Impact of c-MET Signaling on Liver Regeneration
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ABSTRACT: c-Met is a receptor tyrosine kinase for hepatocyte growth factor (HGF). Previous work has established that HGF plays a pivotal role in regulating the onset of S phase and DNA replication following partial hepatectomy. In this study, we used c-Met conditional knockout mice (MetLivKO) in which c-met gene is inactivated in postnatal hepatocytes by Alb-Cre recombinase to directly address the net biological outcome of c-Met on liver regeneration. The priming events appear to be intact in MetLivKO livers. Up-regulation of stress response (e.g MAFK, IKBZ, SOCS3) and early growth response (e.g. MYC, DUSP1 and 6) genes as judged by microarray profiling was similar in c-Met deficient regenerating livers as compared to Alb-Cre controls. This was consistent with an early induction of NF-kB, STAT3, and MAPK/ERK. Nevertheless, in the absence of c-Met signaling in the hepatocytes, ERK phosporylation rapidly declined although it remained high in Cre-Ctrl livers, and MetLivKO mice displayed impaired liver regeneration as determined by a decrease in BrdU incorporation and a delay in timely progression into mitosis. Upstream signaling pathways involved in the blockage of G2-M transition included lack of EGR1 transcription factor induction, and inability to up-regulate the levels of cdc2, aurora B and Mad2 followed by defective histone 3 phosphorylation and lag in chromatin condensation. However, after a delayed passage through G2 phase, c-Met deficient cells eventually entered mitosis. In culture, EGF treatment increased proliferation of MetLivKO hepatocytes and restored expression levels of cell cycle regulators aurora B and Mad2 albeit to a lesser degree as compared to Cre-Ctrl hepatocytes. In conclusion, our results assign a novel function for HGF/c-Met signaling in regulation of G2/M transition during liver regeneration and implicate EGR1 as a potential G2/M target of HGF/c-Met pathway.
ORGANISM(S): Mus musculus
PROVIDER: GSE17609 | GEO | 2010/08/01
SECONDARY ACCESSION(S): PRJNA118563
REPOSITORIES: GEO
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