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TP53: the unluckiest of genes?

Joerger, Andreas C., Stiewe, Thorsten, Soussi, Thierry·2025·Cell Death & Differentiation
DOI 10.1038/s41418-024-01391-6
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Abstract

The transcription factor p53 plays a key role in the cellular defense against cancer development. It is inactivated in virtually every tumor, and in every second tumor this inactivation is due to a mutation in the TP53 gene. In this perspective, we show that this diverse mutational spectrum is unique among all other cancer-associated proteins and discuss what drives the selection of TP53 mutations in cancer. We highlight that several factors conspire to make the p53 protein particularly vulnerable to inactivation by the mutations that constantly plague our genome. It appears that the TP53 gene has emerged as a victim of its own evolutionary past that shaped its structure and function towards a pluripotent tumor suppressor, but came with an increased structural fragility of its DNA-binding domain. TP53 loss of function - with associated dominant-negative effects - is the main mechanism that will impair TP53 tumor suppressive function, regardless of whether a neomorphic phenotype is associated with some of these variants.

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Metadata

Authors
Joerger, A. C., Stiewe, T., & Soussi, T.
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2024-10-23
Volume
32
Issue
2
Pages
219-224
ISSN
  • 1350-9047
  • 1476-5403
DOI
10.1038/s41418-024-01391-6
Cited by
51
References
6
Language
en
Licence
Funders
  • Deutsche Forschungsgemeinschaft (JO 1473/1-3, STI 182/15-1, GRK2573)
  • Cancéropôle IDF

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