Understanding how cell growth and gene expression are co-ordinately regulated during normal cell division and the response to cellular stress is key to developing models of disease progression novel therapeutic strategies. My group are interested in how a diverse range of signals originating at the cell membrane or generated within the nucleus converge to regulate cell growth and gene expression through the actions of a G1-checkpoint pathway. Proper regulation of this pathway is fundamental to the maintenance of normal growth control and the dysregulation of any member is therefore likely to generate abnormal cells that are predisposed to cancer progression

I. Regulation of the p21 tumour modifier
It has become clear that individual members of the G1-checkpoint pathway can have both a negative and positive effects on cell growth dependent on context and cell type. The p21 protein, for example, is involved in a diverse range of cellular processes including: induction of growth arrest in response to negative growth signals; cell cycle regulation; stimulation and inhibition of cyclin-dependent kinase activity; stem cell commitment; regulation of gene expression and the induction, or inhibition, of cellular differentiation. One major focus of our current research is therefore to delineate how p21 activity is regulated following induction of its expression by both mitogenic stimuli and cellular stress. Future work in this area will concentrate on identifying the signalling networks which 'fine tune' p21 activity and how they impact on its activity as a tumour modifier.

II. Co-ordination and integration of the G1-checkpoint pathway
The regulation of cell growth is dependent on the co-ordination and integration of cell signalling pathways. In order to address how individual members of the G1-checkpoint pathway are co-ordinately controlled in response to negative growth signals we have developed cell models to study regulation of the G1-response with respect to physiological outcome. Observations made using this approach are being dissected using biochemical methods and to date we have identified novel factors that impact on cell growth through their ability to modulate the ability of Rb or IRF-1 to regulate gene expression. Current research is therefore focused on determining the mode of action of these factors at the molecular level.