The role of E-type cyclins in liver regeneration and fibrogenesis

Introduction: The current understanding of cell cycle regulation in mammals has completely changed as recent studies demonstrated that the E-type cyclins E1 and E2 are not essential for cell proliferation per se, but for transition of quiescent cells into the cell cycle.

Aims: To investigate the role of E-type cyclins during liver regeneration and c-myc induced liver disease.

Methods: Partial hepatectomy (PH) was performed in cyclin E1 and E2 knockout (KO) mice and wildtype (WT) controls. Regeneration was monitored measuring the liver/body weight ratio after PH and established cell cycle markers for G1, S and M-Phase. Activity of cyclin E/cdk2 complexes were analysed through histone H1 kinase assays. In c-myc transgenic mice we measured collagen I deposition using sensitive immunofluorescence techniques and immunoblot analysis.

Results: Following 2/3 hepatectomy in constitutive cyclin E1 and E2 KO mice, we found that hepatocyte proliferation was only slightly delayed in cyclin E1 KO animals. In contrast, cyclin E2 KO mice showed an earlier onset of liver regeneration with higher cell proliferation and hepatomegaly as found seven days after hepatectomy. In addition, cyclinE-cdk2 kinase activity was also strongly prolonged in these animals. In hepatocyte-specific c-myc transgenic animals (c-myctg) we observed an age-dependent increase in liver collagen I deposition indicating fibrosis progression, which correlated with increased cyclin E1– and decreased cyclin E2 expression. Consistently, in c-myctg/cyclin E1 KO mice collagen I expression was reduced whereas in c-myctg/cyclin E2 KO animals strongly increased collagen I and cyclin E1 expression was evident. The molecular mechanism for c-myc induced collagen I deposition was related to increased liver apoptosis and enhanced mitotic activity in these animals.

Conclusions: We conclude that cyclin E1 is the key player for G1-S phase transition during liver regeneration and may also play an important role for proliferating cells during fibrogenesis. Depletion of cyclin E1 can partially be compensated by Cyclin E2. However, as Cyclin E2 depletion leads to higher proliferation, prolonged cdk2 kinase activity, hepatomegaly and pro-fibrogenic effects it basically seems to be a negative regulator of cyclin E1.