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Zschemisch NH , Liedtke C , Dierssen U , Nevzorova YA , Wustefeld T , Borlak J , Manns MP , Trautwein C
Expression of a cyclin E1 isoform in mice is correlated with the quiescent cell cycle status of hepatocytes in vivo
Hepatology . 2006 Jul;44(1) :164-173
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Cyclin E1 controls G1/S phase transition of the eukaryotic cell cycle. We report the impact of alternative spliced cyclin El isoforms on cell cycle regulation in hepatocytes. We show that expression of new cyclin El mRNA variants IN3, Delta 4, and Delta 5 is associated with retarded proliferation in murine hepatocellular carcinoma. Additionally, we demonstrate that a new cyclin El isoform Delta 3/8 lacking the central part of wild-type mRNA is expressed predominantly in nonproliferating murine hepatocytes. Following partial hepatectomy, Delta 3/8 is downregulated when hepatocytes enter the cell cycle from quiescence. The Delta 3/8 protein does not exhibit any cyclin box motif but binds cyclin-dependent kinase 2 without stimulating kinase activity. We demonstrate that Delta 3/8 lacks any nuclear localization signal and is exclusively located in the cytoplasm. Overexpression of Delta 3/8 in cultured cells leads to a delayed G0-G1 transition, indicating that this splice variant! helps to maintain a quiescent state of hepatocytes. In conclusion, we identified an isoform of cyclin El involved in GO maintenance and suggest an additional mechanism for cell cycle control.