The studies outlined in this application will further examine the role of the cyclin D1/cdk4 complex in hepatocyte proliferation. Cyclin D1 is an important proliferation-control gene that regulates progression through G1 phase of the cell cycle and is an oncogene in many human cancers. Our studies to date suggest that cyclin D1 is a pivotal mediator of hepatocyte proliferation in response to mitogens, extracellular matrix, and nutrients. The focus of this proposal will be to further define novel functions of cyclin D1 based on our studies in hepatocytes. We have found that in addition to promoting cell cycle progression, cyclin D1 induces hepatocyte growth (increased cell size) and global protein synthesis. Our preliminary data indicates that cyclin D1 regulates components of the translation apparatus, which is a novel finding. Since enhanced cell growth and protein synthesis are critical parts of normal and neoplastic proliferation, further studies of these pathways should provide insight into important functions of cyclin D1. We have also found that persistent cyclin D1 expression (over a matter of days) induces disturbances of the mitotic apparatus and chromosomal abnormalities. This suggests that cyclin D1 may promote genomic instability, which could be a significant component of its oncogenic effect. We therefore propose to study regulation of the mitotic apparatus and chromosome stability by cyclin D1. Our hope is that these studies will provide a better understanding of the actions of cyclin D1 in hepatocytes and other cells. ? ?
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