EFFECTS OF NICOTINE AND RELATED ALKALOID ON CELL CYCLE

淋巴细胞增殖的有序调节对正常细胞功能至关重要。细胞周期控制正常途径的破坏可能导致功能障碍或异常生长，如癌症。我们和其他人已经定义了一系列关键事件，这些事件控制淋巴细胞在细胞周期中的进入和进展。这些过程涉及细胞周期蛋白依赖性激酶（CDK）家族成员的一系列表达和激活，它们在抗原或细胞因子受体介导的信号与控制细胞周期进程和增殖的机制之间建立了联系。尼古丁或尼古丁相关生物碱对人类淋巴细胞中CDKs表达或功能的影响尚不清楚，尽管其中一些化合物与其他细胞类型中细胞周期蛋白表达增加和CDKs活性升高有关。本研究将评估急性或慢性暴露于尼古丁或尼古丁相关生物碱如何影响细胞周期。我们的假设是尼古丁，或其主要代谢物可替宁，可以通过干扰CDK表达和活性的程序序列来影响正常细胞的反应。我们在实验室建立的系统非常适合于研究尼古丁及其代谢物对细胞周期激酶表达和活性的潜在影响。来自这些研究的数据将提供关于急性和慢性尼古丁暴露如何改变人类细胞周期进程的新信息（这些烟草衍生生物碱的目标物种）。这一信息将大大促进我们对烟草制品对人类健康和福祉影响的理解。因此，本项目与美国国家癌症研究所的任务具有高度的规划相关性，并有必要纳入PA-98-095项目烟草相关致癌性易感性的遗传调控。

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.