An underlying mechanism of the aging process involves reduced cellular proliferation and repair in response to tissue injury. This involves both diminished DNA replication (S-Phase) and progression into mitosis (G2/M block), resulting in accumulation of polyploid cells with 4N DNA content and ultimately causing chromosome instability and mutations leading to a variety of diseases found in the elderly. The mechanisms involved in the progressive decline in cellular proliferation with aging remain uncharacterized. Recent studies have shown that diminished expression of the proliferation-specific Forkhead Box M1B (FoxM1B) transcription factor is associated with reduction in both cellular proliferation and expression of cell cycle progression genes during aging. We recently performed liver regeneration studies to demonstrate that maintaining hepatocyte expression of FoxMIB in 12-month old (old-aged) transgenic (TG) mice increased hepatocyte proliferation to levels similar to those observed in young regenerating mouse liver. Maintaining FoxM1B levels in old-aged proliferating cells is associated with increased expression of numerous genes required for progression into S-phase and mitosis. Collectively, these results suggest that FoxM1B controls the transcriptional network of genes essential for cellular proliferation and that its reduced expression contributes to the decline in cellular proliferation during aging. Our long-term goal is to determine whether maintaining FoxM1B expression will prevent age-related proliferation defects and result in life span extension. We plan to do so with the following Specific Aims: 1) We will conditionally delete the FoxM1B gene in young adult mice to test the hypothesis that extinguished FoxMIB expression in proliferating cells will lead to defective S-phase and M-phase progression observed in premature aging. 2) We have created TG mice that use the Rosa-26 promoter region to drive FoxM1B expression in all cell types. We will use these mice to examine the hypothesis that maintaining FoxM1B levels in all cell types will stimulate cellular proliferation during aging and lead to life span extension. 3) We find that the tumor suppressor protein, p19ARF (p19), inhibits FoxM1B transcriptional activity. Because the FoxM1B controls expression of cell cycle progression genes, these results suggest that the p19 protein also mediates growth arrest by inhibition of FoxM1B transcriptional activity. We will further characterize the FoxM1B and p19 protein interaction and use mouse embryo fibroblasts (MEFs) from Rosa26-FoxM1B TG mice to test the hypothesis that increased FoxM1 B levels will delay p19 mediated replicative senescence (G1 arrest).
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