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Cited by 305Cancer-related Molecular PathwaysChromatin Remodeling and CancerPI3K/AKT/mTOR signaling in cancer

TP53: an oncogene in disguise

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Soussi, T, Wiman, K G·2015·Cell Death & Differentiation
DOI 10.1038/cdd.2015.53PMC PMC4495363
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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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  • TP53 is inactivated in a major fraction of human tumors, mainly by missense mutations in the DNA-binding core domain, leading to loss of DNA binding and p53-dependent transactivation of target genes.

    “However, TP53 is inactivated in a major fraction of human tumors, mainly by missense mutations in the DNA-binding core domain of p533,4, leading to loss of DNA binding and p53-dependent transactivation of target genes such as p21, Bax and Puma.”

    From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [4]

    The section on mutation patterns (page unavailable) says that more than 80% of TP53 alterations are missense mutations and more than 90% occur in the core domain containing the DNA-binding region. But the section on mutant-p53 heterogeneity (page unavailable) reports that over half of the mutants tested had only partial loss of transcriptional activity. The source therefore does not support the unqualified claim that these mutations lead to loss of DNA binding and p53-dependent transactivation. (LLM, conf=0.88)

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Authors
Soussi, T., & Wiman, K. G.
Affiliations
  • Inserm (FR)
  • Karolinska Institutet (SE)
Corresponding author
Soussi, T
ORCID
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2015-05-29
Volume
22
Issue
8
Pages
1239-1249
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/cdd.2015.53
PMC
PMC4495363
OpenAlex
W613972939
Cited by
305
References
8
Citations by year
2026: 17 · 2025: 28 · 2024: 17 · 2023: 30 · 2022: 27 · 2021: 27 · 2020: 36 · 2019: 36 · 2018: 29 · 2017: 26 · 2016: 24 · 2015: 8
FWCI
3.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Differentiation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
Funders
  • Cancerfonden
  • Karolinska Institutet
  • Vetenskapsrådet
  • Radiumhemmets Forskningsfonder
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
TP53, p53, tumor suppressor, gain-of-function mutations, TP53 hotspot mutations, knock-in mice, therapeutic target
MeSH terms
Animals, Aza Compounds, Humans, Maleimides, Mutation, Phenotype, Tumor Suppressor Protein p53, Bridged Bicyclo Compounds, Heterocyclic

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