The proposed work will determine if adenovirus infection of human cells causes mutations at the p53 tumor suppressor gene locus. Because of a non cytolytic but highly related primate virus (SA7) on p53 gene of human cells. Genetic analysis will be done on adenovirus-infected cells that show p53 protein alterations or anchorage-independent survival and growth. Adenoviruses are postulated to act as """"""""hit and run"""""""" mutation carcinogens based on their capacity to produce genetic and chromosome lesions. Cellular heterogeneity of adenovirus transformed cells is often noted. Adenoviral tumors in vivo are dependent on viral sequence outside early gene transforming regions. Lack or loss of adenoviral genome is compatible with tumor formation. The basis for oncogenic variability of different adenovirus serotypes is unknown. Human and bovine adenoviruses produce gene mutations at the HPRT or ouabain resistance loci in rat or hamster cells. Mutagenic events by adenoviruses at these cellular locations appear as point mutations independent of persistent adenoviral integration. Human and simian adenovirus infections also cause specific types of chromosome damage. Nonrandom cytogenetic damage by oncogenic adenoviruses is localized on human chromosomes 1 and 17. A large number of tumors contain changes or allelic deletions of human chromosomes 1 and 17. Tumor suppressor genes, including p53, are often mutated. Hypothesis that adenovirus oncogenicity may be due to mutation of p53 tumor suppressor gene has not been tested. The p53 locus is a large genetic target for potential mutation by adenovirus infection. Cancer predisposing mutations of p53 can occur in 30 distinct condons. These mutations often create dominant alleles that produce changes in cell phenotype without reduction to homozygosity. Mutation of suppressor genes is often associated with genomic instability and loss or gain of function. This permits isolation of adenoviral mutated cells for genetic analysis.
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