Although the A/J mouse lung adenoma model is valuable because of similar histology to a subtype of human adenocarcinoma, there are some features yet to be desired in order to make this model better. For example, the progression of lung adenomas to adenocarcinomas is rare in A/J mice. The most common genetic alteration associated with these tumors being carcinogen-specific mutations is K-ras. The limited number of large adenocarcinomas produced in this model has been shown to produce characteristic LOH changes. However, even most of these larger adenocarcinomas do not show mutations or loss of the p53 tumor suppressor gene or lost expression of the cyclin D1/cyclin D kinase inhibitor p16 gene, although these or closely related genes are routinely altered in human lung cancer. In order to incorporate these specific alterations into the A/J tumor model, we placed two different transgenes onto the A/J background. canadian pharmacy
We employed a transgene that has a mouse p53 gene, with a missense mutation, at position 135 (Arg to Val), under the control of its own endogenous p53 promoter. The resulting mice and tumors have three copies of the mutated p53 gene, as well as two copies of the wild-type p53 alleles. However, the mutated protein is considered to be dominant over the wild-type p53 protein. To alter p16, we employed a knockout of the INK 4A locus that includes the genes for both p16 as well as the gene for ARF. Finally mice with alterations of both p53 and INK 4A on the A/J background were produced.
In a recent study, p53 transgenic mice, Ink4a/Arf heterozygous deficiency and transgenic mice with both defects were employed to determine the role of p53 and Ink4a/Arf on benzo(a)pyrene-induced lung tumorigenesis and progression.- Six-week-old A/J, p53+/+Ink4a/ Arf+/-, p53+/-Ink4a/Arf+/+, and p53+/-Ink4a/Arf+/- mice were randomized into eight groups according to the p53 and Ink4a/Arf genotypes and treatments. One group of mice was administered vehicle controls, and another group of mice was administered benzo(a)pyrene. Animals were killed 40 weeks after exposure to benzo(a)pyrene.