Deciphering p53 signaling in tumor suppression

Abstract

The p53 transcription factor is mutated in over half of human cancers, and p53-null mice are highly predisposed to cancer, highlighting p53s essential role in tumor suppression. Studies in mouse models have revealed that p53 cell cycle arrest and apoptosis responses to acute DNA damage signals are dispensable for tumor suppression, prompting a search for new mechanisms underlying p53-mediated cancer suppression. p53 responds to other types of stress signals and regulates a host other cellular processes, including maintenance of genomic stability, metabolism, stemness, non-apoptotic cell death, migration/invasion, and cell signaling, any or all of which could be fundamental for suppressing carcinogenesis. The ability of p53 to govern numerous transcriptional programs and cellular functions likely explains its potent tumor suppressor activity.

Figure 1. p53 acute DNA damage responses and tumor suppression

Analysis of different p53 mouse strains, including the p53 transactivation domain 1 Trp53^25,26 mutant strain, the acetylation site Trp53^3KR mutant strain, and the triple knockout p21^−/−;uma⁻⁻;Noxa^−/− strain, demonstrated that p53-induced cell cycle arrest and apoptosis responses to acute DNA damage are dispensable for tumor suppression. Instead, there may be compensatory pathways that are engaged in the absence of acute DNA damage response pathways to allow tumor suppression. Alternatively, acute DNA damage response pathways may be truly dispensable for tumor suppression, and other p53 signaling pathways and downstream p53 functions are responsible for p53 tumor suppressor activity. TAD- transactivation domain, DBD- DNA binding domain, OD- oligomerization domain.

Figure 2. Overview of p53 signaling pathways in tumor suppression

Different stress stimuli relevant to tumor development in vivo, such as chronic low-dose DNA damage, nutrient starvation, and oncogenic signaling activate p53. In response to such signals, p53 binds to specific DNA response elements (REs) and regulates gene expression programs to modulate different cellular processes, thereby leading to tumor suppression.

Figure 3. Detailed schematic of non-canonical p53-regulated cellular processes and p53 target genes implicated in these processes

The various non-canonical p53-modulated cell biological processes that may contribute to tumor suppression are depicted. The figure focuses on p53-regulated pathways described in the text and some direct p53 target genes involved in these pathways; it is not meant to depict every reported gene that may participate in each pathway.