The main goal of the Ashcroft laboratory is to understand the key cellular mechanisms involved in oxygen sensing and hypoxia signalling in mammalian cells. In particular, we have a strong interest in the hypoxia inducible factor (HIF) family of transcription factors and their role in cancer, renal disease and cardiovascular disease.
We are interested in how the oxygen sensing machinery controls cell function and adaptive processes that are associated with a variety of diseases including cancer, renal disease and cardiovascular disease. Our work primarily focuses on the heterodimeric transcription factor family, hypoxia inducible factor (HIF). HIF-1, the prototype of the family is composed of α and β subunits. Regulation of HIF-1 activity is primarily via the HIF-1α subunit, which is rapidly turned over via ubiquitin-mediated degradation by the proteosome; however, the HIF-1β subunit is constitutively expressed. In response to low oxygen tension (hypoxia), HIF-1α protein is stabilised and localises to the nucleus where it binds to HIF-1β and recruits transcriptional coactivators.
Our main goals are to:
1) Evaluate known and novel regulators of the hypoxia/HIF signalling with particular focus on link between mitochondria and the cellular oxygen-sensing machinery.
2) Investigate the key cellular mechanisms regulating hypoxia/HIF signalling in mammalian cells and elucidate how these are mechanistically linked to disease.
3) Identify and develop strategies to exploit hypoxia/HIF signalling in disease.
Mitochondria and hypoxia signalling
(funding: Medical Research Council)
Using a bioinformatics approach to identify novel regulators of HIF-1α, we have identified the highly evolutionary conserved, redox-sensitive mitochondrial coiled-coil helix-coiled-coil helix (CHCH) domain 4 (CHCHD4) proteins. We are investigating the role CHCHD4 (also known as MIA40) in regulating hypoxia/HIF signalling and oxygen sensing.
Targeting hypoxia/HIF signalling in cancer
(funding: Cancer Research UK)
Overexpression of HIF-α occurs in most human cancers and correlates with the severity of tumour grade and a poor prognostic outcome with conventional treatments. Inhibition of HIF activity blocks tumour growth in vivo, and sensitizes hypoxic tumour cells to killing by conventional treatments. We are taking several approaches to identify novel therapeutic strategies to harness hypoxia/HIF signalling in cancer.
Therapeutic potential of PHD inhibitors and HIF-mediated cell survival
(funding: The British Heart Foundation)
We are interested in the potential for activating HIF as a therapeutic approach for mediating protection against cell death particularly in ischaemic and/or hypoxic conditions. This work has involved investigating the cellular mechanisms underlying HIF-mediated cell survival in various systems.
Novel regulators of oxygen sensing and HIF signalling
(funding: Wellcome Trust)
We have identified novel mechanisms involved in the metabolic adaptive response to low oxygen and we have been investigating new molecular controllers of cell fate.