The discovery of the p53 tumor suppressor protein raised fundamental questions about cell cycle regulation that have spanned several decades. TP53 mutations are found in most human cancers, most frequently as missense alterations in the DNA-binding domain (DBD). As a master regulator of both cell-intrinsic and cell-extrinsic functions, mutant p53 contributes to pro-oncogenic activities through gain-of-function (GOF) properties in addition to loss-of-function (LOF) and dominant-negative effects (DNEs). New technologies and improved fidelity of model systems are uncovering the functional consequences caused by p53 mutations at the molecular, cellular, and tissue levels. In a new era of precision medicine, with the context of recent success in targeting genetic mutations, ongoing and future understanding of fundamental mutant p53 biology is of paramount importance.
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