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Paul M. Hwang, M.D., Ph.D.

Laboratory of Cardiovascular and Cancer Genetics

Paul M. Hwang
Paul M. Hwang, M.D., Ph.D.
Senior Investigator
Laboratory of Cardiovascular and Cancer Genetics
Building 10-CRC Room 5-5330
Bethesda, MD 20892
P: +1 (301) 435-3068
F: +1 (301) 402-0888
hwangp@mail.nih.gov

Background

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 the University of Zurich as a Fulbright Scholar. He graduated from the Johns Hopkins University School of Medicine with a 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 and in 2011 he became a Senior Investigator in the NHLBI's Center for Molecular Medicine. In 2006, he received an NIH Bench-to-Bedside Award. Dr. Hwang has authored or coauthored more than 50 papers and reviews. He is on the editorial board of Drug Discovery Today and Frontiers in Mitochondrial Physiology, and he is an elected member of the American Society for Clinical Investigation and a fellow of the American College of Cardiology.

Research Interests

TP53, which 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 in mitochondria to produce energy. This link between cancer and mitochondrial energetics has brought Dr. Hwang's research to the intersection of cancer and cardiovascular biology, where he is pursuing the hypothesis that mitochondrial respiration protects cells from oxidative insults.

Oxidative stress has received a great deal of attention in recent years as a cause of a variety of human diseases. Mitochondria, which are at the center of cellular oxygen consumption, have been thought to be the source of reactive oxygen species generation. Instead, Dr. Hwang’s study indicates 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, Dr. Hwang 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 mitochondrial bioenergetics 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 a dramatic gene dose-dependent decrease in aerobic exercise capacity, suggesting that the metabolic biology of p53 may be a link between cardiovascular fitness and cancer. Dr. Hwang is currently bringing these observations into the clinic by studying metabolism in patients with Li-Fraumeni syndrome (LFS), a condition caused by a diverse set of germ-line mutations in TP53 that predispose to multiple forms of cancer. He is also continuing his investigations into novel modulators of inflammation and cardiovascular diseases. The hope is that the results of his basic and translational work may provide insights into developing novel strategies for preventing cancer and improving cardiovascular health.

Selected Publications

Mitochondrial disulfide relay mediates translocation of p53 and partitions its subcellular activity.
Zhuang J, Wang PY, Huang X, Chen X, Kang JG, Hwang PM
Proc Natl Acad Sci U S A 2013 Oct 22;110(43):17356-61.
Increased oxidative metabolism in the Li-Fraumeni syndrome.
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
N Engl J Med 2013 Mar 14;368(11):1027-32.
Metabolic regulation of oxygen and redox homeostasis by p53: lessons from evolutionary biology?
Zhuang J, Ma W, Lago CU, Hwang PM
Free Radic. Biol. Med. 2012 Sep 15;53(6):1279-85.
Mitochondrial respiration protects against oxygen-associated DNA damage.
Sung HJ, Ma W, Wang PY, Hynes J, O'Riordan TC, Combs CA, McCoy, Bunz F, Kang JG, Hwang PM
Nat Commun 2010;1:5.
p53 regulates mitochondrial respiration.
Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM
Science 2006 Jun 16;312(5780):1650-3.
Paul M. Hwang's Full List of Publications