Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S phase

Two-thirds partial hepatectomy (PH) induces differentiated cells in the liv er remnant to proliferate and regenerate to its original size. The prolifer ation-specific HNF-3/fork head homolog-11B protein (HFH-11B; also known as Trident and Win) is a family member of the winged helix/fork head transcrip tion factors and in regenerating liver its expression is reactivated prior to hepatocyte entry into DNA replication (S phase). To examine whether HFH- 11B regulates hepatocyte proliferation during liver regeneration, we used t he -3-kb transthyretin (TTR) promoter to create transgenic mice that displa yed ectopic hepatocyte expression of HFH-11B. Liver regeneration studies wi th the TTR-HFH-11B mice demonstrate that its premature expression resulted in an 8-h acceleration in the onset of hepatocyte DNA replication and mitos is. This liver regeneration phenotype is associated with protracted express ion of cyclin D1 and C/EBP beta, which are involved in stimulating DNA repl ication and premature expression of M phase promoting cyclin B1 and cdc2. C onsistent with the early hepatocyte entry into S phase, regenerating transg enic livers exhibited earlier expression of DNA repair genes (XRCC1, mHR21s pA, and mHR23B). Furthermore, in nonregenerating transgenic livers, ectopic HFH-11B expression did not elicit abnormal hepatocyte proliferation, a fin ding consistent with the retention of the HFH-11B transgene protein in the cytoplasm. We found that nuclear translocation of the HFH-11B transgene pro tein requires mitogenic signalling induced by PH and that its premature ava ilability in regenerating transgenic liver allowed nuclear translocation to occur 8 h earlier than in wild type.