The tumour suppressor p53 is now known to be an ancient transcription factor that had already evolved interaction sites with its partner protein MDM2 at the dawn of multi-cellular eukaryotic animal life. The billion-year life history of the p53-MDM2 axis has permitted significant time for the proteins to integrate into a distinct range of cellular pathways including binding to hundreds of genomic promoters and regulatory protein-protein interactions with hundreds of distinct functions. This long age of p53 allows us to understand how the protein can regulate a range of functions such as energy generation of the cell, cell motility, genome integrity, virus infection, immune cell response, ageing, and oxidative stress. Due to this deep integration of p53 into the core of eukaryotic life, it is not surprising that the p53 pathway requires inactivation in order for human cancer cells to evade the normal growth controlling processes that have been shaped through evolution by natural selection. This review will focus on the emerging concepts in the protein science field that shed light on p53 protein evolution and function including the nature of thermodynamically unstable regulatory proteins and the growing realisation that the majority of protein-protein interactions in complex eukaryotic cells are driven by intrinsically unstructured and weakly interacting peptide motifs. These concepts help to explain how the vast number of dynamic and specific protein-protein interactions in the p53 pathway evolved, suggest how amino acid modifications like phosphorylation or acetylation in turn evolved to regulate dynamically the p53 interactome, and finally reveal therapeutic strategies for targeting the p53 interactome in human cancers.
