Podcast: Prize Foundation Louis-Jeantet

Lecture: The Physiological Society's 2012 Annual Review Prize

Ludwig Cancer Research group page

My laboratory works on understanding the mechanisms by which cells sense and signal hypoxia (low oxygen levels). Oxygen is of fundamental importance for most living organisms, and the maintenance of oxygen homeostasis is a central physiological challenge for all large animals. Hypoxia is an important component of many human diseases including cancer, heart disease, stroke, vascular disease, and anaemia.

Working initially on regulation of the haematopoietic growth factor erythropoietin (which shows strong transcriptional upregulation by hypoxia), the laboratory discovered that the underlying oxygen sensitive signal pathway is widely operative in mammalian cells, extends to invertebrates, and mediates a range of other transcriptional responses including those regulating angiogenesis and metabolism. The laboratory went to define the oxygen sensing and signalling pathways that link the essential transcription factor, hypoxia inducible factor (HIF) to the availability of oxygen.

The laboratory discovered that these links involve an unprecedented mode of cell signalling involving post-translational hydroxylations at specific prolyl and asparaginyl residues within HIF that are catalysed by a series of non-haem Fe(II) enzymes belonging to the 2-oxoglutarate (2-OG) dependent dioxygenase superfamily. The obligate requirement for molecular oxygen in the reaction confers oxygen dependence, though emerging evidence suggests the enzymes integrate other signals generated by redox and metabolic stresses.

Together with our collaborators, the laboratory operates an extensive range of programmes exploring the extent, mechanisms and biological functions of these and related 2-OG oxygenases. These programmes range across, protein science, structural biology and enzymology, through cell biology, systems physiology, epigenetics and cancer biology, to translational programmes in ischaemia therapeutics and integrative human physiology.

Based on the evolutionary conservation of enzymatic oxidations led to protein degradation, which apparently signal oxygen levels in all four eukaryotic kingdoms, the laboratory has been able to track systems which were previously unknown in human cells, but which offer new opportunities for the understanding of human hypoxic disease, including cancer.