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).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021842-05
Application #
7173380
Study Section
Special Emphasis Panel (ZRG1-SSS-1 (01))
Program Officer
Velazquez, Jose M
Project Start
2003-01-01
Project End
2007-12-31
Budget Start
2007-03-01
Budget End
2007-12-31
Support Year
5
Fiscal Year
2007
Total Cost
$325,297
Indirect Cost
Name
University of Illinois at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Park, Hyun Jung; Gusarova, Galina; Wang, Zebin et al. (2011) Deregulation of FoxM1b leads to tumour metastasis. EMBO Mol Med 3:21-34
Petrovic, Vladimir; Costa, Robert H; Lau, Lester F et al. (2010) Negative regulation of the oncogenic transcription factor FoxM1 by thiazolidinediones and mithramycin. Cancer Biol Ther 9:1008-16
Park, Hyun Jung; Carr, Janai R; Wang, Zebin et al. (2009) FoxM1, a critical regulator of oxidative stress during oncogenesis. EMBO J 28:2908-18
Chen, Yi-Ju; Dominguez-Brauer, Carmen; Wang, Zebin et al. (2009) A conserved phosphorylation site within the forkhead domain of FoxM1B is required for its activation by cyclin-CDK1. J Biol Chem 284:30695-707
Wang, I-Ching; Chen, Yi-Ju; Hughes, Douglas E et al. (2008) FoxM1 regulates transcription of JNK1 to promote the G1/S transition and tumor cell invasiveness. J Biol Chem 283:20770-8
Petrovic, Vladimir; Costa, Robert H; Lau, Lester F et al. (2008) FoxM1 regulates growth factor-induced expression of kinase-interacting stathmin (KIS) to promote cell cycle progression. J Biol Chem 283:453-60
Park, Hyun Jung; Costa, Robert H; Lau, Lester F et al. (2008) Anaphase-promoting complex/cyclosome-CDH1-mediated proteolysis of the forkhead box M1 transcription factor is critical for regulated entry into S phase. Mol Cell Biol 28:5162-71
Park, H J; Wang, Z; Costa, R H et al. (2008) An N-terminal inhibitory domain modulates activity of FoxM1 during cell cycle. Oncogene 27:1696-704
Gusarova, Galina A; Wang, I-Ching; Major, Michael L et al. (2007) A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment. J Clin Invest 117:99-111
Tan, Yongjun; Raychaudhuri, Pradip; Costa, Robert H (2007) Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol Cell Biol 27:1007-16

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