p53: The Multifaceted Roles of Covalent Modifications in Cancer

Abstract

The p53 protein has attracted huge research interest over several decades due to its role as one of the most important tumor suppressors in mammals, which orchestrates a synchronous response from normal cells in the body to various forms of stress. The diverse cellular activities of the p53 protein are regulated mainly via its post-translational modifications (PTMs). PTMs affect p53 on several levels: at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes, at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes; at the level of proteolysis in the absence of stress; and on the contrary, at the level of augmented protein stability in response to stress signals. Disruptions in these regulatory mechanisms can lead to deviations from normal cellular function, boosting tumor initiation and progression. Conversely, targeted interventions in these pathways could prove beneficial for the development of antitumor therapies. Advancing our understanding of p53 modifiers and the proteins involved in its regulation equips researchers with an expanded toolkit for studying cellular processes and for developing biologically active molecules that influence p53-mediated responses.

Keywords: E3 ubiquitin ligases; p53; posttranslational modifications.

Figure 1

Different functions of the p53 protein in mammalian cells.

Figure 2

Major sites of post-translational modifications of p53 in the context of its domain structure. TAD, transactivation domain; PRD, proline-rich domain; DBD, DNA-binding domain; OD, oligomerization domain; SRD, C-terminal regulatory domain.

Figure 3

Molecular structure of effectors p53-MDM-2 interaction.

Figure 4

The conversion of APR-246 to the active substance.

Figure 5

The mechanistic principle of PROTAC action and structures of PROTAC ligands. (A), PROTAC exemplified by a chimera of ligands for Von Hippel–Lindau (VHL) E3 ligase and MDM2, where VHL proximity leads to MDM2 degradation and p53 stabilization followed by tumor cell death. (B), typical PROTACs for p53 stabilization. POI ligands are shown in green, linkers in black, and E3 ligase ligands in orange.