Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PL011

Plenary Lecture

Elucidation of oxygen sensing pathways in human and animal cells: Implications for physiology

P. J. Ratcliffe1,2

1. University of Oxford, Oxford, United Kingdom. 2. The Francis Crick Institute, London, United Kingdom.

Animal cells deploy a set of 2-oxoglutarate dependent dioxygenases to signal oxygen levels in cells by modulating the catalytic rate of post-translational hydroxylation of specific amino acids in hypoxia inducible factors (HIFs). HIF prolyl hydroxylation targets HIF-alpha polypeptides for destruction by the von Hippel-Lindau (pVHL) ubiquitin E3 ligase, whilst HIF asparaginyl hydroxylation inhibits co-activator recruitment and reduces transcriptional activation. In hypoxia these process are suppressed, allowing HIF-alpha to escapade destruction and form an active transcriptional complex. HIFs binds to DNA at hypoxia response elements and activates several thousand direct transcriptional targets across the genome, which transduce extensive cellular and systemic responses to hypoxia and play a major in the defence of physiological homeostasis. This lecture will review advances and challenges in the field including insights into the interface between the biochemistry of HIF hydroxylation, the physiology of oxygen homeostasis, and the potential for therapeutic manipulation in disease.

Where applicable, experiments conform with Society ethical requirements