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Cell Growth & Differentiation Vol. 10, 397-404, June 1999
© 1999 American Association for Cancer Research

Cyclin D1 Promotes Mitogen-independent Cell Cycle Progression in Hepatocytes1

Jeffrey H. Albrecht2 and Linda K. Hansen

Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota 55415 [J. H. A.]; Minneapolis Medical Research Foundation, Minneapolis, Minnesota 55404 [J. H. A.]; and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455 [L. K. H.]

Cyclin D1 is widely believed to regulate progression through G1 phase of the cell cycle, and previous studies have shown that this protein is induced during hepatocyte proliferation in culture and in vivo. In this study, the role of cyclin D1 in the cell cycle of primary rat hepatocytes was further examined. Following epidermal growth factor stimulation, cyclin D1 was up-regulated at time points corresponding to the mitogen restriction point, and this was associated with enhanced cyclin D1-associated kinase activity. To test whether cyclin D1 expression was sufficient to promote mitogen-independent progression through the G1-S transition, we constructed a replication-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 activation of downstream biochemical events, including cyclin A and proliferating cell nuclear antigen expression and cyclin E- and cyclin A-associated kinase activation. These results suggest that cyclin D1 expression is sufficient to promote progression of hepatocytes through the G1 restriction point.




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