ROLE OF RAS ONCOGENES IN CHEMICAL CARCINOGENESIS

致癌物诱导的动物肿瘤模型系统，其中特定的癌基因 被发现是可重复激活的，提供了一种手段， 了解癌基因激活在肿瘤形成中的作用。 我们发现 诱导大鼠乳腺癌中H-ras-1癌基因的激活 单次施用直接作用致癌物N-亚硝基N '- 甲基脲（NMU），在青春期。 每个H-ras-1的激活 致癌基因是由G到A的转变引起的，这是已知的致癌基因的作用模式。 NMU。 这些结果代表了第一次鉴定出一种生物学上 相关基因作为致癌物的靶点，并与ras癌基因有关。 启动致癌作用。 为了在时间上分离癌症起始事件，假定 癌基因的激活，以及性行为所起的促进作用。 激素，我们检查了新生儿，而不是青春期诱导的肿瘤 大鼠暴露于NMU。 有了这个方案，50%的乳腺肿瘤， 在青春期后出现的癌细胞中含有G → A激活的H-ras-1癌基因。 在 相反，接近90%的肾肿瘤含有G to A激活的K-ras-2， 致癌基因 这些数据再次提供了强有力但只是间接的证据 ras癌基因参与癌发生的启动。 使用 聚合酶链反应（PCR）技术，我们打算寻找激活的 ras癌基因在乳腺和肾脏细胞中的出现 检测肿瘤，并确定是否存在激活的ras癌基因 在其他组织中不会发生肿瘤。 我们还将讨论 在恶性激活的表达中活跃的细胞分裂， 静止ras癌基因，如再生肝。 最后，我们将 探索免疫组织化学的有用性， 激活的rasp 21蛋白与单一氨基酸取代，研究 肾脏肿瘤的起源和发展阶段。

Carcinogen-induced animal tumor model systems, in which specific oncogenes are found to be reproducibly activated, are providing a means of understanding the role of oncogene activation in neoplasia. We have found activated H-ras-1 oncogenes in mammary carcinomas of rats induced by a single administration of the direct acting carcinogen, N-nitroso N'- methylurea (NMU), during puberty. Activation of each of the H-ras-1 oncogenes was caused by a G to A transition, the known mode of action of NMU. These results represented the first identification of a biologically revelant gene as a target of carcinogen and implicated ras oncogenes in the initiation of carcinogenesis. In order to separate, temporally, the cancer-initiating event, presumed to be activation of the oncogene, and the promotional role played by sexual hormones, we examined tumors induced by neonatal, rather than pubertal exposure of rats to NMU. With this protocol, 50% of mammary tumors that arose following puberty contained G to A activated H-ras-1 oncogenes. In contrast, close to 90% of kidney tumors contained G to A activated K-ras-2 oncogenes. These data again provide strong but only circumstantial evidence for ras oncogene involvement in initiation of carcinogenesis. Using the polymerase chain reaction (PCR) technique, we intend to look for activated ras oncogenes in cells of the mammary gland and kidney before the appearance of a detectable neoplasm, and to determine if activated ras oncogenes exist in other tissues that never develop tumors. We will also address the role of active cell division in the expression of malignantly activated, but quiescent ras oncogenes, such as in regenerating liver. Lastly, we will explore the usefulness of immunohistochemistry with antibodies specific for activated ras p21 proteins with single amino acid substitutions, to study the origin and stages of development of the kidney tumors.