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。 细胞周期控制的正常途径的破坏可能会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控制淋巴细胞进入细胞周期和进展的关键事件。 这些涉及细胞周期蛋白依赖性激酶（CDK）家族的各种成员的连续表达和激活，并且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展和增殖的机制之间建立联系。尼古丁或尼古丁相关生物碱对人淋巴细胞中CDK表达或功能的影响尚不清楚，尽管这些化合物中的一些与其他细胞类型中细胞周期蛋白表达增加和CDK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产物可替宁，可以通过干扰CDK表达和活性的程序化序列来远离正常的细胞反应。 我们在实验室建立的系统非常适合于解决尼古丁及其代谢产物对细胞周期激酶表达和活性的潜在影响。这些研究的数据将提供有关急性和慢性尼古丁暴露如何改变人类（这些烟草衍生生物碱的靶种属）细胞周期进程的新信息。 这些信息将大大促进我们对烟草产品对人类健康和福祉的影响的理解。 因此，该项目与国家癌症研究所的使命具有高度的计划相关性，并且与纳入计划PA-98-095烟草相关致癌易感性的遗传调节相关。

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.