Paul M. Hwang, M.D., Ph.D.
Laboratory of Cardiovascular and Cancer Genetics
Building 10, Room 5-5330
10 Center Drive
Bethesda, MD 20814
TP53 that encodes the tumor suppressor protein p53 is one of the most commonly mutated genes in cancer and a key transcriptional regulator of multiple genetic programs that control cell growth and death. Earlier work in Dr. Hwang’s lab revealed that p53 also regulates mitochondrial respiration by controlling the assembly of the enzyme complex that consumes molecular oxygen to produce cellular energy. This link between cancer and mitochondrial energetics has brought Dr. Hwang's research to the intersection of cancer and cardiovascular biology, where he has explored the role of mitochondrial function in normal and abnormal cellular processes.
Oxidative stress has received a great deal of attention as a cause of a variety of human diseases. Mitochondria, which are the center of cellular oxygen consumption, have been thought to be the source of reactive oxygen species generation. Instead, Dr. Hwang’s studies indicate that mitochondria are part of the solution imposed by evolution to facilitate life in an oxygen rich environment. They not only provide energy but also protect the cell from an overabundance of reactive molecular oxygen. For example, he and his colleagues have shown that cells lacking SCO2 (Synthesis of Cytochrome c Oxidase 2)—a gene regulated by p53 and essential for eukaryotic oxygen consumption—have paradoxically increased levels of oxidative DNA damage and that decreasing ambient oxygen exposure delays de novo tumorigenesis. As such, p53's regulation of the mitochondria may be part of its overall function to maintain genomic integrity in an oxidizing environment.
Many human observational studies have reported an inverse relationship between exercise capacity and cancer. Mice deficient in p53 are prone to develop cancer and display decreased aerobic exercise capacity, suggesting that the metabolic biology of p53 may be a link between cardiovascular fitness and cancer. In addition to advancing our understanding of cancer and cardiovascular biology in model systems, Dr. Hwang is examining metabolism in patients with Li-Fraumeni syndrome (LFS), a cancer predisposition disorder caused by diverse germ-line mutations in TP53. Ongoing work suggests that modulating mitochondrial metabolism in a mouse model of LFS can affect tumorigenesis. Ultimately, the goal of his basic and translational work is to provide insights into developing novel strategies for preventing cancer and improving cardiovascular health.
Dr. Paul Hwang earned a B.A. in biochemistry and chemistry from the University of Kansas in 1985, after which he spent a year at the Swiss Federal Institute of Technology and University of Zurich as a Fulbright Scholar. He graduated from the Johns Hopkins University School of Medicine with an M.D. and Ph.D in 1993. He did his internship and residency in internal medicine at the UCSF School of Medicine in San Francisco, followed by a clinical fellowship in cardiology and postdoctoral research in molecular oncology at the Johns Hopkins University School of Medicine.
Upon completion of his training in 2001, Dr. Hwang joined the NHLBI as a tenure-track investigator in the Cardiovascular Branch. In 2011 he became a senior investigator in NHLBI's Center for Molecular Medicine. He was elected as member of American Society for Clinical Investigation and fellow of the American College of Cardiology. He has served on the editorial boards of Drug Discovery Today, Frontiers in Mitochondrial Physiology, and Mitochondrion, and has authored research articles in major journals.
Wang PY, Ma W, Park JY, Celi FS, Arena R, Choi JW, Ali QA, Tripodi DJ, Zhuang J, Lago CU, Strong LC, Talagala SL, Balaban RS, Kang JG, Hwang PM. Increased oxidative metabolism in the Li-Fraumeni syndrome. N Engl J Med. 2013;368(11):1027-32.
Kamp WM, Wang PY, Hwang PM. TP53 mutation, mitochondria and cancer. Curr Opin Genet Dev. 2016;38:16-22.
Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM. p53 regulates mitochondrial respiration. Science. 2006;312(5780):1650-3.
Wang PY, Li J, Walcott FL, Kang JG, Starost MF, Talagala SL, Zhuang J, Park JH, Huffstutler RD, Bryla CM, Mai PL, Pollak M, Annunziata CM, Savage SA, Fojo AT, Hwang PM. Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. J Clin Invest. 2017;127(1):132-136.
Zhuang J, Kamp WM, Li J, Liu C, Kang JG, Wang PY, Hwang PM. Forkhead Box O3A (FOXO3) and the Mitochondrial Disulfide Relay Carrier (CHCHD4) Regulate p53 Protein Nuclear Activity in Response to Exercise. J Biol Chem. 2016;291(48):24819-24827.
Related Scientific Focus Areas
Genetics and Genomics
This page was last updated on August 18th, 2017