Belinsky S A, Swafford D S, Finch G L, Mitchell C E, Kelly G, Hahn F F, Anderson M W, Nikula K J
Inhalation Toxicology Research Institute, Albuquerque, New Mexico 87185, USA.
Environ Health Perspect. 1997 Jun;105 Suppl 4(Suppl 4):901-6. doi: 10.1289/ehp.97105s4901.
Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. Only two agents, TNM and plutonium, led to mutation frequencies of > 10%. In both cases, the transition mutations formed could have been derived from deamination of cytosine. The identification of non-ras transforming genes in rat lung tumors induced by mutagenic and nonmutagenic exposures such as NNK and beryllium would help define some of the mechanisms underlying cancer induction by different types of DNA damage. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarcinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 to 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors.
K-ras原癌基因的激活和p53肿瘤抑制基因的失活是多种人类癌症共有的事件。分子流行病学研究已将这些基因中的突变谱与特定暴露联系起来。本文的目的是综述那些研究K-ras和p53基因在诱变和非诱变暴露诱导的F344大鼠肺肿瘤中作用的调查。如果在大鼠肺肿瘤中存在K-ras和p53基因内的突变谱，将有助于确定各种环境因素诱导癌症的一些分子机制。肺腺癌或鳞状细胞癌由四硝基甲烷（TNM）、4-甲基亚硝胺基-1-（3-吡啶基）-1-丁酮（NNK）、铍金属、钚-239、X射线、柴油机废气或炭黑诱导产生。选择这些因素是因为它们产生的肿瘤可能通过不同类型的DNA损伤而发生。K-ras基因的突变通过包括DNA转染、直接测序、错配杂交和限制性片段长度多态性分析在内的方法来确定。K-ras基因的突变频率与暴露有关。只有TNM和钚这两种因素导致的突变频率>10%。在这两种情况下，形成的转换突变可能源于胞嘧啶的脱氨作用。在由诱变和非诱变暴露（如NNK和铍）诱导的大鼠肺肿瘤中鉴定非ras转化基因，将有助于确定不同类型DNA损伤诱导癌症的一些机制。通过对p53蛋白的免疫组织化学分析和外显子4至9的单链构象多态性（SSCP）分析来评估p53基因的改变。所检查的93例腺癌中没有一例对抗p53抗体CM1呈免疫反应性。相比之下，14至71例鳞状细胞癌表现出核p53免疫反应性，与暴露类型无关。然而，SSCP分析仅在14例具有免疫反应性的鳞状细胞肿瘤中的2例中检测到突变，这表明蛋白质稳定并非源于p53基因内的突变。因此，p53基因似乎不参与大多数大鼠肺肿瘤的发生。
