Similar incidence of K-ras mutations in lung carcinomas of FVB/N mice and FVB/N mice carrying a mutant p53 transgene

Abstract

Mutated p53 genes are capable of complementing activated ras genes in the transformation of primary rat embryo fibroblasts in vitro. Mutations in both genes have also been found in several human cancers, including lung carcinomas. We generated transgenic mice containing a p53 construct with a missense mutation in exon 5 (ala135val) to study the role of p53 mutations in lung tumorigenesis, and to facilitate identification of other genetic events that might complement p53 mutations in mouse lung carcinogenesis. The p53 transgenic lines exhibited a higher frequency of lethal lung tumors than the parental FVB/N strain. We examined the spontaneously-arising lung carcinomas from mice expressing the mutated p53 transgene for K-ras mutations using single-stranded conformation polymorphism (SSCP) and/or direct sequencing approaches. Fifteen of 29 (52%) carcinomas contained mutations in the K-ras oncogene. Six of 15 of the K-ras mutations were in codon 61 and 9/15 were in codon 12. Subsequent analysis of spontaneous lung carcinomas from mice of the FVB/N parental strain showed that 9/12 (75%) carcinomas examined contained K-ras mutations. Two of these were in codon 12, one in codon 13, and 6 were in codon 61. These results demonstrate that the frequency of ras mutations does not differ between the p53 FVB/N transgenic mice and their parental FVB/N strain but suggest that a high frequency of mutations K-ras can be correlated with lung tumorigenesis in both groups of mice.

Lung-specific expression of human mutant p53-273H is associated with a high frequency of lung adenocarcinoma in transgenic mice

“…(b) Average lung tumor size in age-matched SP-C/p53-273H transgenic mice (tumors, n=13, 4 -6 months=1, 7 -9 months=1, 10 -12 months=2, 13 -15 months=9) and non-transgenic (tumors, n=4, 4 -6 months=0, 7 -9 months=0, 10 -12 months=2, 13 -15 months=2) littermates Lung adenocarcinoma in p53-273H transgenic mice W Duan et al knock-in model was created in which mice heterozygous for a p53-172H allele (arginine to histidine substitution at murine codon 172, corresponding to human codon 175) were prone to the development of highly metastatic tumors (Liu et al, 2000). In addition, transgenic mice expressing murine mutant p53-135V (alanine to valine substitution at codon 135) under the transcriptional regulation of the p53 promoter were also predisposed to a variety of tumor types (Lavigueur et al, 1989;Harvey et al, 1995;Shafarenko et al, 1997). Although lung adenocarcinomas have been observed in several of these models, they occur at a low frequency relative to the predominant tumor types (e.g., lymphomas), thus limiting the utility of these models in addressing the role of p53 mutation in lung tumorigenesis.…”

“…A number of p53 transgenic and knock-out mouse tumor models have been developed that contribute to an understanding of the role of p53 mutation in lung tumorigenesis (Lavigueur et al, 1989;Donehower et al, 1992;Jacks et al, 1994;Purdie et al, 1994;Shafarenko et al, 1997;Liu et al, 2000). However, the majority of these models involve alteration of p53 function in all tissues and organs of the animal.…”

Tumors in mice transgenic for the envelope protein of Jaagsiekte sheep retrovirus

“…The K line founder was derived from a C57Bl6 and Balb/C hybrid embryo, and it was crossed against FVB/N mice to generate the F1s. FVB/N mice have high tumorigenic frequencies and are susceptible to mutations in the intracellular signal transducer K-ras [29,30], The genetic makeup of the K line F1s was 50% FVB/N. Taken together, these results indicate the JSRV envelope is able to induce tumors in transgenic mice.…”

Glycine-Extended Gastrin Promotes the Growth of Lung Cancer

“…In fact, gastrin overexpression in lung adenocarcinoma may be a direct consequence of oncogenic ras mutations. Activating ras mutations have been reported to occur in up to 50% of human adenocarcinomas (35) and in the large majority of mouse lung tumors (36,37). Furthermore, it has been shown in colon cancer cell lines that activated ras can increase gastrin expression (38), suggesting that the expression of gastrin seen in lung cancers may be secondary to activating ras mutations.…”