Regulation of Hypoxia Inducible Factor (HIF)

Our group characterizes pathways by which our cells recognize and respond to changes in their environment or metabolic status. As misregulation of such pathways frequently contributes to the progression of human diseases, we hope to use this information to develop new therapeutic strategies.

Hypoxia Inducible Factors (HIFs) are important transcriptional regulators in diseases in which oxygen delivery is compromised: anemia, strokes, heart attacks, cancer, and other conditions. We have identified several factors that regulate HIF in response to changes in oxygen availability.

We are also working to identify opportunities to regulate HIF beyond oxygen availability. Recently, in collaboration with Drs. Kevin Gardner, John MacMillan, and Uttam Tambar, we have discovered several small organic compounds that directly and specifically antagonize HIF-2 in living cells. Such molecules may provide a basis for developing treatments for cancers in which HIF-2 is particularly important.

Our current work focuses on identifying endogenous ligands that act as HIF antagonists and linking cellular metabolism with these key transcriptional regulators.

HIF diagram
The HIF-2 transcription factor is assembled from two subunits that dimerize through their PAS and bHLH domains. The PAS-B domain of the HIF-2α subunit (green) contains a cavity within its hydrophobic core. Small molecules can bind within this pocket, inducing conformational changes that disrupt protein-protein interactions and antagonize HIF-2 in disease settings such as clear cell renal carcinomas.