There is compelling evidence that carcinogenesis is a multistep process and multiple genetic lesions are necessary to develop cancer in human. Among the genetic lesions, the dysfunction of p53 protein (because of mutation of p53 gene or infection by """"""""high risk"""""""" human papillomaviruses [HPV], e.g., type 16 or 18 HPV) is the most frequently found genetic disorder in human cancers including oral cancer. In spite of such frequent p53 dysfunction in oral cancer cells, alter p53 function (by transfection with HPV DNA or mutant p53 cDNA) alone is not sufficient for neoplastic conversion of normal human oral keratinocytes in vitro. Therefore, the dysfunction of p53 protein may be an early event at least in oral carcinogenesis and also be necessary for subsequent genetic disorders of other genes to convert normal cells to tumor cells in the human oral cavity. In fact, our recent studies show that human oral keratinocytes containing negligible amount of wild-type (wt) p53 protein (because of HPV transfection) convert to tumorigenic cells when exposed to tobacco-carcinogens, but the normal counterpart does not. Inasmuch as wild-type p53 protein plays a major role in the regulation of cell cycle arrest, we hypothesize that normal human oral keratinocytes containing wt p53 protein repair damaged DNA more efficiently than oral keratinocytes with defective p53 function (by mutation of p53 gene or by infection with """"""""high risk"""""""" HPV). As demonstrated by many studies, cells expressing wt p53 protein have the ability to establish transient delays in the progression of cell cycle when exposed to genotoxic agents. However, cells with defective p53 protein do not possess such ability. Since the arrest of the cell cycle progression is assumed to be necessary for cells to repair damaged DNA prior to replication of damaged DNA template and segregation of damaged chromosome, cells with defective p53 function may fail to repair the damaged DNA when exposed to DNA damaging agents. In the proposed study, we will test the above hypothesis by (1) investigating the carcinogen-induced mutation frequencies: (2) determining the repair of damaged DNA: and (3) determining the effect of chemical carcinogens, alone or in combination with ethanol, on the progression of cell cycle, the activity of cyclin-dependent kinases (cdks) and the expression of major growth arrest and DNA damage inducible genes (p53, WAF1/C1P1, gadd45, and gadd153) in normal human oral keratinocytes with normal p53 function, HOK expressing HPV-16 or HPV-18 E6 protein, HOK expressing mutant p53 protein, and HPV-immortalized oral keratinocytes. These proposed studies would help us gain more insight into molecular mechanisms of oral carcinogenesis.
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