Research: Project 2

Hypoxia, hydroxylation and tumorigenesis

HIF1 signaling is primarily controlled at the level of protein stability. HIF1a, the cytoplasmic portion of the HIF1 dimer, is constantly transcribed and translated. Under normal oxygen tension, HIF1a is quickly hydroxylated by an iron- and oxygen-dependent enzyme called PHD. Once hydroxylated, the HIF1a protein is targeted for degradation by the Von Hippel Lindau (VHL) tumor suppressor protein. Under hypoxic conditions, the PHD is inhibited and HIF1a becomes stabilized and translocates to the nucleus, where it can dimerize with ARNT to form the functional transcription factor, HIF1. HIF1 regulates the expression of wide battery of adaptive genes that will allow the cell to cope with the hypoxic environment. These genes include vascular endothelial growth factor (VEGF), glycolytic enzymes and erythropoietin. This signaling cascade is critical for tumor growth and understanding the early events in cellular transformation is the goal of this project. It is focused on the relationship between PHD activity, HIF1 signaling and cellular transformation. Using engineered cell lines and various transformation assays, this project is attempting to determine if changes in PHD/HIF1/hypoxia signaling can alter a cell's tumor forming potential. In addition, this project is using metabolite profiling to characterize the biochemical consequences of these changes and their relationship to a transformed phenotype.