SIGNAL TRANSDUCTION EVENTS AND THE REGULATION OF CELL GROWTH

“这个项目旨在提高我们的 了解癌细胞生物学并开发新的方法 通过研究生长调节信号来治疗癌症 转导事件。目前主要集中在以下几个方面：（1）创新 癌细胞生长的调节方面， 视网膜母细胞瘤易感基因家族和（2）分子 抑制剂的负生长调节机制 HMG-CoA还原酶途径。视网膜母细胞瘤蛋白是 目前认为它只在细胞核中起作用， 细胞周期的G1期。相比之下，使用共焦显微镜 和免疫共沉淀技术，我们发现Rb是 与细胞骨架相关，这种定位是 作为细胞周期的一个功能。这些数据得到了支持 通过使用野生型和 突变型GST-Rb构建体，并通过使用 血凝素标记的野生型和突变型Rb构建体。这些 数据提示了一种新的肿瘤抑制基因功能模型， 其中肿瘤抑制基因产物对细胞-细胞 或细胞-基质相互作用。在研究抗癌作用时， HMG-CoA还原酶抑制剂洛伐他汀， 洛伐他汀导致乳腺癌和前列腺癌细胞周期蛋白D1丢失 细胞使用洛伐他汀和其他生长停滞信号， 证明钙蛋白酶在细胞周期蛋白D1翻译后 调控近年来，我们对这一机制的研究 洛伐他汀诱导前列腺癌细胞G1期阻滞 洛伐他汀诱导细胞周期蛋白依赖性激酶的转录 抑制剂p21。我们已经确定了洛伐他汀反应元件 在p21启动子上，并已开始表征 转录因子调节启动子位点。"

"This project is designed to increase our understanding of cancer cell biology and to develop a new approach to cancer treatment through the study of growth-regulatory signal transduction events. This work is currently focused on (1) novel aspects of the regulation of cancer cell growth by the retinoblastoma susceptibility gene family and (2) the molecular mechanism of negative growth regulation by an inhibitor of the HMG-CoA reductase pathway. The retinoblastoma protein is currently thought to function only in the cell nucleus and only in the G1 phase of the cell cycle. In contrast, using confocal microscopy and co-immunoprecipitation techniques we found that Rb is associated with the cell cytoskeleton and that this localization is regulated as a function of the cell cycle. These data were supported by in vitro transcription-translation experiments using wild type and mutant GST-Rb constructs, and by transient transfections using hemagglutinin-tagged wild type and mutant Rb constructs. These data suggest a new model of tumor suppressor gene function, in which the tumor suppressor gene product is responsive to cell-cell or cell-substratum interactions. While studying the anticancer action of the HMG-CoA reductase inhibitor lovastatin we determined that lovastatin causes loss of cyclin D1 in breast and prostate cancer cells. Lovastatin and other growth arrest signals were used to demonstrate the role of calpain in cyclin D1 posttranslational regulation. Our recent studies on the mechanism of lovastatin-induced G1 arrest in prostate cancer cells demonstrated that lovastatin induced transcription of the cyclin-dependent kinase inhibitor p21. We have identified the lovastatin-responsive element on the p21 promoter and have begun characterizing the transcription factors regulating that promoter site."