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

Abstract

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.

Putting p53 in Context

“…As examples, p53 can modulate autophagy, alter metabolism, repress pluripotency and cellular plasticity, and facilitate an iron-dependent form of cell death known as ferroptosis (reviewed in Aylon and Oren, 2016). Even basal levels of p53 can reinforce multiple other tumor suppressive networks (Pappas et al, 2017).…”

“…Trp53 knockout mice exhibit a variety of low-penetrance tissue-specific developmental abnormalities in the neural tube, eyes and testes (Danilova et al, 2008). p53 orthologs in more primitive species can also exhibit conserved non-canonical p53 functions, such as promoting redox control and survival (reviewed in Aylon and Oren, 2016). Moreover, the ortholog Lvp53 is expressed in the soma in shrimp, where cross-talk with NF-kB eliminates virally infected cells and activates innate immunity (Li et al, 2017).…”

p53 shades of Hippo

“…[4][5][6][7][8] Recently, pro-survival functions have been attributed also to wt p53, with some activities shared between the wt and mutant isoforms. 3,[9][10][11][12][13] This may reflect a physiological role for p53 in maintaining homeostasis in the face of transient or fluctuating stress, and may confer contextdependent selective advantages also in those tumors that retain wt p53. 10 The p53 family of transcription factors consists of three paralogs, p53, p63 and p73, which evolved from a common ancestor through two gene duplication events.…”

“…3,[9][10][11][12][13] This may reflect a physiological role for p53 in maintaining homeostasis in the face of transient or fluctuating stress, and may confer contextdependent selective advantages also in those tumors that retain wt p53. 10 The p53 family of transcription factors consists of three paralogs, p53, p63 and p73, which evolved from a common ancestor through two gene duplication events. 14 Interestingly, in organisms, which possess a single p53 family gene, for example, C. Elegans and Drosophila, this gene is more similar to an ancestral p63/p73 hybrid gene and less to p53 itself.…”

Differential contribution of p300 and CBP to regulatory elements in mESCs

“…It is possible that the maintenance of p53-associated acetylation in p300-depleted cells is to ensure proper mESC differentiation. In support, findings from numerous in vivo and in vitro studies now suggest that p53 plays a gatekeeper function to ensure high-fidelity development, promoting specification of cells that undergo cell-cycle arrest and are apoptosis-competent (Aylon and Oren 2016). This connection is highly deserving of future studies.…”