Enhanced liver regeneration in transgenic mice overexpressing stable β‐catenin

Abstract

Previously, our lab demonstrated an essential role of β‐catenin in liver regeneration. In order to elucidate the effect of β‐catenin overexpression on regeneration, we utilized recently generated transgenic (TG) mice that express a constitutively active form of β‐catenin in regeneration studies and found that constitutively active β‐catenin leads to an increase in cell proliferation after partial hepatectomy (PHx). In TG mice, proliferation (as measured by PCNA immunohistochemistry) was increased over wild‐type (WT) mice at all time points analyzed. At 40H after PHx, before the onset of proliferation in WT FVB mice, almost every hepatocyte in the TG liver stains positive for PCNA. This proliferative increase in TG mice extends to D14; while PCNA in the WT is near resting levels, TG mice continue to show increased PCNA staining. Analysis of cyclin D1 expression by Western blotting showed that levels of this cell‐cycle regulator are approximately equal in both WT and TG mice 10 hours after PHx. However, at 40H, cyclin D1 levels in TG mice are several‐fold higher than WT. Conversely, protein levels of glutamine synthetase (GS), a known downstream target of β‐catenin which is not involved in the cell cycle, remains unchanged between TG and WT. In conclusion, β‐catenin overexpression causes an upregulation of downstream targets such as cyclin D1, which causes an increase in proliferation during regeneration.