Phase Separation and Prion-Like Aggregation of p53 Family Tumor Suppressors: From Protein Evolution to Cancer Treatment

Abstract

Biomolecular condensates, formed through phase separation (PS), are essential in various physiological processes, but they can also transition into amyloid-like structures, contributing to diseases like cancer and neurodegenerative disorders. This review centers on the tumor suppressor protein p53 and its paralogs, p63 and p73, which play significant roles in cancer biology. Mutations in the TP53 gene, present in over half of all malignant tumors, disrupt the function of p53 and contribute to cancer progression. Mutant p53 not only misfolds but also forms biomolecular condensates and amyloid-like aggregates, like the toxic amyloids seen in neurodegenerative diseases. These amyloid-like structures, characteristic of mutant p53, might be associated with its gain of function (GoF) in cancer. Recent in vitro and in cell studies demonstrate that mutant p53 can exert a prion-like effect on its paralogs, p63 and p73, which typically do not form amyloids under physiological conditions. Heparin inhibits the prion-like effect of mutant p53 on p63 and p73. These findings underscore the critical role of mutant p53 in promoting the aggregation of p63 and p73, and likely of other transcription factors, suggesting new therapeutic targets. The amyloid-like aggregation of mutant p53 is an excellent candidate target for cancer, as evidenced by recent studies. By understanding the phase transitions and amyloid formation of mutant p53, innovative diagnostic and treatment strategies have been explored to reveal and disrupt these processes, offering hope for improved cancer therapies.