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Review
. 2015 Aug;22(8):1239-49.
doi: 10.1038/cdd.2015.53. Epub 2015 May 29.

TP53: an oncogene in disguise

T Soussi  1 , K G Wiman  2
Affiliations
Review

TP53: an oncogene in disguise

T Soussi et al. Cell Death Differ. 2015 Aug.

Abstract

The standard classification used to define the various cancer genes confines tumor protein p53 (TP53) to the role of a tumor suppressor gene. However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins. This statement is based on multiple arguments including the mutation signature of the TP53 gene in human cancer, the various gains-of-function (GOFs) of the different p53 mutants and the heterogeneous phenotypes developed by knock-in mouse strains modeling several human TP53 mutations. In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated. Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors. The use of Muller's classical definition of mutations based on quantitative and qualitative consequences on the protein product, such as 'amorph', 'hypomorph', 'hypermorph' 'neomorph' or 'antimorph', allows a more meaningful assessment of the consequences of cancer gene modifications, their potential clinical significance, and clearly demonstrates that the TP53 gene is an atypical cancer gene.

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Figures

Figure 1
Figure 1
Mutation spectrum of frequently mutated genes in human cancer—Green: missense mutations; Grey: in-frame insertions and deletions; red: out-of-frame insertions/deletions and splice mutations; orange: nonsense mutations; Blue: nonsense mutations. Data were obtained from the cosmic database (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/) except for those of the TP53 gene, obtained from http.p53.fr. BRAF: v-raf murine sarcoma viral oncogene homolog B1: KRAS, v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog; IDH1, isocitrate dehydrogenase 1; IDH2, isocitrate dehydrogenase 2; PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide; TP53, tumor protein p53; BRCA1, familial breast/ovarian cancer gene 1; PTEN, phosphatase and tensin homolog gene; ARID1A, AT-rich interactive domain 1 A; RB1, retinoblastoma gene; APC, adenomatous polyposis coli gene
Figure 2
Figure 2
Genes most frequently mutated in various types of cancer in the Pan-Cancer study. Only the 40 most significantly mutated genes in the Pan-Cancer study are shown on this graph. The PAN-CANCER study included glioblastoma multiforme (GBM), lymphoblastic acute myeloid leukemia (LAML), head and neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), breast carcinoma (BRCA), kidney renal clear-cell carcinoma (KIRC), ovarian carcinoma (OV), bladder carcinoma (BLCA), colon adenocarcinoma (COAD), uterine cervical and endometrial carcinoma (UCEC) and rectal adenocarcinoma (COADREAD). Pan-cancer: integrated data with all cancer types. Data were generated by analysis of the mutations released by Kandoth et al.
Figure 3
Figure 3
Most frequent protein variants in human cancer. (a) Fifteen most frequent protein mutants in the 12 types of cancer included in the Pan-Cancer study. (b) Ten most frequent protein mutants in four different types of cancer. Left y-axis: mutant variant frequency; Right y-axis: number of cancer worldwide associated with the different variants. p53 mutants are shown in red. Hotspot p53 mutants found in LUSC, such as p.R158L or p.V157F, are specific hotspot mutations associated with smoking. Frequencies for other types of cancer are shown in Supplementary Figure 1. This analysis included lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), breast carcinoma (BRCA) and colon and rectal adenocarcinoma (COAD/READ)
Figure 4
Figure 4
Strategies for therapeutic targeting of mutant TP53. 1: p53 turnover is dependent on E3 ligases such as MDM2 or CHIP that mediate ubiquitination and degradation of TP53. In tumor cells, TP53 protein as well as MDM2 and CHIP can be sequestered in high molecular weight complexes by chaperone proteins HSP70 and HSP90. This blocks the ubiquitin ligase activity of MDM2 and CHIP, leading to mutant TP53 accumulation which is fundamental for its GOF activities. Such accumulation can be targeted by drugs that disrupt TP53-chaperone binding, allowing proteosomal degradation of TP53. Furthermore, small molecules such as PK7088, APR-246 and NSC319726 have been shown to target specific or multiple forms of mutant TP53—Onco TP53—and promote TP53 refolding. This leads to restoration of TP53-dependent transcription and reactivation of TP53 biological responses such as cell-cycle arrest, senescence and apoptosis. It may also inhibit pathways associated with TP53 GOF, including binding and inactivation of TP53 family member proteins TP63 and TP73 ,
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