Lecture: Nobel Prize for Medicine or Physiology 2019

Podcast: Prize Foundation Louis-Jeantet

Lecture: The Physiological Society's 2012 Annual Review Prize

Ludwig Cancer Research Ratcliffe 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 hydroxylation of 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.

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 biochemistry, cell biology, integrative physiology, and cancer biology. We are especially interested in kidney cancer in which the HIF system is constitutively upregulated following inactivation of the von-Hippel-Lindau tumour suppressor, which normally functions as a ubiquitin E3 ligase, directing prolyl-hydroxylated HIF for proteasomal proteolysis.

Another area that we are investigating is the interface of HIF hydroxylase pathways with rapid oxygen chemo-sensing mechanisms that direct neurosecretory responses in the carotid body and related sympathoadrenal tissues. We are interested both in the mechanism of chemo-sensitivity and in its relationship to oncogenicity, as exemplified by paraganglioma and phaeochromocytoma, tumours that arise from these tissues in association with activated hypoxia signalling pathways.