The Paradox of p53: What, How, and Why?

Unlike the rather stereotypic image by which it was portrayed until not too many years ago, p53 is now increasingly emerging as a multifaceted transcription factor that can sometimes exert opposing effects on biological processes. This includes pro-survival activities that seem to contradict p53's canonical proapoptotic features, as well as opposing effects on cell migration, metabolism, and differentiation. Such antagonistic bifunctionality (balancing both positive and negative signals) bestows p53 with an ideal attribute to govern homeostasis. The molecular mechanisms underpinning the paradoxical activities of p53 may be related to a protein conformational spectrum (from canonical wild-type to "pseudomutant"), diversity of DNA response elements, and/or higher-order chromatin configuration. Altogether, this functional flexibility positions p53 as a transcriptional "super hub" that dictates cell homeostasis, and ultimately cell fate, by governing a hierarchy of other functional hubs. Deciphering the mechanisms by which p53 determines which hubs to engage, and how one might modulate the preferences of p53, remains a major challenge for both basic science and translational cancer medicine.