Gain of function of mutant p53 by coaggregation with multiple tumor suppressors
Abstract
Many p53 missense mutations possess dominant-negative activity and oncogenic gain of function. We report that for structurally destabilized p53 mutants, these effects result from mutant-induced coaggregation of wild-type p53 and its paralogs p63 and p73, thereby also inducing a heat-shock response. Aggregation of mutant p53 resulted from self-assembly of a conserved aggregation-nucleating sequence within the hydrophobic core of the DNA-binding domain, which becomes exposed after mutation. Suppressing the aggregation propensity of this sequence by mutagenesis abrogated gain of function and restored activity of wild-type p53 and its paralogs. In the p53 germline mutation database, tumors carrying aggregation-prone p53 mutations have a significantly lower frequency of wild-type allele loss as compared to tumors harboring nonaggregating mutations, suggesting a difference in clonal selection of aggregating mutants. Overall, our study reveals a novel disease mechanism for mutant p53 gain of function and suggests that, at least in some respects, cancer could be considered an aggregation-associated disease.
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In some cell types, mutant p53 can sequester p73 and block p73-mediated downstream signaling.
“In some cell types mtp53 can sequester p73, which leads to a blockade of p73-mediated downstream signaling (35).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [35]
Xu and colleagues showed that mutant p53 R282W and R110P are misfolded/aggregated, which increases aggregation with p73 and inhibits p73 function.
“Xu and colleagues demonstrated that mutant p53 (mtp53) (R282W and R110P) exhibit a misfolded/aggregated state which leads to increased aggregation of mtp53 with p73 causing inhibition of p73 function (35).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [35]
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- Authors
- Xu, J., Reumers, J., Couceiro, J. R., De Smet, F., Gallardo, R., Rudyak, S., Cornelis, A., Rozenski, J., Zwolinska, A., Marine, J.-C., Lambrechts, D., Suh, Y.-A., Rousseau, F., & Schymkowitz, J.
- Affiliations
- Vrije Universiteit Brussel (BE)
- Rega Institute for Medical Research (BE)
- Vlaams Instituut voor Biotechnologie (BE)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Schymkowitz, Joost
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2011-03-27
- Volume
- 7
- Issue
- 5
- Pages
- 285-295
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W1967058595
- Cited by
- 543
- References
- 48
- Citations by year
- 2026: 19 · 2025: 31 · 2024: 36 · 2023: 32 · 2022: 53 · 2021: 41 · 2020: 43 · 2019: 37 · 2018: 42 · 2017: 24 · 2016: 46 · 2015: 30 · 2014: 39 · 2013: 29 · 2012: 29
- FWCI
- 16.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- mutant p53, gain-of-function, p63, p73, heat shock response, clonal selection, germline p53 mutation
- MeSH terms
- Tumor Protein p73, Animals, DNA-Binding Proteins, Humans, Mutation, Neoplasms, Nuclear Proteins, Protein Conformation, Transcription Factors, Tumor Cells, Cultured, Trans-Activators, Genes, p53, Tumor Suppressor Protein p53, Spectroscopy, Fourier Transform Infrared, Spectrometry, Mass, Electrospray Ionization, Tumor Suppressor Proteins, Mice, Hydrophobic and Hydrophilic Interactions
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