title: 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.
authors: Switch Laboratory, Flanders Institute for Biotechnology, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Jie
authors: J
authors: Xu
authors: Joke
authors: J
authors: Reumers
authors: José R
authors: JR
authors: Couceiro
authors: Frederik
authors: F
authors: De Smet
authors: Rodrigo
authors: R
authors: Gallardo
authors: Stanislav
authors: S
authors: Rudyak
authors: Ann
authors: A
authors: Cornelis
authors: Jef
authors: J
authors: Rozenski
authors: Aleksandra
authors: A
authors: Zwolinska
authors: Jean-Christophe
authors: JC
authors: Marine
authors: Diether
authors: D
authors: Lambrechts
authors: Young-Ah
authors: YA
authors: Suh
authors: Frederic
authors: F
authors: Rousseau
authors: Joost
authors: J
authors: Schymkowitz
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016158:Genes, p53; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins