학술논문
Reduced Levels of Misfolded and Aggregated Mutant p53 by Proteostatic Activation.
Document Type
Article
Author
Naus, Evelyne; Derweduwe, Marleen; Lampi, Youlia; Claeys, Annelies; Pauwels, Jarne; Langenberg, Tobias; Claes, Filip; Xu, Jie; Haemels, Veerle; Atak, Zeynep Kalender; van der Kant, Rob; Van Durme, Joost; De Baets, Greet; Ligon, Keith L.; Fiers, Mark; Gevaert, Kris; Aerts, Stein; Rousseau, Frederic; Schymkowitz, Joost; De Smet, Frederik
Source
Subject
*HEAT shock proteins
*CELLULAR inclusions
*DRUG target
*PROTEASOME inhibitors
*BORTEZOMIB
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Language
ISSN
2073-4409
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. [ABSTRACT FROM AUTHOR]