Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets

Selective functional inhibition of a tumor-derived p53 mutant by cytosolic chaperones identified using split-YFP in budding yeast

“…Overexpression of these same chaperones in cells not coexpressing p53 has no such effect (Sopko et al 2006;Johnson et al 2015). High-level p53 expression is toxic to yeast and is thought to involve p53 binding to endogenous yeast genes and thereby perturbing essential gene expression (Inga and Resnick 2001;Leão et al 2013;Park et al 2021). We noticed that the chaperones with the strongest effect on non-selective growth (i.e., those that induced the most p53 "toxicity") had the work, these results support the idea that p53 toxicity in yeast requires nuclear localization.…”

“…Indeed, experiments in mammalian cells with a different TS p53 mutant, C135V, suggested that at high temperature binding of cytosolic Hsp70 chaperones to the mutant p53 renders the NLS inaccessible without directly occluding it (Akakura et al 2001). p53 expressed in yeast can adopt several forms with distinct localization patternsboth punctate and diffuse, and in the cytosol, vacuole, or nucleussome of which can be stably propagated in prion-like ways, suggesting conformational changes in p53 drive the changes in localization (Park et al 2021). Since most of the chaperones we overexpressed are normally found diffusely in the cytosol, we think that the distinct patterns of p53 mislocalization outside the nucleus upon overexpression of distinct chaperones (punctate, diffuse, vacuolar) may have more to do with the conformation of p53 resulting from chaperone interaction than with chaperone binding per se.…”

Phase separation of p53 precedes aggregation and is affected by oncogenic mutations and ligands

“… 64 Interestingly, transient p53 overexpression in yeast induced the formation of p53 prion aggregates; however, liquid-like p53 condensates were generated in response to stress and disappeared after stress removal. 65 …”

p53, A Victim of the Prion Fashion

“…However, as soon as mutant p53 expression was shut off, wild-type p53 fully recovered its transcriptional abilities [14]. These results thus show that mutant p53 did not print its [p53 MUT ] conformation on wild-type p53 in a prion-like manner in S. cerevisiae, although recent data also suggest that when fused to EYFP, p53 overexpression leads, in some rare yeast cells, to the formation of aggregates that are transmitted across generations [161]. Altogether, these data show that the dominant-negative effect of mutant p53 is dose-dependent and can be reduced or even neutralized by increasing the wild-type/mutant p53 ratio.…”