Centre for Cell Signalling and Molecular Genetics
Centre for Cell Signalling and Molecular Genetics is part of the Division of Medicine
The main goal of the Centre is to understand the key cellular mechanisms involved in oxygen sensing and hypoxia signalling in mammalian cells. In particular, the Centre has a strong interest in the hypoxia inducible factor (HIF) family of transcription factors and their role in cancer and other diseases. Complementing these interests in HIF, The Centre also works on understanding the role of HIF in cardioprotection and genetic kidney diseases.
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 a and ß subunits. Regulation of HIF-1 activity is primarily via the HIF-1a subunit, which is rapidly turned over via ubiquitin-mediated degradation by the proteosome; however, the HIF-1ß subunit is constitutively expressed. In response to low oxygen tension (hypoxia), HIF-1a protein is stabilised and localises to the nucleus where it binds to HIF-1ß and recruits transcriptional coactivators.
Our main goals are to:
- Evaluate known and novel regulators of the HIF/oxygen sensing pathway with particular focus on link between mitochondria and the HIF/oxygen sensing machinery.
- Elucidate the key cellular mechanisms regulating the HIF-1 pathway in normal cells, and to understand why these may become deregulated in tumour cells.
- Identify and develop strategies to target the HIF pathway as a basis for inhibiting the HIF pathway in cancer and inducing HIF in ischemic disease.
Mitochondria and hypoxia signalling
(funding: Cancer Research UK and Medical Research Council)Using a bioinformatics approach to identify novel protein-protein interacting regulators of HIF-1a this approach we have identified a redox-sensitive mitochondrial protein that interacts with HIF-1a and contains a highly evolutionarily conserved coiled-coil helix-coiled-coil helix (CHCH) domain. We are investigating the role of this novel CHCH domain-containing protein in regulating HIF function and oxygen sensing.
Novel regulators of oxygen sensing and HIF signalling
(funding, Wellcome Trust)
We have identified novel mechanisms involved in the cellular adaptive response to low oxygen, and we have been investigating new molecular controllers of cell fate.
Targeting the HIF pathway in cancer
(funding, Therapeutic Innovation Fund (UCL), Wellcome Trust)
Overexpression of HIF-a occurs in most human cancers and correlates with the severity of tumour grade and a poor prognostic outcome. 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 target the HIF/hypoxia pathway in cancer. Recently, we have performed a high content imaging siRNA screen to identify novel components of the apoptotic machinery important for inhibiting HIF and eliciting cell death in hypoxia.
Therapeutic potential of PHD inhibitors
(funding, The British Heart Foundation)
We are interested in the potential for activating HIF as a therapeutic approach, particularly in ischaemic conditions. This has involves investigating the underlying mechanisms for HIF-mediated protection in various systems.
Genetic Investigation of Kidney Disease
(funding Medical Research Council, in collaboration with Patrick Maxwell, University of Cambridge, UK)
We have assembled a number of multiply affected families with renal disease and are investigating the genetic mechanism(s) leading to the disease.