. Stowers;E. Miller;M. Anderson;J. Miller
人类 c-K-ras 癌基因的激活。
影响因子：
14.9
作者：
Yamamoto,F;Perucho,M
通讯作者：
Perucho,M