Activation of the cellular DNA replication machinery is central to the process of neoplastic transformation. The proliferating cell nuclear antigen (PCNA) functions in DNA replication as an auxiliary factor in leading strand synthesis. In accord with this function, the cellular PCNA level increases in response to mitogenic agents such as growth factors and viral oncogenes, including the 12S transforming product of the adenovirus E1A oncogene. The goal of this project is to explore the relationship between gene activation and oncogenic transformation by elucidating the E1A-mediated induction of PCNA gene expression. The approach consists of identifying the regions of the E1A protein that are required for induction of PCNA transcription by use of cotransfection assays. These mapping results will be correlated with known functions of the E1A proteins, particularly with their ability to bind cellular proteins such as the retinoblastoma susceptibility gene product and p60/cyclin A. To gain further mechanistic insight, the cis-acting E1A- responsive elements of the PCNA promoter will be delineated in the co- transfection assay and the trans-acting factors that mediate the E1A response will be identified by genetic and biochemical approaches. These findings will be extended by examining a variety of cell types of rat and human origin that exhibit both normal and transformed growth properties. The results of these experiments will contribute to an understanding of the mechanism whereby a viral oncoprotein can stimulate the expression of a cellular growth-regulated gene.
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