New developments in the multi-site phosphorylation and integration of stress signalling at p53

Purpose: To summarize recent progress in the understanding of the role of multi-site phosphorylation in mediating the integration of stress signals at the p53 tumour suppressor protein. Results: The p53 protein plays a key role in the response to a range of cellular stresses including agents that can damage DNA; consequently the involvement of p53 in sensing these effects is central to the prevention of tumour development. p53 is a potent but latent transcription factor that can be activated by a range of cellular stresses leading to the induction of cellular growth arrest or controlled cell removal through apoptosis. Accordingly, p53 is under tight control and is subject to several levels of regulation including multi-site phosphorylation. Recent evidence has implicated individual phosphorylation events in the activation of p53 by different types of stress (e.g. ionizing radiation, UV and mitotic spindle damage). Conclusions: A picture is now emerging of the p53 protein as an integration point for stress signals. Different signals impinge on different domains of the protein and may cooperate in modulating the type of p53 response, depending on the nature of the incoming signal.