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Detection of Aggregation-Prone Behavior in Mutant P53 V157F Breast Cancer Cells Using Multipoint Thioflavin T Fluorescence
Published on: December 30, 2025
Gain of function of mutant p53 by coaggregation with multiple tumor suppressors
Jie Xu1, Joke Reumers, José R Couceiro
1Switch Laboratory, Flanders Institute for Biotechnology, Vrije Universiteit Brussel, Brussels, Belgium.
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.
Insights
Structurally destabilized p53 mutants cause cancer by inducing aggregation of wild-type p53 and its paralogs, triggering a heat-shock response. Suppressing this aggregation restores normal function and impacts cancer progression, suggesting cancer is an aggregation-associated disease.
Area of Science:
- Molecular Biology
- Cancer Biology
- Protein Aggregation
Background:
- Many p53 missense mutations exhibit dominant-negative activity and oncogenic gain of function.
- The precise mechanisms underlying these oncogenic properties are not fully understood.
Purpose of the Study:
- To investigate the role of protein aggregation in the gain of function of structurally destabilized p53 mutants.
- To elucidate the disease mechanism of mutant p53-associated cancers.
Main Methods:
- Analysis of p53 mutant aggregation.
- Mutagenesis to suppress aggregation propensity.
- Assessment of wild-type p53 and paralog activity.
- Examination of p53 germline mutation database and tumor data.
Main Results:
- Destabilized p53 mutants induce coaggregation of wild-type p53 and its paralogs (p63, p73), triggering a heat-shock response.
- Aggregation is mediated by a conserved sequence in the DNA-binding domain exposed upon mutation.
- Mutagenesis abrogating aggregation restored normal protein function and altered clonal selection in tumors.
- Aggregation-prone p53 mutations were associated with lower frequencies of wild-type allele loss.
Conclusions:
- Mutant p53 gain of function arises from induced coaggregation of wild-type p53 and its paralogs.
- Cancer can be viewed as an aggregation-associated disease.
- Targeting protein aggregation may offer novel therapeutic strategies for p53-mutated cancers.
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