NDM Research Building
Sir Peter Ratcliffe
Professor of Clinical Medicine
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.
OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation
Singleton RS. et al, (2014), Proceedings of the National Academy of Sciences, 111, 4031 - 4036
Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer
Salama R. et al, (2015), PLOS ONE, 10, e0134645 - e0134645
Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway
Grampp S. et al, (2017), PLOS Genetics, 13, e1006872 - e1006872
PHD2 inactivation in Type I cells drives HIF‐2α‐dependent multilineage hyperplasia and the formation of paraganglioma‐like carotid bodies
Fielding JW. et al, (2018), The Journal of Physiology, 596, 4393 - 4412
‐binding specificities of the
‐2α transcription factors in chromatin
Smythies JA. et al, (2019), EMBO reports, 20
Multi-level interaction between HIF and AHR transcriptional pathways in kidney carcinoma
Lafleur VN. et al, (2023), Life Science Alliance, 6, e202201756 - e202201756
Widespread hydroxylation of unstructured lysine-rich protein domains by JMJD6
Cockman ME. et al, (2022), Proceedings of the National Academy of Sciences, 119
Factor inhibiting HIF can catalyze two asparaginyl hydroxylations in VNVN motifs of ankyrin fold proteins.
Leissing TM. et al, (2022), The Journal of biological chemistry, 298