Grant: Project Grant

Oxygen homeostasis or balance is a vital organizing principle for human development and physiology. A universal response to compromised oxygen availability involves a protein called hypoxia-inducible factor (HIF), which accumulates during low oxygen levels or hypoxia to trigger the expression of numerous genes including those that promote new blood vessel formation (angiogenesis), anaerobic metabolism, and the production of oxygen-carrying red blood cells to facilitate adaptation and survival in hypoxia. We and others have shown that von Hippel-Lindau (VHL) tumour suppressor protein targets HIF for oxygen-dependent degradation. Mutations in VHL cause VHL disease, characterized by the development of tumours in multiple organs including the kidney, as well as a chronic condition called polycythemia where patients produce too many red blood cells. Notably, kidney cancer remains to be the leading cause of both morbidity and mortality for VHL patients. More recently, mutations in HIF have been reported to cause certain types of cancers also observed in VHL patients as well as polycythemia, revealing a new class of HIF-driven disease. However, it remains unclear what drives the metastatic process of kidney cancer and why certain HIF mutations cause cancer while other HIF mutations cause polycythemia. This proposal, based on our promising preliminary data, aims to elucidate the molecular mechanisms underlying these mysteries with important clinical implications.