Multisite phosphorylation and the integration of stress signals at p53

The p53 tumour suppressor protein is a potent transcription factor that plays a major role in the defence against tumour development. p53 exists in a latent form that can be activated by a range of stresses including DNA damage, hypoxia, cytokines, metabolic changes, viral infection, and activated oncogenes. Activation of p53 can lead to cellular growth arrest prior to entry into either S phase or mitosis or can trigger cell death through apoptosis. The modification of p53 by multisite phosphorylation provides a potential link between stress signalling and the regulation of p53 activity, and there is now striking evidence that agents that activate p53 can lead to selective changes in its phosphorylation status. Topologically, the phosphorylation sites in p53 fall into two discrete functional domains. Four phosphorylation events take place within the N-terminal 83 amino acids containing the transactivation domain and a region involved in transcription-independent growth suppression. At least three of these modifications occur in response to agents that cause cellular stress such as DNA damage. At the C-terminus, there are three phosphorylation events, each of which can independently regulate the specific DNA-binding function of p53, suggesting convergent control by different signalling pathways. The multiplicity of these covalent modifications and their responsiveness to a wide range of signals suggest that p53 activity is tightly and coordinately controlled in response to stresses and changes in the cellular environment.