Professor Sir Peter Ratcliffe

Background

Sir Peter Ratcliffe grew up in north Lancashire and won an open scholarship to study medicine at Gonville and Caius College, Cambridge. He undertook clinical training at St. Bartholomew’s Hospital, London, and after series of posts at the London postgraduate hospitals, moved to Oxford to train in nephrology. In 1990 he obtained a Wellcome Trust Senior Fellowship to work on cellular responses to hypoxia, retrained in molecular biology and founded a new laboratory working on hypoxia biology in cancer and circulatory diseases. He was appointed Nuffield Professor and Head of the Nuffield Department of Clinical Medicine in 2003, a position he held until 2016. He is currently a Distinguished Scholar of the Ludwig Institute for Cancer Research at Oxford and Director of Clinical Research at the Francis Crick Institute, London. He is a Fellow of the Royal Society and the Academy of Medical Sciences and is an honorary member of the American Academy of Arts and Sciences. In the 2014 New Year’s Honours List, he was knighted for services to clinical medicine. His work was recognised by the award of the Nobel Prize for Physiology or Medicine 2019.

Research Interests

Professor Ratcliffe has led the hypoxia biology laboratory at Oxford for more than 30 years. The laboratory discovered the widespread operation of a system of direct oxygen sensing that is conserved throughout the animal kingdom and operates through a novel form of cell signalling involving post-translational hydroxylation of specific amino acids. Catalysis of these hydroxylations requires molecular oxygen and this generates the oxygen-sensitive signal. The laboratory works extensively on how hypoxia signalling pathways are integrated to achieve physiological oxygen homeostasis and on the implications of dysregulating massively interconnected pathways for the cancer phenotype.

Key Previous Publications

• The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. P.H.Maxwell, M.S.Wiesener, G.-W.Chang, S.C.Clifford, E.C.Vaux, M.E.Cockman, C.C.Wykoff, C.W.Pugh, E.R.Maher, P.J.Ratcliffe. Nature 399 (1999) 271-275.
• Targeting of HIF-a to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. P.Jaakkola, D.R.Mole, Y.-M.Tian, M.I.Wilson, J.Gielbert, S.J.Gaskell, A.vonKriegsheim, H.F.Hebestreit, M.Mukherji, C.J.Schofield, P.H.Maxwell, C.W.Pugh, P.J.Ratcliffe. Science 292 (2001) 468-472.
• C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. A.C.R.Epstein, J.M.Gleadle, L.A.McNeill, K.S.Hewitson, J.F.O’Rourke, D.R.Mole, M.Mukherji, E.Metzen, M.I.Wilson, A.Dhanda, Y.-M.Tian, N.Masson, D.L.Hamilton, P.Jaakkola, R.Barstead, J.Hodgkin, P.H.Maxwell, C.W.Pugh, C.J.Schofield, P.J.Ratcliffe. Cell 107 (2001) 43-54
• 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.
• 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.
• Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, Pollard PJ. Cancer Cell. 20 (2011) 524-37.
• Proteomics-based identification of novel factor inhibiting HIF (FIH) substrates indicates widespread asparaginyl hydroxylation of ankyrin repeat domain-containing proteins. M.E.Cockman, J.D.Webb, H.B.Kramer, B.M.Kessler, P.J.Ratcliffe. Molecular & Cellular Proteomics 8 (2009) 535-546.
• Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. M.Mazzone, D.Dettori, R.L.deOliveira, S.Loges, T.Schmidt, B.Jonckx, Y.-M.Tian, A.A.Lanahan, P.Pollard, C.R.deAlmodovar, F.DeSmet, S.Vinckier, J.Aragones, K.Debackere, A.Luttun, S.Wyns, B.Jordan, A.Pisacane, B.Gallez, M.G.Lampugnani, E.Dejana, M.Simons, P.Ratcliffe, P.Maxwell, P.Carmeliet. Cell 136 (2009) 839-851.

Selected Recent publications

• Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants. Masson N, Keeley TP, Giuntoli B, White MD, Puerta ML, Perata P, Flashman E, Licausi F, Ratcliffe PJ. Science 365 (2019) 65-69. PMID: 31273118. PMCID: 6715447
• Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control. Cheng X, Prange-Barczynska M, Fielding JW, Zhang M, Burrell AL, Lima JD, Eckardt L, Argles I, Pugh CW, Buckler KJ, Robbins PA, Hodson EJ, Bruick RK, Collinson LM, Rastinejad F, Bishop T, Ratcliffe PJ. J Clin Invest. (2020) PMID: 31999648
• Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma. Eckardt L, Prange-Barczynska M, Hodson EJ, Fielding JW, Cheng X, Lima JDCC, Kurlekar S, Douglas G, Ratcliffe PJ, Bishop T. Endocr Relat Cancer. 28 (2021) 757-772. PMID: 34658364
• Widespread hydroxylation of unstructured lysine-rich protein domains by JMJD6. ME Cockman, Y Sugimoto, HB Pegg, N Masson, E Salah, A Tumber, HR Flynn, JM Kirkpatrick, CJ Schofield and PJ Ratcliffe. PNAS (2022) 119(32):e2201483119. PMID: 35930668
• Isoform-resolved mRNA profiling of ribosome load defines interplay of HIF and mTOR dysregulation in kidney cancer. Y Sugimoto and PJ Ratcliffe. Nature Struct & Mol Biol. 29 (2022) 871-880. PMID: 36097292
• Comparative analysis of N-terminal cysteine dioxygenation and prolyl-hydroxylation as oxygen-sensing pathways in mammalian cells. Tian YM, Holdship P, To TQ, Ratcliffe PJ, Keeley TP.J Biol Chem. 2023 Sep;299(9):105156. (2023) PMID: 37572852
• Oncogenic cell tagging and single-cell transcriptomics reveal cell type-specific and time-resolved responses to Vhl inactivation in the kidney. S Kurlekar, JD Lima, R Li, O Lombardi, N Masson, A Barros, V Pontecorvi , DR Mole, CW Pugh, J Adam, PJ Ratcliffe. Cancer Research. (2024) PMID: 38502859