The p53 response to DNA damage
David W. Meek
The p53 tumour suppressor protein is a highly potent transcription factor which, under normal circumstances, is maintained at low levels through the action of MDM2, an E3 ubiquitin ligase which directs p53 ubiquitylation and degradation. Expression of the mdm2 gene is stimulated by p53 and this reciprocal relationship forms the basis of a negative feedback loop. Both genotoxic and non-genotoxic stresses that induce p53 focus principally on interruption of the p53-MDM2 loop with the consequence that p53 becomes stabilised, leading to changes in the expression of p53-responsive genes. The biological outcome of inducing this pathway can be either growth arrest or apoptosis: factors affecting the functioning of the loop, the biochemical activity of p53 itself and the cellular environment govern the choice between these outcomes in a cell type- and stress-specific manner.