Nature chemical biology, 2011-05, Vol.7 (5), p.285-295
2011
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- Autor(en) / Beteiligte
- Titel
- Gain of function of mutant p53 by coaggregation with multiple tumor suppressors
- Ist Teil von
- Nature chemical biology, 2011-05, Vol.7 (5), p.285-295
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1552-4450eISSN: 1552-4469DOI: 10.1038/nchembio.546Titel-ID: cdi_pubmed_primary_21445056
- Format
- –
- Schlagworte
- Animals, DNA-Binding Proteins - chemistry, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Genes, p53, Humans, Hydrophobic and Hydrophilic Interactions, Mice, Mutation, Neoplasms - genetics, Neoplasms - metabolism, Neoplasms - pathology, Nuclear Proteins - chemistry, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Protein Conformation, Spectrometry, Mass, Electrospray Ionization, Spectroscopy, Fourier Transform Infrared, Trans-Activators - chemistry, Trans-Activators - genetics, Trans-Activators - metabolism, Transcription Factors, Tumor Cells, Cultured, Tumor Protein p73, Tumor Suppressor Protein p53 - chemistry, Tumor Suppressor Protein p53 - genetics, Tumor Suppressor Protein p53 - metabolism, Tumor Suppressor Proteins - chemistry, Tumor Suppressor Proteins - genetics, Tumor Suppressor Proteins - metabolism