Oxygen is of fundamental importance for most living organisms. In higher animals such as human beings appropriate delivery of oxygen (by the lungs, heart, blood, circulation and blood vessels) to all the cells is a considerable challenge - particularly as inadequate delivery will impair metabolism whereas excess oxygen is toxic. Not surprisingly, inappropriate oxygen delivery to cells plays a major role in many human diseases.
The group is analysing transcriptional responses to oxygen availability that regulate processes such as angiogenesis, cellular energy metabolism and proliferation/survival signals that operate in development. An important focus is on the hypoxia inducible factor (HIF) system that is regulated through oxygen dependent targeting of the transcription factor for ubiquitin mediated proteolysis. The group has demonstrated that this involves a novel method of protein recognition in which oxygen sensitive prolyl hydroxylation of HIF regulates ineraction with the von Hippel-Lindau tumour suppressor E3 ubiquitin ligase. Current lines of investigation include the general importance of prolyl hydroxylation as a signalling mechanism, the structural analysis of oxygen sensitive prolyl hydroxylases, the role of the HIF system in development, ischaemia/hypoxic disease, and tumour biology, and the interaction between oxygen and iron signalling.
Hypoxia drives glucose transporter 3 expression through HIF-mediated induction of the long non-coding RNA NICI.
Lauer V. et al, (2019), The Journal of biological chemistry
MITF controls the TCA cycle to modulate the melanoma hypoxia response.
Louphrasitthiphol P. et al, (2019), Pigment Cell Melanoma Res
Inherent DNA-binding specificities of the HIF-1α and HIF-2α transcription factors in chromatin.
Smythies JA. et al, (2019), EMBO Rep, 20
Studying the effects of disease associated polymorphism on a transcriptional pathway: A case study in renal cell carcinoma
Schmid V. et al, (2018), EUROPEAN JOURNAL OF HUMAN GENETICS, 26, 549 - 550
Studying effects of disease associated polymorphism on a transcriptional pathway: A case study in renal cell cancer
Schmid V. and Mole D., (2018), CANCER RESEARCH, 78