forkhead box M1B and liver defects

Doug Skrecky oberon at vcn.bc.ca
Fri Sep 28 22:50:18 EST 2001

 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.


     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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