P53 Aggregation and prionoid effect and the modulation of this process by PRIMA‐1 and its active metabolite, 2‐methylene‐3‐quinuclidinone hydrate (754.4)

Abstract

Among other functions, p53 acts as a transcription factor and is involved in cell cycle control, leading to apoptosis or to the arrest of the cell cycle for DNA damage repair. It is mutated in around 50% of all tumors. In general, mutations occur on the DNA‐binding domain, leading to its loss of function as a transcription factor. The mutation in a single allele leads to the complete loss of function due to a phenomenon called negative dominance. It has been postulated that mutant p53 can form aggregates that are related to loss‐of‐function and cancer development. Also, new data have contributed to the spread the application of the prion concept on different amyloid disesases. In this work, we show that the effect of mutant p53 on wild type p53 aggregation occurs in a prionoid manner. We have also observed that PRIMA‐1, a classical drug described to stabilize mutant p53 structure and function, exerts its effect on aggregated mutant p53. Also, 2‐methylene‐3‐quinuclidinone hydrate (MQ) has been shown to inhibit WT and mutant recombinant p53 central core domain (p53C) aggregation at 37oC. The WT form has been protected in a lower degree. MQ has also been shown to inhibit the seeding promoted by mutant p53 cellular extracts fractions enriched in oligomers on WTp53C. The same seeding inhibition effect was observed for extracts from cells treated with PRIMA‐1. These results might lead to a different understanding on the controversial mechanism of action of PRIMA‐1 and to further understanding of the seeding and aggregation process of p53, as well as its modulation.Grant Funding Source: Supported by FAPERJ and CNPq