EFFECTS OF NICOTINE AND RELATED ALKALOID ON CELL CYCLE

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The orderly regulation of lymphocyte proliferation is paramount for normal cell function. The disruption of the normal pathways of cell cycle control may alternatively lead to dysfunction or aberrant growth such as cancer. We and others have defined a series of critical events that control entry and progression of lymphocytes through the cell cycle. These involve the serial expression and activation of various members of the cyclin-dependent kinase (CDK) family, and they establish a link between the antigen or cytokine receptor-mediated signals and the machinery that controls cell cycle progression and proliferation. The effects of nicotine or nicotine-related alkaloids on the expression or function of CDKs in human lymphocytes is unknown, although some of these compounds have been associated with increased expression of cyclins and elevated activity of CDKs in other cell types. This study will evaluate how acute or chronic exposure to nicotine or nicotine-related alkaloids affect the cell cycle. Our hypothesis is that nicotine, or its major metabolite cotinine, can distant normal cell responses by interfering with the programmed sequence of CDK expression and activity. The system that we have established in our laboratory is exceptionally well-suited to address the potential effects of nicotine and its metabolites on the expression and activity of cell cycle kinases. The data from these studies will provide novel information of how acute and chronic nicotine exposure may alter cell cycle progression in humans (the target species for these tobacco-derived alkaloids). This information will advance substantially our understanding of the effects of tobacco products on human health and well being. As such, this project has high programmatic relevance for mission of the National Cancer Institute, and it is pertinent for inclusion in program PA-98-095 Genetic Regulation of Susceptibility to Tobacco- Related Carcinogenesis.