Mathematical modelling of the p53 signalling pathway

Stem cells drive the regeneration and repair of damaged tissues and are, thus, essential for survival. The proliferative capacity of stem cells is, however, a double-edged sword. With every cell division there is a chance of an error occurring during DNA replication and/or repair, which makes stem cells prone to undergo malignant transformation into cancer cells. Fortunately, the body has protection barriers, known as tumour suppressor systems, that prevent uncontrolled growth of damaged cells. The most important of such systems is the p53 pathway. The p53 protein acts as a subcellular sensor that is triggered by potentially cancer-inducing stimuli, such as exposure to DNA damaging agents. In response to such stress conditions, p53 enhances DNA repair, inhibits cell proliferation, or induces programmed cell death. Due to these activities, p53 is regarded as highly attractive target for cancer therapy. Although the nearly 40,000 research articles published on p53 have revealed some of its secrets, they have also uncovered new layers of complexity, resulting in even more unanswered questions. Given the intrinsic complexity and implicit quantitative nature of some these questions, we aim to exploit theoretical thinking and mathematical modelling to gain deeper insight into the regulatory mechanisms of the p53 pathway. It is anticipated that the proposed research will complement and reinforce the biological knowledge acquired by empirical methods.

The p53 tumour suppressor acts as a subcellular sensor that is triggered by potentially oncogenic stimuli, including hypoxia, oncogene activation, telemore shortening and exposure to DNA damaging agents. In response to such stress conditions, p53 induces changes in the expression of hundreds of target genes, resulting in enhanced DNA repair, cell-cycle arrest or apoptosis. As p53 governs the life and death of cells, it is not surprising the p53 itself is tightly controlled by several layers of regulation. We aim to develop, solve and exploit novel mathematical models to enhance our understanding of the mechanisms of p53 regulation. In particular, we will explore the role of the main negative p53 regulator, mdm2, which keeps p53 levels low in the absence of stress, and investigate the impact of the step-wise nature of the ubiquitination/de-ubiquitination of p53. An essential aspect of these theoretical studies will be their co-ordination and integration with the ongoing empirical research at the Dept Surgery Mol Oncol, Dundee: experimental studies will provide assumptions and parameter values for the models, whereas the models will generate new hypotheses and, thereby, stimulate entirely new experiments.