We have shown that p53 promotes aerobic metabolism through its positive regulation of mitochondrial respiration. p53 null mice, a model of de novo tumorigenesis, display profound deficiencies in aerobic exercise capacity. Remarkably, the promotion of exercise capacity by a tumor suppressor gene in a mouse model parallels the human epidemiologic observation of a strong inverse relationship between exercise capacity and cancer incidence. We hypothesized that these two independent observations may share mechanisms and that studying them will yield insights useful for developing disease prevention strategies. Specifically, we are focusing on cardiovascular and metabolic functions in individuals with Li-Fraumeni syndrome, a premature cancer syndrome caused by germline mutations in the p53 gene, with the goal of developing strategies for maintaining health.

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12
Fiscal Year
2016
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U.S. National Heart Lung and Blood Inst
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Park, Ji-Hoon; Li, Jie; Starost, Matthew F et al. (2018) Mouse Homolog of the Human TP53 R337H Mutation Reveals Its Role in Tumorigenesis. Cancer Res 78:5375-5383
Wang, Ping-Yuan; Li, Jie; Walcott, Farzana L et al. (2017) Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. J Clin Invest 127:132-136
Kamp, William M; Wang, Ping-Yuan; Hwang, Paul M (2016) TP53 mutation, mitochondria and cancer. Curr Opin Genet Dev 38:16-22
Bouchard, Claude; Antunes-Correa, Ligia M; Ashley, Euan A et al. (2015) Personalized preventive medicine: genetics and the response to regular exercise in preventive interventions. Prog Cardiovasc Dis 57:337-46
Kang, Ju-Gyeong; Wang, Ping-yuan; Hwang, Paul M (2014) Cell-based measurements of mitochondrial function in human subjects. Methods Enzymol 542:209-21
Zhuang, Jie; Wang, Ping-yuan; Huang, Xinglu et al. (2013) Mitochondrial disulfide relay mediates translocation of p53 and partitions its subcellular activity. Proc Natl Acad Sci U S A 110:17356-61
Wang, Ping-Yuan; Ma, Wenzhe; Park, Joon-Young et al. (2013) Increased oxidative metabolism in the Li-Fraumeni syndrome. N Engl J Med 368:1027-32
Zhuang, Jie; Ma, Wenzhe; Lago, Cory U et al. (2012) Metabolic regulation of oxygen and redox homeostasis by p53: lessons from evolutionary biology? Free Radic Biol Med 53:1279-85
Mai, Phuong L; Malkin, David; Garber, Judy E et al. (2012) Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet 205:479-87
Wang, Ping-Yuan; Zhuang, Jie; Hwang, Paul M (2012) p53: exercise capacity and metabolism. Curr Opin Oncol 24:76-82

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