Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a 'dominant-positive' mechanism

// Dawid Walerych 1 , Magdalena Pruszko 1 , Lukasz Zyla 2 , Michalina Wezyk 1 , Katarzyna Gaweda-Walerych 1 and Alicja Zylicz 2 1 Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland 2 International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland Correspondence to: Dawid Walerych, email: dwalerych@imdik.pan.pl Keywords: p53; oligomerization; FRET; dominant-negative; gain-of-function Received: February 05, 2018 Accepted: July 21, 2018 Published: August 10, 2018 ABSTRACT Human p53 protein acts as a transcription factor predominantly in a tetrameric form. Single residue changes, caused by hot-spot mutations of the TP53 gene in human cancer, transform wild-type (wt) p53 tumor suppressor proteins into potent oncoproteins - with gain-of-function, tumor-promoting activity. Oligomerization of p53 allows for a direct interplay between wt and mutant p53 proteins if both are present in the same cells – where a mutant p53’s dominant-negative effect known to inactivate wt p53, co-exists with an opposite mechanism – a “dominant-positive” suppression of the mutant p53’s gain-of-function activity by wt p53. In this study we determine the oligomerization efficiency of wt and mutant p53 in living cells using FRET-based assays and describe wt p53 to be more efficient than mutant p53 in entering p53 oligomers. The biased p53 oligomerization helps to interpret earlier reports of a low efficiency of the wt p53 inactivation via the dominant-negative effect, while it also implies that the “dominant-positive” effect may be more pronounced. Indeed, we show that at similar wt:mutant p53 concentrations in cells – the mutant p53 gain-of-function stimulation of gene transcription and cell migration is more efficiently inhibited than the wt p53’s tumor-suppressive transactivation and suppression of cell migration. These results suggest that the frequent mutant p53 accumulation in human tumor cells does not only directly strengthen its gain-of-function activity, but also protects the oncogenic p53 mutants from the functional dominance of wt p53.