Proc Natl Acad Sci U S A 98(20): 11468-73 Sep 25 2001
Increased levels of forkhead box M1B transcription factor in transgenic
mouse hepatocytes prevent age-related proliferation defects in
regenerating liver.
Abstract:
The forkhead box (Fox) family of transcription factors share homology
in the winged helix/forkhead DNA-binding domain and play important roles
in regulating cellular proliferation, differentiation, longevity, and
cellular transformation. Forkhead box M1B (FoxM1B) is a ubiquitously
expressed member of the Fox transcription factor family whose expression
is restricted to proliferating 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 dimished expression of the FoxM1B
transciption factor. Here, we show that increased levels of FoxM1B in
regenerating liver of old transgenic mice restore the sharp peaks in
hepatocyte DNA replication and mitosis that are the hallmarks of young
regenerating mouse liver. Restoration of the young regenerating liver
phenotype is associated with increased expression of numerous cell cycle
regulatory genes that include cyclin D1, cyclin A2. cyclin F, cyclin B1,
cyclin B2, Cdc25B, and p55cdc. Cotransfection assays in the human
hepatoma HepG2 cell line demonstrated that FoxM1B protein stimulated
expression of both the cyclin B1 and cyclin D1 promoters, suggesting that
these cyclin genes are a direct FoxM1B transcriptional target. These
results suggest that FoxM1B controls the transcriptional network of genes
that are essential for cell division and exit from mitosis. Our results
indicate that reduced expression of the FoxM1B transcription factor
contributes to the decline in cellular proliferation observed in the
aging process.
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