Oxygen Sensing in Eukaryotes
Cellular and physiological responses to changes in oxygen levels are mediated via transcriptional regulation of a gene array including in human vascular endothelial growth factor and erythropoietin. Our group, in collaboration with that of Peter Ratciffe and Chris Pugh in the Department of Medicine, has been working to define the molecular events that enable the hypoxic response. Central to this response is the oxygen dependent post translational modification of a transcription factor, hypoxia inducible factor (HIF). A set of human oxgenases (the HIF hydroxylases) catalyse the oxygen dependent hydroxylation of HIF thereby both ablating its transcriptional activity and signalling for its degradation by the proteasome. Many interactions for HIF have been identified; we have recently shown that one of the HIF hydroxylases also accepts substrates from the NFkb inflammatory response pathway thus linking two major human signalling systems. In collaboration with theoreticians using detailed computer simulations we hope to link to experimental data, ranging from the molecular to the physiological, to address how the HIF pathway system acts as an integrated unit to enable a robust and graded response in a range of very different cell types.