SIGNAL TRANSDUCTION EVENTS AND THE REGULATION OF CELL GROWTH

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"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."