With regard to STI571 established “stop” signals of hepatocyte proliferation and liver regeneration, this study can only partly corroborate the conclusions of most previous studies. We can however,
report the “finding” of genes associated with genes known to interact with cell cycle propagation and apoptosis. For instance, TGF-β was not found in our material. However, TOB1 (Transducer of ERBB2, 1), a down regulated gene in regenerating livers, has been reported to bind SMAD4 (Small Mothers Against Decapentaplegic) and thereby render some cells resistant to TGF-β selleck chemicals [30, 31]. This gene occurred in the resection group at time-contrast 6–0, indicating a down-regulation of its antiproliferative property in the middle of the experiment. At the same time, the TOB1-SMAD4 complex inhibits IL-2, IL-4 and Interferon-gamma-γ (IFNγ) and induces apoptosis and G1 cell cycle arrest in hepatocytes [30]. SKI (Sloan-Kettering Viral Gene Oncolog) was down-regulated in early phase of sham group, indicating an inactivation of SMAD-binding, thereby admitting TGF-β’s antiproliferative
function. Another gene, BMP2 (Bone Morphogenetic Protein 2), a member of the TGF-β-superfamily, was down-regulated in the control group during the early time period. TGF-β has been shown to orchestrate multiple events as part of a large feedback loop during see more regeneration [31] and our findings (TOB1, SKI and BMP2) is in line with previous studies, but without a direct involvement of TGF-β. This again, is in accordance with the findings from Oe et al., concluding cAMP that intact signalling by TGF-beta is not required for termination of liver regeneration [13]. They suggest that an increase of activin A signalling may compensate
to regulate liver regeneration when signalling through the TGF-β pathway is abolished, and may be a principal factor in the termination of liver regeneration [13]. In our opinion, the findings of TOB1, SKI and BMP2 adds credibility to our study, at the same time as the lack of TGF-β support the findings from Oe et al. [13]. In the resection group, we observed a pattern for differentially expressed genes regulating cell cycle and apoptosis, as three out of four genes in the early time phase of regeneration regulated the cell cycle, whereas towards the end of the experiment, seven out of ten genes regulated apoptosis. This suggests an initiating event of up-regulated cell cycle genes, as well as a termination phase governed by apoptotic genes. However, some of these genes had an inhibitory function of both cell cycle and apoptosis, indicating constant control by the opposing actions of pro-mitotic and pro-apoptotic genes. A small wave of apoptosis of hepatocytes seen at the end of DNA synthesis suggests that this is a mechanism to correct an over-shooting of the regenerative response [32].