The overall goal of this project is to develop an animal model to study the role of tumor suppressor genes in cancer. Utilizing gene targeting protocols, the development of a mouse with a germ line mutation in one or both p53 tumor suppressor alleles has been achieved. The bulk of the current proposal is devoted to the characterization of these mice for their susceptibility to tumors of various types. Our hypothesis is that the p53- deficient mice should be more prone to the development of tumors, as is seen in the equivalent human inherited cancer susceptibility syndrome, Li- Fraumeni syndrome. Li-Fraumeni families contain a mutated p53 germ line alle which apparently contributes to their higher rate of cancer development. We hope that our p53-deficient mice will serve as a potential animal model for this inherited cancer syndrome.
Five specific aims are planned.
Specific Aim 1 will entail characterization of p53 RNA and protein expression in the tissues of p53- deficient germ line heterozygote mice and homozygote mice.
In Specific Aim 2, the in vitro growth rate, susceptibility to immortalization, and susceptibility to transformation of embryo fibroblasts derived from heterozygote and homozygote animals will be examined.
In Specific Aim 3, the incidence of spontaneous tumors in wild type, heterozygote, and homozyogote animals will be compared. Tumors developed by the p53- deficient mice will be examined by molecular techniques to gain insights into the molecular role of p53 in tumorigenesis.
In Specific Aim 4, p53- deficient heterozygotes and homozygotes will be assessed for accelerated development of cancers following treatment with tissue-specific carcinogens. In addition, the heterozygotes and homozygotes will be bred with oncogene-containing transgenic mice to examine the tumorigenic cooperativity of tissue-specific oncogenes and p53 deficiency.
Specific Aim 5 outlines a novel approach to generate a p53 mutation in the germ line of mice identical to that observed in two Li-Fraumeni families. Such Li- Fraumeni mice should serve as a model for this human inherited cancer susceptibility syndrome. We anticipate that the p53-deficient mice will provide powerful models to test the role of tumor suppressor genes in cancer development. The animals may also provide a more sensitive in vivo screening system for potential carcinogenic substances.
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