Cancer Research UK Edinburgh Centre

Kathryn Ball: Cell Signalling

Research Programme

Cell Signalling mediated by IRF-1

IRF-1 is an interferon regulated transcription factor with roles in a diverse range of growth control and immunological processes. These processes include apoptosis, cell cycle control, antigen presentation, differentiation and the response to pathogen infection. In addition IRF-1 is a component of an intrinsic tumour suppressor network that acts to defend the cell from oncogenic stimuli or from disruption of its genetic material. The loss of IRF-1 function is associated with the development of cancers of the breast and GI tract, as well as a wide variety of leukaemias. Interestingly however decreased IRF-1 expression enhances resistance to HIV infection whereas elevated levels of the protein can promote autoimmune diseases. IRF-1 therefore represents a potential therapeutic target as it controls a cohort of genes with fundamental roles in human health and disease.  However it is currently impractical to design IRF-1 targeted therapies as we know relatively little about how the protein is regulated at the post-translational level and whether deficiencies in the enzymes and protein which form the IRF-1 interactome can enhance or impede the development of human pathologies. This has driven the Ball group to focus their research on defining the intrinsic and extrinsic mechanisms that control IRF-1 protein function.

The group have recently discovered that the post-translational regulatory network controlling IRF-1 function and turnover is rate-limiting for the modulation of downstream genes involved in immunity and tumour suppression. In order to capitalise on this they are using a cross-disciplinary approach to study IRF-1 structure in relation to its turnover, modification by ubiquitin, regulation by reversible phosphorylation and biological function(s). They are also combining biochemistry with biophysics, chemistry and cell biology in order to develop novel biologics and small molecules which can be used to study the regulation of endogenous IRF-1 pathway components and to link them to physiological outcome using chemical genetics.

To ensure the success of their research programme, the Ball group are actively involved in a number of exciting local and international collaborations which give access to expertise in protein structure and biophysics, dynamic protein modelling, state of the art mass spectrometry and chemistry. In addition, they interact with molecular immunologists and clinical collaborators to gain insight into human health and disease.