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 liver remnant to proliferate and regenerate to its original size. The proliferation-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 transcription 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 the -3-kb transthyretin (TTR) promoter to create transgenic mice that displayed ectopic hepatocyte expression of HFH-11B. Liver regeneration studies with the TTR-HFH-11B mice demonstrate that its premature expression resulted in an 8-h acceleration in the onset of hepatocyte DNA replication and mitosis. This liver regeneration phenotype is associated with protracted expression of cyclin D1 and C/EBPbeta, which are involved in stimulating DNA replication and premature expression of M phase promoting cyclin B1 and cdc2. Consistent with the early hepatocyte entry into S phase, regenerating transgenic livers exhibited earlier expression of DNA repair genes (XRCC1, mHR21spA, and mHR23B). Furthermore, in nonregenerating transgenic livers, ectopic HFH-11B expression did not elicit abnormal hepatocyte proliferation, a finding consistent with the retention of the HFH-11B transgene protein in the cytoplasm. We found that nuclear translocation of the HFH-11B transgene protein requires mitogenic signalling induced by PH and that its premature availability in regenerating transgenic liver allowed nuclear translocation to occur 8 h earlier than in wild type.
Ye
H
H
Department of Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60607-7170, USA.
Holterman
A X
AX
Yoo
K W
KW
Franks
R R
RR
Costa
R H
RH
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002467:Cell Nucleus / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009687:Nuclear Proteins / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D016196:S Phase; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1
D022762:CCAAT-Enhancer-Binding Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C000619352:Xrcc1 protein, mouse