Expression of a cyclin E1 isoform in mice is correlated with the quiescent cell cycle status of hepatocytes in vivo.
Cyclin E1 controls G1/S phase transition of the eukaryotic cell cycle. We report the impact of alternative spliced cyclin E1 isoforms on cell cycle regulation in hepatocytes. We show that expression of new cyclin E1 mRNA variants IN3, Delta4, and Delta5 is associated with retarded proliferation in murine hepatocellular carcinoma. Additionally, we demonstrate that a new cyclin E1 isoform Delta3/8 lacking the central part of wild-type mRNA is expressed predominantly in nonproliferating murine hepatocytes. Following partial hepatectomy, Delta3/8 is downregulated when hepatocytes enter the cell cycle from quiescence. The Delta3/8 protein does not exhibit any cyclin box motif but binds cyclin-dependent kinase 2 without stimulating kinase activity. We demonstrate that Delta3/8 lacks any nuclear localization signal and is exclusively located in the cytoplasm. Overexpression of Delta3/8 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 E1 involved in G0 maintenance and suggest an additional mechanism for cell cycle control.
Zschemisch
Nils-Holger
NH
Department of Cardiology, Medical School of Hannover, Hannover, Germany.
Liedtke
Christian
C
Dierssen
Uta
U
Nevzorova
Yulia A
YA
Wüstefeld
Torsten
T
Borlak
Jürgen
J
Manns
Michael P
MP
Trautwein
Christian
C
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics*; D002478:Cells, Cultured; D019927:Cyclin E / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D012334:RNA, Neoplasm