Oral cancer is a common malignancy in the United States and worldwide. A number of studies indicate that the molecular basis of oral cancer involves the activation of oncogenes, inactivation of tumor suppressor genes, and the interaction of DNA tumor viruses. A critical genetic event in the molecular pathogenesis of oral cancer is cyclin D1 over expression. The cyclin D1 oncogene product interacts with cyclin-dependent kinases (cdks), cdk inhibitors and proliferating cell nuclear antigen (PCNA) in the G1 phase of the cell cycle. Cyclin D1 over expression results in cells traversing the G1 phase in a shorter period of time and entering the S phase more rapidly. The net result is greater proliferation and eventual transformation. Genetic models of oral carcinogenesis in animals are lacking. Transgenic mouse approaches allow the development of a model of multistage oral carcinogenesis. Ultimately, a transgenic mouse mode of oral carcinogenesis has the further advantage of developing molecular diagnostics and testing the efficacy of chemopreventive agents and novel therapeutic drugs. We have developed a novel and unique transgenic mouse model in which the cyclin D1 oncogene has been targeted to the tongue squamous epithelium by employing the Epstein-Barr virus ED-L2 promoter. Since this promoter has been shown by us to be active in basal and suprabasal cells of oral keratinocytes, we have found that cyclin overexpression in the tongue causes several dysplasia, a prominent precursor of cancer. The cyclin D1 mice also display increased cell proliferation, and acquire alterations in other genes, namely p53 mutations and epidermal growth factor receptor (EGFR) over expression. The work described in this Project is designed to focus on the role of cyclin D1 in oral carcinogenesis through a transgenic mouse model. These goals will be achieved through the following Specific Aims and the overall Program Project: (1) To study interrelated cell cycle genetic alterations in transgenic mice as a function of cyclin D1 over expression; (2) To cross-breed the cyclin D1 mice with p53 homozygous hull mice since p53 mutation is associated with dysplasia in the cyclin D1 mice; and 93) To study cyclin D1 properties in oral cell lines.
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