C/EBPbeta contributes to hepatocyte growth factor-induced replication of rodent hepatocytes.

BACKGROUND/AIMS Hepatocyte replication can be induced in vivo by hepatocyte growth factor (HGF), which might be used for gene therapy or to promote liver regeneration. However, the biochemical steps critical for this process are not clear. C/EBPbeta and C/EBPalpha are liver-enriched transcription factors that induce and inhibit hepatocyte replication, respectively. Because of their role in hepatocyte replication, this study examined the effect of HGF upon C/EBP proteins in vivo. METHODS Rats were treated with HGF, and the effect upon C/EBPs was evaluated in liver extracts. Normal or C/EBPbeta-deficient mice were treated with HGF, and the effect upon hepatocyte replication was determined. RESULTS HGF had no effect in rat liver upon C/EBPalpha or C/EBPbeta mRNA, nuclear protein, or nuclear DNA binding activity. However, HGF increased phosphorylated p90-RSK and ERK to 18- and 3-fold normal, respectively. These kinases phosphorylate C/EBPbeta and increase its transcriptional activity. The percentage of hepatocytes that replicated in C/EBPbeta-deficient mice after HGF administration was only 1.1%, which was lower than the value of 6.6% for hepatocytes from HGF-treated normal mice (P=0.005). CONCLUSIONS C/EBPbeta contributes to the induction of hepatocyte replication in response to HGF in rodents, which is likely due to post-translational modifications.