Cell proliferation with excessive vascularisation: early stage cancer in a hypoxic state.

Peter Ratcliffe : Areas of interest

Introduction

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