Assembly of Toxic Amyloid Fibrils of p53 at Physiological Conditions: Is Tumor Mutant of p53 a Prionoid?

p53 function is lost in over 50% of human cancers evidencing its role in tumorigenesis. Accumulation of wild type inactive p53 has been described in various cancers. We have previously demonstrated that the p53 core domain (p53C) can form aggregates. We investigate here aggregation of p53C and its mutant, R248Q at pH 7.2 and 5.0, which are conditions found in the cellular milieu. Under physiological conditions, we find that wt and R248Q undergo aggregation into amyloid species. More extensive aggregation was elicited at higher temperatures or pressure treatment. The aggregates were further characterized by electron microscopy and the amyloid nature was confirmed by x‐ray diffraction analysis. In addition, pH 7.2 aggregates can interact with oligomer‐specific antibody as shown by dot‐blot assay. Moreover, the aggregates were toxic to cells by live dead assay. Searching for a pathological correlation, we had the striking finding that the R248Q mutant co‐localizes with protofibrils and oligomers, through immunofluorescence assay, using anti‐aggregate antibody and anti‐p53 in breast cancer paraffin‐embedded tissue. Our data demonstrate that aggregation of mutant p53 into amyloid‐like fibrils might be involved in cancer pathogenesis and shed light into the mechanism of negative dominance, which would rank p53 as a prionoid. Support: INBEB