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|Type:||Artigo de periódico|
|Title:||Mutant p53 Aggregates into Prion-like Amyloid Oligomers and Fibrils IMPLICATIONS FOR CANCER|
de Oliveira, GAP
|Abstract:||Over 50% of all human cancers lose p53 function. To evaluate the role of aggregation in cancer, we asked whether wild-type (WT) p53 and the hot-spot mutant R248Q could aggregate as amyloids under physiological conditions and whether the mutant could seed aggregation of the wild-type form. The central domains (p53C) of both constructs aggregated into a mixture of oligomers and fibrils. R248Q had a greater tendency to aggregate than WT p53. Full-length p53 aggregated into amyloid-like species that bound thioflavin T. The amyloid nature of the aggregates was demonstrated using x-ray diffraction, electron microscopy, FTIR, dynamic light scattering, cell viabilility assay, and anti-amyloid immunoassay. The x-ray diffraction pattern of the fibrillar aggregates was consistent with the typical conformation of cross beta-sheet amyloid fibers with reflexions of 4.7 angstrom and 10 angstrom. A seed of R248Q p53C amyloid oligomers and fibrils accelerated the aggregation of WTp 53C, a behavior typical of a prion. The R248Q mutant co-localized with amyloid-like species in a breast cancer sample, which further supported its prion-like effect. A tumor cell line containing mutant p53 also revealed massive aggregation of p53 in the nucleus. We conclude that aggregation of p53 into a mixture of oligomers and fibrils sequestrates the native protein into an inactive conformation that is typical of a prionoid. This prion-like behavior of oncogenic p53 mutants provides an explanation for the negative dominance effect and may serve as a potential target for cancer therapy.|
|Editor:||Amer Soc Biochemistry Molecular Biology Inc|
|Appears in Collections:||Unicamp - Artigos e Outros Documentos|
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