Posttranslational Modification of p53: Cooperative Integrators of Function

The p53 protein is modified by as many as 50 individual posttranslational modifications. Many of these occur in response to genotoxic or nongenotoxic stresses and show interdependence, such that one or more modifications can nucleate subsequent events. This interdependent nature suggests a pathway that operates through multiple cooperative events as opposed to distinct functions for individual, isolated modifications. This concept, supported by recent investigations, which provide exquisite detail as to how various modifications mediate precise protein–protein interactions in a cooperative manner, may explain why knockin mice expressing p53 proteins substituted at one or just a few sites of modification typically show only subtle effects on p53 function. The present article focuses on recent, exciting progress and develops the idea that the impact of modification on p53 function is achieved through collective and integrated events.