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Updated: Aug 5, 2025
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
Reduced Levels of Misfolded and Aggregated Mutant p53 by Proteostatic Activation
Evelyne Naus1,2, Marleen Derweduwe3, Youlia Lampi1,2
1VIB-KU Leuven Center for Brain & Disease Research, Herestraat 49, 3000 Leuven, Belgium.
Abstract:
In malignant cancer, excessive amounts of mutant p53 often lead to its aggregation, a feature that was recently identified as druggable. Here, we describe that induction of a heat shock-related stress response mediated by Foldlin, a small-molecule tool compound, reduces the protein levels of misfolded/aggregated mutant p53, while contact mutants or wild-type p53 remain largely unaffected. Foldlin also prevented the formation of stress-induced p53 nuclear inclusion bodies. Despite our inability to identify a specific molecular target, Foldlin also reduced protein levels of aggregating SOD1 variants. Finally, by screening a library of 778 FDA-approved compounds for their ability to reduce misfolded mutant p53, we identified the proteasome inhibitor Bortezomib with similar cellular effects as Foldlin. Overall, the induction of a cellular heat shock response seems to be an effective strategy to deal with pathological protein aggregation. It remains to be seen however, how this strategy can be translated to a clinical setting.
Insights
Inducing a heat shock response with Foldlin reduces aggregated mutant p53 and SOD1 levels. The proteasome inhibitor Bortezomib showed similar effects, suggesting heat shock is a viable strategy for pathological protein aggregation.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Malignant cancers often feature excessive mutant p53 aggregation, a druggable target.
- Misfolded and aggregated proteins contribute to various pathologies.
Purpose of the Study:
- To investigate the potential of inducing a heat shock response to reduce aggregated mutant p53.
- To identify compounds that can mitigate pathological protein aggregation.
Main Methods:
- Utilized Foldlin, a small-molecule tool compound, to induce a heat shock-related stress response.
- Screened a library of 778 FDA-approved compounds to identify agents reducing misfolded mutant p53.
- Assessed the effects on mutant p53, wild-type p53, and SOD1 variants.
Main Results:
- Foldlin selectively reduced protein levels of misfolded/aggregated mutant p53, sparing contact mutants and wild-type p53.
- Foldlin inhibited the formation of stress-induced p53 nuclear inclusion bodies.
- Bortezomib, a proteasome inhibitor, was identified with similar cellular effects to Foldlin on mutant p53.
Conclusions:
- Inducing a cellular heat shock response is a promising strategy for addressing pathological protein aggregation.
- Further research is needed to translate this strategy into clinical applications for cancer treatment.
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