Cardiovascular and Cancer Genetics

Cardiovascular and Cancer Genetics

Earlier work in Dr. Hwang’s lab revealed that p53, the most commonly mutated tumor suppressor gene in human cancers that controls multiple pathways involved in cell growth, also regulates mitochondrial respiration as part of its adaptive activities against oxidative and other cellular stresses. Their work using mouse models as well as translational studies in patients with Li-Fraumeni syndrome (LFS), a cancer predisposition disorder caused by diverse inherited mutations in TP53, revealed that mutant p53 can have gain-of-function activities to promote oxidative metabolism and increase aerobic exercise capacity. Furthermore, they found that inhibiting mitochondrial metabolism can prevent tumorigenesis in LFS mouse models and that p53 can prevent chemotherapy-induced heart failure by maintaining the mitochondrial genome, both of which have important clinical implications. While continuing to examine the role of p53 in cardiac muscle homeostasis, they have recently identified a specific gene that regulates the mitochondria and appears to cause skeletal muscle bioenergetic deficiency in chronic fatigue syndrome. They have also identified a specific mitochondrial signaling pathway that mediates skeletal muscle adaptation to exercise, thereby increasing fatty acid oxidation and preventing obesity. The clinical relevance of these mechanistic insights are being determined through human translational studies with the potential to develop novel strategies for improving cardiovascular health.