MULTIPLE FACTORS IN THE ETIOLOGY OF ORAL CANCER

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An important etiological factor in oral cancer is exposure to mutagens; this project will analyze the mutagenic activity of the herpes simplex virus type-1 (HSV-1). The way in which HSV-L raises the mutation frequency of cells will be examined. The functions of the virus that are involved will be determined. HSV-1 will be progressively inactivated by irradiation with ultraviolet light to find which virus functions are necessary for mutagenesis. Cloned fragments of HSV-L DNA will be screened to find which regions of the genome are responsible for raising the mutation frequency. In particular we will find the relationship between the host cell shut-off function of the virus and the mechanisms of mutagenesis and malignant transformation. The effects on cells of viral proteins that might raise the mutation frequency will be tested. The role of a viral protein, MUT, that was identified in the present grant period will be examined and be compared with a protein, HSO, of HSV-2. The hypothesis will be tested that the MUT and HSO proteins each mediate the shut-off of host cell functions. The genes for the two proteins will be cloned in expression vectors and transfected into Vero cells. The growth rates of the cells and stability of cellular RNA will be measured. The genes for MUT and HSO will be tested to find if they transform oral epithelial cells to a malignant phenotype. If transformation is obtained, then we will locate the sites on the proteins that are involved in transformation. The MUT and HSO protein of HSV-2 will be characterized. The main physical properties of the two proteins will be compared to find if the two proteins are functionally related. The project will lead to a detailed description of the "hit and run" mechanism by which HSV transforms cells to a malignant phenotype.