Oncogenic Phase Transitions: How Mutant p53 Drives Amyloid Formation in p63 and p73 Liquid Droplets

Abstract

Phase separation (PS) of p53 is critical in its path to amyloid aggregation, a process linked to cancer. P63 and p73 exhibit dual roles as tumor suppressors and oncogenes and are often heightened in tumors. Their coaggregation has been proposed in cancer, yet their PS contribution remains unknown. This study investigates the phase behaviors of p53, p63, and p73. P63 and p73 undergo liquid-liquid phase separation (LLPS). Unlike p53, p63 and p73 do not form amyloids under increased temperatures, underscoring an aspect of the processes involved in cancer. Unlike p63 and p73, wild-type and the M237I mutant p53 initially form droplets at 4{degrees}C, but at temperatures up to 37{degrees}C, they begin to aggregate and bind to Congo red, showing amyloidogenesis. Intriguingly, mutant p53 promotes amyloid-like states in p63 and p73 and hijacks p73 into membrane less organelles. Wild-type p53 has a moderate effect on p63 and p73s amyloid aggregation. Additionally, heparin prevents the prion-like aggregation of p63 and p73 induced by p53. Our results shed light on how mutant and wild-type p53 may trigger amyloid aggregation of p63 and p73, revealing the capacity of p53 amyloid droplets within cancer. These insights expand the possibilities for developing cancer therapies targeting the prion-like conversion of p63 and p73 influenced by mutated p53. RelevanceThe prion-like action of mutant p53 on p63 and p73 droplets would be the basis for an oncogenic gain of function of the p53 mutation.