FoxM1B in Preventing Age-Related Proliferation Defects

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An underlying mechanism of the aging process involves a significant decline in cellular proliferation [DNA replication (S-Phase and mitosis) causing defective cellular repair in response to tissue injury leading to a vari8ety of diseases found in the elderly. The mechanisms involved in the progressive decline in cellular proliferation with aging remain uncharacterized. The forkhead box (Fox) proteins are an extensive family of transcription factors that share homology in the winged helix/forkhead DNA binding domain and play important roles in regulating cellular proliferation, differentiation, and longevity. Expression of Forkhead Box M1B (FoxM1B) is stimulated during cellular proliferation, but in post- mitotic differentiated cells its expression is extinguished. However, when terminally differentiated hepatocytes are induced to proliferate during liver regeneration, FoxM1B expression is reactivated prior to S-phase and sustained throughout the period of hepatocyte proliferation. Premature expression of human FoxM1B in regenerating transgenic mouse liver caused accelerated hepatocyte entry into S-phase and mitosis and was associated with earlier expression of cell cycle promoting genes. We recently showed that preventing age-related reduction of FoxM1B expression during liver regeneration in old transgenic mice increased the percentage of hepatocytes entering S-phase and mitosis to levels similar to those observed in young regenerating mouse liver. Elevated FoxM1B levels in regenerating liver of old transgenic mice are associated with increased expression of cell cycle regulatory genes required for hepatocyte to progression through DNA replication and mitosis. Collectively, these results suggest that FoxM1B controls the transcriptional network of genes essential for cell division and exit from mitosis that is required to restore cellular proliferation during aging. In this grant proposal we describe plans to extend these liver regeneration studies to examine the hypothesis that increased FoxMIB protein levels in all cell types of the Rosa26 promoter-FoxM1B transgenic mice will stimulate cellular proliferation in response to organ injury. A long-term goal of these studies ti examine whether Rosa26-FoxM1B transgenic mice display sustained cellular proliferation during aging and exhibit life span extension.