Current and Previous Research
We have a long-standing interest in the regulation and function of the CDKN2A locus and its role in tumour suppression. CDKN2A has the unusual capacity to encode two completely distinct proteins, designated p16^INK4a and p14^ARF, by exploiting different first exons spliced to a common second exon that is translated in alternative reading frames. While p16^INK4a binds to and inhibits Cdk4 and Cdk6, the cyclin-dependent kinases that initiate the phosphorylation and functional inactivation of the retinoblastoma gene product (pRb), p14^ARF binds to and inhibits MDM2, a multifaceted protein that antagonises p53 function and facilitates its ubiquitination and proteasome-mediated degradation. As ARF expression is regulated by the E2F1 transcription factor, it provides a direct link between the pRb and p53 pathways.

Based on current evidence, both INK4a and ARF appear to be involved in the mechanisms that protect cells against aberrant proliferative signals and other forms of stress. Examples include the erosion of the telomeres that occurs when primary cells are propagated in tissue culture, oxidative stress as a consequence of oncogenic signalling or hyperoxia, and less well defined stresses caused by abnormal cell-substratum interactions. The common outcome is that cells enter a state of irreversible growth arrest that is referred to as senescence or stasis. There is growing evidence that senescence occurs in vivo and is a feature of certain pre-malignant lesions.

Future projects
We are continuing to investigate the regulatory networks that control p16^INK4a and p14^ARF expression, particularly its activation by oncogenes such as Ras and Myc, and its repression by Polycomb group proteins such as Cbx7 and Bmi1. We also have a unique opportunity to study primary cells obtained from three rare individuals who have inherited germline mutations in both CDKN2A alleles. These cells are specifically deficient for p16^INK4a function. Introduction of telomerase allows us to propagate these cells indefinitely and to explore the number nature of the genetic changes required to convert a normal cell into a malignant tumour.