Peter Ratcliffe

Hypoxia Biology Laboratory

We study mechanisms by which cells sense oxygen levels to direct a range of adaptive responses that are important in cancer, cardiovascular and metabolic disease. 

The key transcription factor mediating many cellular and systemic responses to hypoxia is HIF (hypoxia inducible factor). HIF itself is regulated by an unprecedented mode of signalling in which specific prolyl and asparaginyl residues are hydroxylated in the presence of oxygen by a set of 'oxygen splitting' enzymes that are members of the 2-oxoglutarate dependent dioxygenase family.

HIF prolyl hydroxylation promotes destruction by the von Hippel-Lindau tumour suppressor (pVHL), a ubiquitin E3 ligase that binds specifically to the hydroxylated form of HIF; HIF asparaginyl hydroxylation blocks co-activator recruitment to the complex.

In hypoxia (low oxygen), both these processes are suppressed, leading HIF to escape destruction and activate a very extensive transcriptional cascade involving thousands of genes involved in homeostatic, adaptive or reparative responses to hypoxia.

The laboratory is studying a range of questions raised by these insights. We are interested in understanding how widely signalling by protein hydroxylation operates in biology and whether the HIF hydroxylases and closely related enzymes have other substrates that transduce different responses to hypoxic and metabolic stress.

We are also interested in linking these basic insights into cellular biochemistry to the integrated physiology of hypoxia and to the pathophysiology of hypoxia disease.

Of particular interest is kidney cancer, where inactivation of the pVHL tumour suppressor is associated with constitutive activation of HIF in the presence of oxygen. We are trying to understand how this contributes to the development of this common form of cancer, and, more generally, how the unphysiological oncogenic switching of massively interconnected pathways impacts on the cancer phenotype.

Selected publications

Targeting of HIF-a to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. P Jaakkola, DR Mole, Y-M Tian, MI Wilson, J Gielbert, SJ Gaskell, A von Kriegsheim, HF Hebestreit, M Mukherji, CJ Schofield, PH Maxwell, CW Pugh, PJ Ratcliffe. Science 292 (2001) 468-472. PMID: 11292861

C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. ACR Epstein, JM Gleadle, LA McNeill, KS Hewitson, JF O'Rourke, DR Mole, M Mukherji, E Metzen, MI Wilson, A Dhanda, Y-M Tian, N Masson, DL Hamilton, P Jaakkola, R Barstead, J Hodgkin, PH Maxwell, CW Pugh, CJ Schofield, PJ Ratcliffe. Cell 107 (2001) 43-54. PMID: 11595184

Post-translational hydroxylation of ankyrin repeats in IĸB proteins by the HIF asparaginyl hydroxylases, FIH. ME Cockman, DE Lancaster, IP Stolze, KS Hewitson, MA McDonough, ML Coleman, CH Coles, X Yu, RT Hay, SC Ley, CW Pugh, NJ Oldham, N Masson, CJ Schofield, PJ Ratcliffe. PNAS 103 (2006) 14767-14772. PMID: 17003112 PMCID: 1578504

The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. Masson N, Singleton RS, Sekirnik R, Trudgian DC, Ambrose LJ, Miranda MX, Tian YM, Kessler BM, Schofield CJ, Ratcliffe PJ. EMBO Rep. 13 (2012)251-7. PMID: 22310300 PMCID: 3323130

Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1expression. Schödel J, Bardella C, Sciesielski L, Brown JM, Pugh CW, Buckle V, Tomlinson IP, Ratcliffe PJ, Mole DR. Nature Genetics 44 (2012) 420-5. PMID: 22406644 PMCID: 3378637

OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation. Singleton RS, Liu-Yi P, Formenti F, Ge W, Sekirnik R, Fischer R, Adam J, Pollard PJ, Wolf A, Thalhammer A, Loenarz C, Flashman E, Yamamoto A, Coleman ML, Kessler BM, Wappner P, Schofield CJ, Ratcliffe PJ, Cockman ME. Proc Natl Acad Sci USA. 111 (2014) 4031-6. PMID: 24550447 PMCID: 3964040

Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer. Salama R, Masson N, Simpson P, Sciesielski LK, Sun M, Tian YM, Ratcliffe PJ, Mole DR. PLoS One. (2015) PMID: 26262842

Capture-C reveals preformed chromatin interactions between HIF-binding sites and distant promoters. Platt J, Salama R, Smythies J, Choudhry H, Davies JOJ, Hughes J, Ratcliffe PJ, Mole DR. Embo Reports. (2016). PMID: 27506891

Reviews

Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. Ratcliffe PJ. J Physiol. 591 (2013) 2027-42. PMID: 23401619 PMCID: 3634517

HIF Hydroxylase Pathways in Cardiovascular Physiology and Medicine. Bishop T, Ratcliffe PJ. Circ Res. 117 (2015) 65-79. Review. PMID: 26089364 PMCID: 4501273

Pharmacological targeting of the HIF hydroxylases - A new field in medicine development. Chan MC, Holt-Martyn JP, Schofield CJ, Ratcliffe PJ. Mol Aspects Med. 47-48 (2016) 54-75. PMID: 26791432

Peter Ratcliffe

Peter Ratcliffe

peter.ratcliffe@crick.ac.uk
+44 (0)20 379 63153

  • Qualifications and history
  • 1978 MB ChB, Cambridge University and St Bartholomew's Hospital, London
  • 1987 MD, University of Cambridge
  • 1990 Wellcome Trust Senior Fellow in Clinical Science, Oxford
  • 1996 Professor of Nephrology, University of Oxford
  • 2004 Nuffield Professor of Medicine, University of Oxford
  • 2016 Director, Target Discovery Institute, University of Oxford
  • 2016 Clinical Research Director, the Francis Crick Institute, London