Increased Hepatic Forkhead Box M1B (FoxM1B) Levels in Old-aged Mice Stimulated Liver Regeneration through Diminished p27Kip1 Protein Levels and Increased Cdc25B Expression

作者：Xinhe Wang, Katherine Krupczak-Hollis, Yongjun Tan, Margaret B. Dennewitz, Guy R. Adami, Robert H. Costa · 发表于：Journal of Biological Chemistry · 年份：2002 · DOI：10.1074/jbc.m207510200 · 被引用次数：158 · 研究领域：FOXO transcription factor regulation、Pancreatic function and diabetes、Hippo pathway signaling and YAP/TAZ

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, C...