Inherited predisposition to cancer is associated with mutations in tumor suppressor genes. The p53 tumor suppressor gene regulates cell proliferation, apoptosis, and cell cycle arrest and repair in response to DNA damage. Families with the Li-Fraumeni syndrome have a point mutation in one copy of the p53 tumor suppressor gene resulting in increased susceptibility to sarcomas, brain tumors, breast cancer, and other tumors. A recent case control study revealed a slightly increased risk of mesothelioma in people exposed to asbestos who also had first degree relatives with the Li-Fraumeni syndrome. Other familial clusters of malignant mesotheliomas associated with exposure to asbestos or erionite have been described. They have shown that p53-deficient mice show increased sensitivity to induction of mesotheliomas by crocidolite asbestos fibers. Mutations or deletions of the p53 tumor suppressor gene are found in only 25% of human malignant mesotheliomas. Inactivation of another cell cycle regulatory gene, p16, has been reported in 70-100% of human mesotheliomas. They have shown that 81% of murine mesothelioma cell lines derived from wild-type mice injected weekly with crocidolite asbestos fibers have inactivated the p16 tumor suppressor gene. A heterozygous transgenic mouse model will be used to test this hypothesis. The specific objectives of the proposed research are: 1) To determine whether p16-deficient mice show increased sensitivity to induction of mesotheliomas by crocidolite asbestos fibers; 2) To determine whether exposure to crocidolite asbestos fibers inactivates the wild-type allele in heterozygous p16-deficient mice; 3) To validate whether inactivation of the wild-type allele in heterozygous p16-deficient mice can be used as a biomarker for potentially carcinogenic fibers; and, 4) To determine whether oxidants inactivate the wild-type allele in heterozygous p16-deficient mice exposed to asbestos or refractory ceramic fibers.
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