CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy.
After two-thirds hepatectomy, normally quiescent liver cells are stimulated to reenter the cell cycle and proliferate to restore the original liver mass. The level of bZIP transcription factor CCAAT enhancer-binding protein beta (C/EBPbeta) increases in the liver during the period of cell proliferation. The significance of this change in C/EBP expression is not understood. To determine the role of C/EBPbeta in the regenerating liver, we examined the regenerative response after partial hepatectomy in mice that contain a targeted disruption of the C/EBPbeta gene. Posthepatectomy, hepatocyte DNA synthesis was decreased to 25% of normal in C/EBPbeta -/- mice. The reduced regenerative response was associated with a prolonged period of hypoglycemia that was independent of expression of C/EBPalpha protein and gluconeogenic genes. C/EBPbeta -/- livers showed reduced expression of immediate-early growth-control genes including the Egr-1 transcription factor, mitogen-activated protein kinase protein tyrosine phosphatase (MKP-1), and HRS, a delayed-early gene that encodes an mRNA splicing protein. Cyclin B and E gene expression were dramatically reduced in C/EBPbeta -/- livers whereas cyclin D1 expression was normal. The abnormalities in immediate-early gene expression in C/EBPbeta -/- livers were distinct from those seen in IL-6 -/- livers. These data link C/EBPbeta to the activation of metabolic and growth response pathways in the regenerating liver and demonstrate that C/EBPbeta is required for a normal proliferative response.
Greenbaum
L E
LE
Department of Genetics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145, USA.
Li
W
W
Cressman
D E
DE
Peng
Y
Y
Ciliberto
G
G
Poli
V
V
Taub
R
R
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D016213:Cyclins / Q000235:genetics; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000032:analysis / Q000145:classification / Q000378:metabolism / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport; D005786:Gene Expression Regulation / Q000235:genetics; D005943:Gluconeogenesis / Q000502:physiology; D006498:Hepatectomy; D007150:Immunohistochemistry; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000145:classification / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D016196:S Phase / Q000235:genetics; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology
D022762:CCAAT-Enhancer-Binding Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D004247:DNA