Increased hepatic Forkhead Box M1B (FoxM1B) levels in old-aged mice stimulated liver regeneration through diminished p27Kip1 protein levels and increased Cdc25B expression.
Recent liver regeneration studies indicate that maintaining hepatic Forkhead Box M1B (FoxM1B) expression in 12-month-old (old-aged) Transthyretin-FoxM1B transgenic mice increases hepatocyte proliferation and expression of cell cycle regulatory genes. Because these transgenic CD-1 mice maintain FoxM1B levels during the aging process, we conducted the current study to determine whether adenovirus delivery of the FoxM1B gene (AdFoxM1B) is sufficient to stimulate liver regeneration in old-aged Balb/c mice. Here we show that AdFoxM1B infection of old-aged mice caused a significant increase in FoxM1B expression, hepatocyte DNA replication, and mitosis following partial hepatectomy. This stimulation in hepatocyte S-phase progression was associated with diminished protein expression and perinuclear localization of cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) (p27) protein following partial hepatectomy. In contrast, old-aged mice infected with control virus displayed high hepatocyte levels of p27 protein, which had been localized to the nucleus prior to S-phase. Furthermore, we found that restoring FoxM1B expression did not influence p27 mRNA levels, and this new finding implicates FoxM1B in regulation of p27 protein levels. Likewise, AdFoxM1B-infected regenerating livers displayed elevated S-phase levels of Cdk2 kinase activity compared with old-aged mice infected with control virus. Furthermore, restoring FoxM1B expression in old-aged mice caused elevated levels of Cyclin B1, Cyclin B2, Cdc25B, Cdk1, and p55CDC mRNA as well as stimulating Cdc25B nuclear localization during liver regeneration, all of which are required for mitosis. These studies indicated that an acute delivery of the FoxM1B gene in old-aged mice is sufficient to re-establish proliferation of regenerating hepatocytes, suggesting that FoxM1B can be used for therapeutic intervention to alleviate the reduction in cellular proliferation observed in the elderly.
Wang
Xinhe
X
Department of Molecular Genetics, University of Illinois at Chicago, College of Medicine and Dentistry, 60607, USA.
Krupczak-Hollis
Katherine
K
Tan
Yongjun
Y
Dennewitz
Margaret B
MB
Adami
Guy R
GR
Costa
Robert H
RH
D000256:Adenoviridae / Q000378:metabolism; D000375:Aging; D000818:Animals; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000096:biosynthesis; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D019925:Cyclin A / Q000096:biosynthesis; D056751:Cyclin A2; D019926:Cyclin B / Q000096:biosynthesis; D056744:Cyclin B1; D056765:Cyclin B2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004591:Electrophoresis, Polyacrylamide Gel; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010750:Phosphoproteins / Q000096:biosynthesis; D011506:Proteins / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D020687:cdc25 Phosphatases / Q000096:biosynthesis*
C503721:CCNA2 protein, human; C534699:CCNB1 protein, human; C503758:CCNB2 protein, human; C534700:Ccnb1 protein, mouse; C503759:Ccnb2 protein, mouse; D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056751:Cyclin A2; D019926:Cyclin B; D056744:Cyclin B1; D056765:Cyclin B2; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C577488:CDC20 protein, human; D012313:RNA; D016203:CDC2 Protein Kinase; D012260:Ribonucleases; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases