TP53 mutations in cancer: Molecular features and therapeutic opportunities (Review)

Abstract

The tumour suppressor factor p53 plays an essential role in regulating numerous cellular processes, including the cell cycle, DNA repair, apoptosis, autophagy, cell metabolism and immune response. TP53 is the most commonly mutated gene in human cancers. These mutations are primarily non‑synonymous changes that produce mutant p53 proteins characterized by loss of function, a dominant negative effect on p53 tetramerisation and gain of function (GOF). GOF mutations not only disrupt the tumour‑suppressive activities of p53 but also endow the mutant proteins with new oncogenic properties. Recent studies analysing different pathogenic features of mutant p53 in cancer‑derived cell lines have demonstrated that restoring wild‑type p53, rather than removing GOF mutations, reduces cancer cell growth. These findings suggest that therapeutic strategies for reactivating wild‑type p53 function in cancer cells may bring a greater benefit than approaches halting mutant p53. This approach could involve the use of small molecules, gene therapy and other methods to re‑establish wild‑type p53 activity. This review describes the complexity of the biological activities of different p53 mutants and summarizes the current therapeutic approaches to restore p53 function.

Keywords: TP53; dominant negative effect; gain‑of‑function; loss‑of‑function; missense mutations; therapy; tumour suppressor.

Figure 1

Under physiological conditions, cell stress promotes the activation and stabilization of p53 by post-translational modifications (phosphorylation, acetylation, etc.). The stabilized p53 forms tetramers, which bind the p53-dependent promoters and activate the expression of genes involved in different biological functions, such as cell cycle control, DNA repair, senescence and apoptosis. The p53 protein directly interacts with numerous other proteins and regulates cellular pathways such as ferroptosis, ROS, autophagy and metabolism. The level of p53 protein is regulated by a p53-MDM2/MDMX feedback loop via proteasomal degradation of p53. 14-3-3-s, 14-3-3 protein sigma; ALDH4, aldehyde dehydrogenase 9 family member A1; ALOX12, arachidonate 12-lipoxygenase, 12S type; AMPK, protein kinase AMP-activated catalytic subunit alpha 2; ATM, ataxia telangiectasia mutant; ATR, ataxia telangiectasia related; BAX, BCL2 associated X, apoptosis regulator; Casp 7, caspase 7; CBP/p300, CREB-binding protein/p300; Cdc2, cyclin-dependent kinase 1; CDK, cyclin-dependent kinase; CDKN1A, CDK inhibitor 1; CHK1, checkpoint kinase 1; COX2, prostaglandin-endoperoxide synthase 2; CPT1C, carnitine palmitoyltransferase 1C; DDB2, damage specific DNA binding protein 2; DPP4, dipeptidyl peptidase 4; FANCC, Fanconi anemia complementation group C; Fas/Fas L, Fas cell surface death receptor/Fas cell surface death receptor ligand; FDXR, ferredoxin reductase; G6PDH, glucose-6-phosphate dehydrogenase; GADD45, growth arrest and DNA damage-inducible 45; GLS2, glutaminase 2; GLUT 1, solute carrier family 2 member 1; GPX1, glutathione peroxidase 1; HK2, hexokinase 2; HMGB1, high mobility group box 1; LPIN1, lipin 1; MCD, malonyl-CoA decarboxylase; mTOR, mechanistic target of rapamycin kinase; NOXA, NADPH oxidase activator; P19^ARF, CDK inhibitor 2A; p38, p38 kinase; PAI1, serpin family E member 1; PANK1, pantothenate kinase 1; PGM, phosphoglucomutase 1; PHGDH, phosphoglycerate dehydrogenase; PIGs, phosphatidylinositol glycan anchor biosynthesis class S; PKM2, pyruvate kinase M1/2; PML, promyelocytic leukemia protein; POX, proline dehydrogenase 1; PTGS2, prostaglandin-endoperoxide synthase 2; PUMA, BCL2 binding component 3; RRM2, ribonucleotide reductase regulatory subunit M2; ROS, reactive oxygen species; SAT1, spermidine/spermine N1-acetyltransferase 1; SLC7A11, solute carrier family 7 member 11; TFR1, transferrin receptor; TIGAR, TP53 induced glycolysis regulatory phosphatase; TP53INP1, tumor protein p53 inducible nuclear protein 1; XPC, xeroderma pigmentosum, complementation group C; YAP1, Yes1-associated transcriptional regulator.

Figure 2

TP53 gene mutations in the curated set of non-redundant studies including TCGA and non-TCGA datasets (n=10,953 patients from 32 studies) that do not include overlapping samples (www.cbioportal.org/). TCGA, The Cancer Genome Atlas; CNA, copy number alterations.

Figure 3

Lollipop plot produced by the MutationMapper tool of cBioPortal shows the frequency and position of TP53 mutations in 10953 tumours from 32 studies. Domain organization of p53 is also described, followed by the C-terminus containing the nuclear export signal. TAD, transactivation domain; PRD, proline rich domain; DBD, DNA binding domain; NLS, nuclear localization signal; NLS, nuclear localization signal; TET, tetramerisation domain.