Understanding the p53 Aggregation Process through its Activators Resveratrol and PRIMA‐1

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. 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 diseases. In this work, we show that the effect of mutant p53 on wild type p53 aggregation occurs in a prion‐like fashion. We have also observed that resveratrol, a natural polyphenol known for its p53 activation properties, and PRIMA‐1, a classical stabilizer and reactivator of mutant p53 structure and function, exert their effects on aggregated mutant p53. Also, resveratrol and 2‐methylene‐3‐quinuclidinone hydrate (MQ), the major PRIMA‐1 active metabolite, have been shown to inhibit WT and mutant p53 core domain (p53C) aggregation at 37oC. The p53 WT form has been protected in a lower degree. MQ has also been shown to inhibit the seeding promoted by mutant p53 cellular extract on WTp53C. The same seeding inhibition effect was observed for extracts from cells treated with PRIMA‐1. Altogether, these findings indicate that prion‐like aggregation of p53 is a good therapeutic target in cancer. Supported by FAPERJ and CNPq.