Cell cycle regulation in the liver : differential functions of E-type cyclins E1 and E2 for G1/S-phase transition and endoreplication in mice

E-type cyclins are important regulators for driving quiescent cells into the cell cycle. The aim of the present study was to investigate the relevance of cyclin E1 and E2 for directing quiescent hepatic cells into the cell cycle in vivo. In the partial hepatectomy (PH) model it was shown that cyclin E1-/- deletion results in normal liver regeneration with slight delay of G1/S-phase transition but absent endoreplication in hepatocytes. In contrast, cyclin E2-/- mice showed over-expression of cyclin E1 and prolonged cdk2 kinase activity leading to earlier and sustained DNA synthesis. Higher DNA synthesis in cyclin E2-/- mice did not result in significant more hepatocyte mitosis and proliferation, but was associated with higher polyploidy in the dividing hepatocytes due to endoreplication. Consistently, cyclin E2-/- mice showed a 45% higher liver/body weight ratio compared to WT animals after regeneration as a result of excessive polyploidization. In summary, this data suggests a new and unexpected role for cyclin E2 in repressing cyclin E1 function thus explaining increased S-phase entry and excessive endoreplication of cyclin E2-/- hepatocytes as a result of cyclin E1 over-expression. Moreover, this study demonstrates that cyclin E1 is dispensable for the onset of S-phase, but essential for endoreplication during liver regeneration. The second aim of this study was to investigate a potential contribution of E-type cyclins for liver fibrogenesis. In this context, over-expression of the proto-oncogene c-myc in murine hepatocytes was shown to serve as an interesting new model for liver fibrosis which is dependent on cyclin E1 and E2. Accordingly, alb-myctg mice are prone to spontaneous liver fibrosis which can be inhibited by depletion of cyclin E1, but is even enhanced with a knockout of cyclin E2. In the established animal model of CCl4 – induced liver fibrosis it was demonstrated that cyclin E1 is an essential pro-fibrotic factor, whereas Cyclin E2 provides inhibitory functions on the early onset of liver fibrogenesis. In summary, this study shows for the first time a phenotype for cyclin E1 and E2 knockout mice and provides evidence for non-redundant, individual functions of both E-type cyclins during cell cycle progression and endoreplication.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2009

Author dc:creator

• Nevzorova, Yulia

Contributors dc:contributor

• Liedtke, Christian

• info:eu-repo/classification/ddc/570
• Leber
• G-0-Phase
• Zellzyklus
• Cycline
• DNS-Synthese
• Fibrose
• Leberepithelzelle
• Proliferation
• Biowissenschaften, Biologie
• liver
• cell cycle
• cyclins
• DNA synthesis
• fibrosis
• hepatocytes
• hepatic stellate cells

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113930%22

OAI record oai:identifier

https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A51661