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The functionality of the tumor suppressor p53 is altered in more than 50% of human cancers, and many individuals with cancer exhibit amyloid-like buildups of aggregated p53. An understanding of what triggers the pathogenic amyloid conversion of p53 is required for the further development of cancer therapies. Here, perturbation of the p53 core domain (p53C) with subdenaturing concentrations of guanidine hydrochloride and high hydrostatic pressure revealed native-like molten globule (MG) states, a subset of which were highly prone to amyloidogenic aggregation. We found that MG conformers of p53C, probably representing population-weighted averages of multiple states, have different volumetric properties, as determined by pressure perturbation and size-exclusion chromatography. We also found that they bind the fluorescent dye 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid (bis-ANS) and have a native-like tertiary structure that occludes the single Trp residue in p53. Fluorescence experiments revealed conformational changes of the single Trp and Tyr residues before p53 unfolding and the presence of MG conformers, some of which were highly prone to aggregation. p53C exhibited marginal unfolding cooperativity, which could be modulated from unfolding to aggregation pathways with chemical or physical forces. We conclude that trapping amyloid precursor states in solution is a promising approach for understanding p53 aggregation in cancer. Our findings support the use of single-Trp fluorescence as a probe for evaluating p53 stability, effects of mutations, and the efficacy of therapeutics designed to stabilize p53.

P53 Phase separation is crucial towards amyloid aggregation and p63 and p73 have enhanced expression in tumors. This study examines the phase behaviors of p53, p63, and p73. Here we show that unlike the DNA-binding domain of p53 (p53C), the p63C and p73C undergo phase separation, but do not form amyloids under physiological temperatures. Wild-type and mutant p53C form droplets at 4°C and aggregates at 37 °C with amyloid properties. Mutant p53C promotes amyloid-like states in p63C and p73C, recruiting them into membraneless organelles. Amyloid conversion is supported by thioflavin T and Congo red binding, increased light scattering, and circular dichroism. Full-length mutant p53 and p63C (or p73C) co-transfection shows reduced fluorescence recovery after photobleaching. Heparin inhibits the prion-like aggregation of p63C and p73C induced by p53C. These findings highlight the role of p53 in initiating amyloid aggregation in p63 and p73, opening avenues for targeting prion-like conversion in cancer therapy. Phase separation of p53 is crucial in its progression towards amyloid aggregation, while its paralogous forms p63 and p73 have enhanced expression in tumors but reduced aggregation propensity. Here, the authors report the prion-like aggregation of p63 and p73 mediated by p53 and outline that this process can be inhibited by heparin. [ABSTRACT FROM AUTHOR]

Despite being referred to as the guardian of the genome, when impacted by mutations, p53 can lose its protective functions and become a renegade. The malignant transformation of p53 occurs on multiple levels, such as altered DNA binding properties, acquisition of novel cellular partners, or associating into different oligomeric states. The consequences of these transformations can be catastrophic. Ongoing studies have implicated different oligomeric p53 species as having a central role in cancer biology; however, the correlation between p53 oligomerization status and oncogenic activities in cancer progression remains an open conundrum. In this review, we summarize the roles of different p53 oligomeric states in cancer and discuss potential research directions for overcoming aberrant p53 function associated with them. We address how misfolding and prion-like amyloid aggregation of p53 seem to play a crucial role in cancer development. The misfolded and aggregated states of mutant p53 are prospective targets for the development of novel therapeutic strategies against tumoral diseases. [ABSTRACT FROM AUTHOR]