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Metabolic Regulation by Tumor Suppressor p53 in Li-Fraumeni Syndrome

18 Years
Open (Enrolling)
Li-Fraumeni Syndrome, Cardiovascular Capacity

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Trial Information

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.

Inclusion Criteria


1. At least 18 years of age and able to give informed consent

2. In overall good health;

3. Able to exercise on a treadmill (if participating in the treadmill exercise

4. Able to perform hand or leg exercises (if participating in the MRS Portion)


1. Blood pressure higher than 190/100 mmHg

2. Diabetes requiring medical treatment

3. Anemia

4. Tobacco use within the past three months

5. Symptomatic heart disease, heart failure or poor blood circulation

6. Diseases predisposing to vasculitis or Raynaud's phenomenon

7. Undergone stem cell transplantation

8. Inflammatory disease or immunosuppressive therapy

9. Claustrophobia and/or unable to lie on your back in the MRI machine

10. Pregnant or breast feeding

11. Body mass index under 19 or over 45

12. Metal medical implantable device or other MRI incompatible materials

Additional Exclusion Criteria for the Muscle Biopsy:


Type of Study:


Study Design:

Time Perspective: Prospective

Principal Investigator

Paul M Hwang, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Heart, Lung, and Blood Institute (NHLBI)


United States: Federal Government

Study ID:




Start Date:

November 2006

Completion Date:

Related Keywords:

  • Li-Fraumeni Syndrome
  • Cardiovascular Capacity
  • Mitochondria
  • Ischemia
  • Oxygen Consumption
  • Aerobic Capacity
  • Magnetic Resonance Spectroscopy
  • Li-Fraumeni Syndrome
  • Li-Fraumeni Syndrome



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892