Metabolic Regulation by Tumor Suppressor p53 in Li-Fraumeni Syndrome
We have recently reported that TP53 (encoding p53 protein), one of the most frequently
mutated genes in human cancers, dose dependently modulates the balance between the
utilization of oxidative and glycolytic pathways for energy generation in human colon cancer
cells and mouse liver mitochondria. Though morphologically similar to their wild-type
littermates, mice deficient in p53 display a gene dose-dependent decrease in aerobic
exercise capacity, implying that p53 has functions beyond its well characterized cell cycle
activities. These current findings have broad implications in fields ranging from cancer
and aging research to cardiovascular physiology.
In the Li-Fraumeni familial cancer syndrome (LFS), affected individuals harbor a germline
mutation in TP53, hence they are heterozygous with reduced wild-type p53 activity. We
hypothesize that the heterozygous individuals will display deficiency in aerobic capacity
and metabolism that previously has been unappreciated. This IRB proposal translates our
experimental observation to human subjects in collaboration with an extramural group
studying this rare familial syndrome. The results may not only help clarify why mutations
of p53 gene are so common in cancers by potentially conferring metabolic advantages in
tumorigenesis, but they may also give us an opportunity to understand a fundamental
regulatory mechanism in cellular energy generation relevant to other processes.
Time Perspective: Prospective
Paul M Hwang, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
United States: Federal Government
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