p53 and Tumor Suppression: It Takes a Network

Abstract

The TP53 tumor suppressor is the most frequently mutated gene in human cancer. p53 suppresses tumorigenesis by transcriptionally regulating a network of target genes that play roles in various cellular processes. Though originally characterized as a critical regulator for responses to acute DNA damage (activation of apoptosis and cell cycle arrest), recent studies have highlighted new pathways and transcriptional targets downstream of p53 regulating genomic integrity, metabolism, redox biology, stemness, and non-cell autonomous signaling in tumor suppression. Here, we summarize our current understanding of p53-mediated tumor suppression, situating recent findings from mouse models and unbiased screens in the context of previous studies and arguing for the importance of the pleiotropic effects of the p53 transcriptional network in inhibiting cancer.

Keywords: cancer; mouse models; network; p53; transcription factor; tumor suppression.

Figure 1.. p53 structure and function.

(a) p53 protein includes six major domains essential for transcriptional activation: two amino-terminal transcriptional activation domains (TADs), a proline-rich domain (PRD), a sequence-specific DNA binding domain (DBD), an oligomerization domain (OD), and a C-terminal domain (CTD). (b) p53 is activated by various cellular stresses, driving a transcriptional response that impacts a wide range of cellular processes. A p53 tetramer binds DNA in a sequence-specific fashion at p53 response elements (RE), then activates transcription of target genes involved in different cellular processes.

Figure 2.. Two distinct models to explain p53-mediated tumor suppression.

(a) A proposed model for p53-mediated tumor suppression where a cell- or context-specific subset of p53 function is critical. (b) A model attributing p53 tumor suppression to the pleiotropic activity of p53 in modulating many different cellular processes. New evidence detailing the pleiotropy of p53 in a single tumor-suppressive setting supports this model. A limited set of p53-dependent processes are illustrated here to provide an example, rather than to enumerate a conclusive list of important processes.

Figure 3.. The p53 transcriptional network.

The p53 transcriptional network contains target genes that regulate diverse cellular processes including apoptosis, cell cycle arrest (including senescence), DNA repair, metabolism, ferroptosis/redox levels, cellular differentiation/reprogramming, and regulators of non-cell autonomous functions that impact the tumor microenvironment (TME).