Activated H-ras genes are present in a number of skin tumors induced in animals by carcinogen treatment. The involvement of the ras oncogenes in tumorigenesis was investigated in keratoacanthomas, benign and self-regressing tumors, as well as malignant squamous cell carcinomas. Both tumors were induced in rabbit ears by repeated applications of 7,12 dimethylbenz(a)anthracene (DMBA). The rabbit H-ras gene was cloned and sequenced. PCR analysis revealed that approximately 82% of the keratoacanthoma DNAs contained an A:T to T:A transversion in codon 61. The relative levels of H-ras transcript were increased in keratoacanthomas compared to normal skin and the activated allele was expressed in tumors, even during the regressing phase. Although a G:C to A:T mutation in codon 12 of the H-ras and an activated N-ras gene were found in two squamous cell carcinomas, the frequency of H-ras activation in codon 61 was much lower (40%) in the malignant tumours induced by the same carcinogen treatment. Therefore, DMBA induced at least two types of genetic lesions in this system: H-ras activation, present in most regressing keratoacanthomas, and activation of other unidentified oncogenes which may result in the development of malignant tumors. Our observations indicate that expression of an activated H-ras gene, in this system, is neither sufficient to induce a malignant phenotype nor even capable of maintaining the growth of a benign tumor and suggest that it could be involved in tumor regression.

译文

活化的H-ras基因存在于通过致癌物治疗在动物中诱导的许多皮肤肿瘤中。在角膜瘤,良性和自我消退的肿瘤以及恶性鳞状细胞癌中研究了ras癌基因在肿瘤发生中的作用。通过重复施用7,12二甲基苯并 (a) 蒽 (DMBA) 在兔耳中诱导了这两种肿瘤。克隆并测序了兔H-ras基因。PCR分析显示大约82% 的角化棘皮瘤dna在密码子61中含有A:T至T:A转换。与正常皮肤相比,角膜acanthomas中H-ras转录本的相对水平增加,并且即使在消退阶段,激活的等位基因也在肿瘤中表达。尽管在两个鳞状细胞癌中发现了H-ras 12密码子中的G:C至a: T突变和激活的N-ras基因,但在由相同致癌物治疗诱导的恶性肿瘤中,密码子61中的H-ras激活频率要低得多 (40%)。因此,DMBA在该系统中诱导了至少两种类型的遗传病变: H-ras激活 (存在于大多数退化的角膜瘤中) 和其他可能导致恶性肿瘤发展的未鉴定癌基因的激活。我们的观察结果表明,在该系统中,活化的H-ras基因的表达既不足以诱导恶性表型,甚至无法维持良性肿瘤的生长,并表明它可能与肿瘤消退有关。

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