Burns P A, Kemp C J, Gannon J V, Lane D P, Bremner R, Balmain A
Beatson Institute for Cancer Research, Glasgow, UK.
Oncogene. 1991 Dec;6(12):2363-9.
Functional alterations or loss of tumor-suppressor genes are an important feature of neoplastic progression in humans. The employment of suitable animal model systems would greatly facilitate the detection and manipulation of such genes. We describe here an experimental approach to this problem based on the analysis of skin tumors induced in F1 hybrids between Mus musculus and Mus spretus mice. The results show that loss of heterozygosity on chromosome 11 occurred in 4/13 mouse skin carcinomas, but not in premalignant papillomas. Since the murine p53 gene is located on this chromosome, immunoprecipitation and DNA-sequencing studies were carried out on tumorigenic cell lines and primary tumor DNA respectively to determine the status of p53 alleles. These studies revealed the presence of p53 mutations, both frameshifts and missense, some of which are identical to those found in human tumors. Loss of normal p53 function is found in well-differentiated squamous-cell carcinomas and thus does not appear to be directly responsible for further progression to an undifferentiated spindle cell phenotype.
肿瘤抑制基因的功能改变或缺失是人类肿瘤进展的一个重要特征。使用合适的动物模型系统将极大地促进此类基因的检测和操作。我们在此描述一种基于对小家鼠和西班牙小鼠杂交的F1代小鼠诱发的皮肤肿瘤进行分析的实验方法来解决这个问题。结果显示，13例小鼠皮肤癌中有4例发生了11号染色体杂合性缺失，而癌前乳头瘤中未发生。由于鼠p53基因位于该染色体上，因此分别对致瘤细胞系和原发性肿瘤DNA进行了免疫沉淀和DNA测序研究，以确定p53等位基因的状态。这些研究揭示了p53突变的存在，包括移码突变和错义突变，其中一些与人类肿瘤中发现的突变相同。在高分化鳞状细胞癌中发现了正常p53功能的缺失，因此似乎并不是进一步发展为未分化梭形细胞表型的直接原因。
