Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes

Cyclin Di is widely believed to regulate progression through G(1), phase of the cell cycle, and previous studies have shown that this protein is induc ed during hepatocyte proliferation in culture and in vivo. In this study, t he role of cyclin D1 in the cell cycle of primary rat hepatocytes was furth er examined. Following epidermal growth factor stimulation, cyclin D1 was u pregulated at time points corresponding to the mitogen restriction point, a nd this was associated with enhanced cyclin D1-associated kinase activity. To test whether cyclin D1 expression was sufficient to promote mitogen-inde pendent progression through the G(1),-S transition, we constructed a replic ation-defective adenovirus that overexpressed human cyclin D1. Transfection with the cyclin D1 vector but not a control vector resulted in hepatocyte DNA synthesis in the absence of growth factor that was similar to that seen in mitogen-treated cells. Furthermore, cyclin D1 transfection led to activ ation of downstream biochemical events, including cyclin A and proliferatin g cell nuclear antigen expression and cyclin E- and cyclin A-associated kin ase activation. These results suggest that cyclin D1 expression is sufficie nt to promote progression of hepatocytes through the G(1), restriction poin t.