Journal ArticleDOI
Gain of function of mutant p53 by coaggregation with multiple tumor suppressors
Jie Xu,Joke Reumers,José R. Couceiro,Frederik De Smet,Rodrigo Gallardo,Stanislav Rudyak,Ann Cornelis,Jef Rozenski,Aleksandra Zwolinska,Jean-Christophe Marine,Diether Lambrechts,Young-Ah Suh,Frederic Rousseau,Joost Schymkowitz +13 more
TLDR
This 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.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.read more
Citations
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Molecular chaperones in protein folding and proteostasis
TL;DR: It is suggested that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease, which may spring from a detailed understanding of the pathways underlying proteome maintenance.
Journal ArticleDOI
p53 mutations in cancer
TL;DR: Some of the emerging molecular mechanisms through which mutant p53 proteins can exert oncogenic functions, including invasion, metastasis, proliferation and cell survival, are highlighted.
Journal ArticleDOI
Self-propagation of pathogenic protein aggregates in neurodegenerative diseases
TL;DR: As a unifying pathogenic principle, the prion paradigm suggests broadly relevant therapeutic directions for a large class of currently intractable diseases.
Journal ArticleDOI
Protein Phase Separation: A New Phase in Cell Biology.
Steven Boeynaems,Steven Boeynaems,Simon Alberti,Nicolas L. Fawzi,Tanja Mittag,Magdalini Polymenidou,Frederic Rousseau,Frederic Rousseau,Joost Schymkowitz,Joost Schymkowitz,James Shorter,Benjamin Wolozin,Ludo Van Den Bosch,Peter Tompa,Peter Tompa,Monika Fuxreiter +15 more
TL;DR: A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.
Journal ArticleDOI
Mutant p53: one name, many proteins
TL;DR: Mechanisms by which Mutant p53 exerts its cellular effects are reviewed, with a particular focus on the burgeoning mutant p53 transcriptome, and the biological and clinical consequences of mutant p 53 gain of function are discussed.
References
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