International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F36 p53 modifiers near the D16Mit181 locus on chromosome 16 and in the vicinity of D19Mit123 on chromosome 19

Saito Y.1, Matsuki A.1, Wakabayashi Y.1, Kosugi S.1, Takahashi Y.1, and Niwa O2 , and Kominami R.1
1Department of Biochemistry, Niigata University School of Medicine, Asahimachi 1-757, Niigata 951-8122, 2Radiation Biology Center, Kyoto University, Yoshida-Konoecho, Sakyou-Ku 606-8315. Japan

Individuals inheriting the same mutation predisposing to cancer often express different phenotypes with respect to spectrum of tumors and age of onset. Li-Fraumeni patients with p53 gene mutations, for instance, are susceptible to sarcomas and carcinoma of the breast and their outcomes range from early aggressive cancer to disease-free survival. This may reflect the presence of low penetrance genes in the human population as well as environmental factors that can modify the impact of a given mutation. Experimental mouse models may provide a powerful tool to search genes of that type. In order to map modifiers of the p53 gene mutation, we have induced a total of 374 lymphomas from N2 backcross mice (N2C and N2M) between BALB/c and MSM strains. The MSM mice used for the cross carried a p53-deficient allele and hence about a half of the N2 progeny were heterozygous for p53. The F1 and N2 mice were subjected to gamma-ray irradiation and cumulative frequency distribution of thymic lymphomas and subcutaneous tumors was compiled up to 300 days after irradiation. The frequencies were as high as almost 100% in all three kinds of mice, demonstrating a strong susceptibility given by the KO p53 allele, but the latent periods showed differences, suggesting genetic factors influencing the KO p53 allele-conferred lymphoma susceptibility. Interestingly, p53(KO/+) N2M mice developed subcutaneous tumors in a frequecy of 30% of the mice (69/233), whereas p53(KO/+) F1 and N2C mice developed in much less frequencies (6% and 5%, respectively). These results suggest that a combination of the KO p53 allele and the MSM background brought the development of subcutaneous tumors. Mapping analysis has localized two candidate loci for p53 modifiers; one is present near the D16Mit181 locus on chromosome 16, and the other is in the vicinity of D19Mit123 on chromosome 19.


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