Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver

The forkhead box (Fox) family of transcription factors share homology in th e winged helix/forkhead DNA-binding domain and play important roles in regu lating cellular proliferation, differentiation, longevity, and cellular tra nsformation. Forkhead box M1B (FoxM1B) is a ubiquitously expressed member o f the Fox transcription factor family whose expression is restricted to pro liferating cells and that mediates hepatocyte entry into DNA synthesis and mitosis during liver regeneration. Recent cDNA microarray studies indicated that age-related defects in cellular proliferation are associated with dim inished expression of the FoxM1B transcription factor. Here, we show that i ncreased levels of FoxM1B in regenerating liver of old transgenic mice rest ore the sharp peaks in hepatocyte DNA replication and mitosis that are the hallmarks of young regenerating mouse liver. Restoration of the young regen erating liver phenotype is associated with increased expression of numerous cell cycle regulatory genes that include cyclin D1, cyclin A2, cyclin F, c yclin B1, cyclin B2, Cdc25B, and p55cdc. Cotransfection assays in the human hepatoma HepG2 cell line demonstrated that FoxM1B protein stimulated expre ssion of both the cyclin B1 and cyclin D1 promoters, suggesting that these cyclin genes are a direct FoxM1B transcriptional target. These results sugg est that FoxM1B controls the transcriptional network of genes that are esse ntial for cell division and exit from mitosis. Our results indicate that re duced expression of the FoxM1B transcription factor contributes to the decl ine in cellular proliferation observed in the aging process.