N-NITROSO-N-METHYLUREA-INDUCED RAT MAMMARY-TUMORS ARISE FROM CELLS WITH PREEXISTING ONCOGENIC HRAS1 GENE-MUTATIONS
N-NITROSO-N-METHYLUREA-INDUCED RAT MAMMARY-TUMORS ARISE FROM CELLS WITH PREEXISTING ONCOGENIC HRAS1 GENE-MUTATIONS
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DOI：
10.1073/pnas.91.9.3749
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发表时间：
1994-04-26
影响因子：
11.1
通讯作者：
ZARBL, H
中科院分区：
文献类型：
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作者：
CHA, RS;THILLY, WG;ZARBL, H
Hras 基因第 12 个密码子中的 GGA 至 GAA 突变经常在 N-亚硝基-N-甲基脲 (NMU) 诱导的大鼠乳腺肿瘤中观察到。我们开发了一种测定组织中存在频率为 10(-5) 的点突变的方法，现在已应用该测定法来测量大鼠乳腺上皮中 Hras 基因的特定 G 到 A 转变。我们发现 (i) 70% 未经治疗的大鼠含有可检测水平的 Hras 突变体； (ii) 这些突变体以与其起源一致的方式聚集在腺体内，作为早期器官发育过程中出现的突变； (iii)用致癌剂量的NMU治疗不会导致此类突变体的数量、具有突变细胞的器官部分的分数或含有可检测水平的ras突变体的动物分数显着增加。我们得出的结论是，在 Hras 基因第 12 个密码子处携带 G 到 A 转变的 NMU 诱导的乳腺肿瘤源于先前存在的 ras 突变体，并且 NMU 的独立作用直接或间接导致肿瘤形成。
GGA to GAA mutations in the 12th codon of the Hras gene are frequently observed in rat mammary tumors induced by N-nitroso-N-methylurea (NMU). We developed an assay to measure point mutations present in tissues at a frequency of 10(-5) and have now applied this assay to measure the specific G to A transition of the Hras gene in rat mammary epithelium. We find that (i) 70% of untreated rats contain detectable levels of Hras mutants; (ii) these mutants are clustered within the gland as sectors in a manner consistent with their origin as a mutation arising during early organ development; and (iii) treatment with a carcinogenic dose of NMU did not result in a significant increase in the number of such mutants, the fraction of organ sectors with mutant cells, or the fraction of animals containing detectable levels of ras mutants. We conclude that the NMU-induced mammary tumors carrying the G to A transition at the 12th codon of the Hras gene arose from preexisting ras mutants and that an independent effect of NMU was directly or indirectly responsible for tumor formation.