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Regeneration advantage in beta‐catenin overexpressing transgenic mice after partial hepatectomy
Author(s) -
NejakBowen Kari D,
Monga Satdarshan S
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.741.11
Subject(s) - liver regeneration , regeneration (biology) , genetically modified mouse , cyclin d1 , transgene , phosphorylation , biology , immunoprecipitation , catenin , cell growth , medicine , endocrinology , microbiology and biotechnology , proliferating cell nuclear antigen , chemistry , wnt signaling pathway , cell cycle , apoptosis , signal transduction , biochemistry , gene
Previously, our lab demonstrated an essential role for β‐catenin in liver regeneration. In order to elucidate the effect of β‐catenin overexpression on regeneration, we utilized recently generated transgenic (TG). Using the partial hepatectomy (PHx) model of liver regeneration, we found a dramatic increase in cell proliferation in TG mice as compared to WT at 40H after PHx, before the onset of proliferation in WT FVB mice that occurs at 72H. Coincident with the earlier onset of proliferation, β‐catenin translocates to the nucleus at 40H post‐PHx in TGs, whereas this translocation does not occur until 72H in WT. Analysis of cyclin D1 expression by Western blotting showed that levels of this cell‐cycle regulator are several‐fold higher in TG than in WT at 40H. The differences in liver weight to body weight ratios between WTs and TGs at all time points after PHx are unremarkable. However, restoration of gross lobular architecture is noted in TG livers harvested 1M after PHx, while WT livers from the same time point show restored mass but not normal lobulation. To determine the mechanism of β‐catenin activation during liver regeneration, we utilized immunoprecipitation studies and found that β‐catenin dissociates from Met earlier in TG mice than in WTs after PHx. This was confirmed by increase in β‐catenin phosphorylation (and thus activation) 40H after PHx in TG mice as compared to T0, while in WT mice, β‐catenin phosphorylation does not increase until 72H tyrosine‐654, suggesting that Met/β ‐catenin interactions play a key role during the initiation of liver regeneration in TG mice. In conclusion, β‐catenin overexpression causes an upregulation of downstream targets such as cyclin D1, which gives these mice a regenerative advantage.