The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration.
The Forkhead Box (Fox) proteins are an extensive family of transcription factors that shares homology in the winged helix DNA-binding domain and whose members play essential roles in cellular proliferation, differentiation, transformation, longevity, and metabolic homeostasis. Liver regeneration studies with transgenic mice demonstrated that FoxM1B regulates the onset of hepatocyte DNA replication and mitosis by stimulating expression of cell cycle genes. Here, we demonstrate that albumin-promoter-driven Cre recombinase-mediated hepatocyte-specific deletion of the Foxm1b Floxed (fl) targeted allele resulted in significant reduction in hepatocyte DNA replication and inhibition of mitosis after partial hepatectomy. Reduced DNA replication in regenerating Foxm1b(-/-) hepatocytes was associated with sustained increase in nuclear staining of the cyclin-dependent kinase (Cdk) inhibitor p21(Cip1) (p21) protein between 24 and 40 h after partial hepatectomy. Furthermore, increased nuclear p21 levels and reduced expression of Cdc25A phosphatase coincided with decreases in Cdk2 activation and hepatocyte progression into S-phase. Moreover, the significant reduction in hepatocyte mitosis was associated with diminished mRNA levels and nuclear expression of Cdc25B phosphatase and delayed accumulation of cyclin B1 protein, which is required for Cdk1 activation and entry into mitosis. Cotransfection studies demonstrate that FoxM1B protein directly activated transcription of the Cdc25B promoter region. Our present study shows that the mammalian Foxm1b transcription factor regulates expression of cell cycle proteins essential for hepatocyte entry into DNA replication and mitosis.
Wang
Xinhe
X
Department of Molecular Genetics, University of Illinois College of Medicine, 900 South Ashland Avenue, Chicago, IL 60607, USA.
Kiyokawa
Hiroaki
H
Dennewitz
Margaret B
MB
Costa
Robert H
RH
D000818:Animals; D016203:CDC2 Protein Kinase / Q000502:physiology; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism; D019926:Cyclin B / Q000502:physiology; D056744:Cyclin B1; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000032:analysis; D004254:DNA Nucleotidyltransferases / Q000502:physiology; D004261:DNA Replication; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D022781:Hepatocytes / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D045522:Recombinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000378:metabolism
C534700:Ccnb1 protein, mouse; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D045522:Recombinases; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D004254:DNA Nucleotidyltransferases; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases