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

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.

First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models

“…Changes in a single residue by hot-spot mutations can impair p53 activity which transforms p53 into a gain-of-function oncoprotein [ 49 ]. Two scenarios have been demonstrated where both TP53 WT and mutant p53 ( TP53 MT ) can affect each other, one being “dominant-positive” effect, where TP53 WT activity suppresses TP53 MT activity, or “dominant-negative effect” where TP53 MT allele inactivates TP53 WT allele [ 50 ]. We did not test the combination of ALRN-6924 and paclitaxel or eribulin in a setting with both TP53 MT and TP53 WT ; further studies are needed in order to determine if this combination can rescue TP53 WT and suppress mutant p53 activity in order to enhance paclitaxel or eribulin sensitivity.…”

Gain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis

“…This observation can be explained either by the fact that p53 mutant:WT heterotetramers may retain, in these cells, some WT functions, or that there is a bias towards WT p53 homotetramer formation. Indeed, a subsequent study [93] revealed that WT p53 oligomerization is more efficient than the oligomerization of mutant p53. At equimolar levels of WT p53 and mutant p53, mutant p53 GOF activities are restrained.…”

A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer

“…Wild-type (WT) p53 is a tumor suppressor protein, which upon induction by stress factors acts mainly as a teterameric transcription factor which induces multiple events-such as metabolic adaptation, proliferation arrest or apoptosis. Due to these p53 properties mutations in the TP53 gene in the context of cancer may lead to three events: loss of function (LOF) of WT p53 tumor suppressor protein which mainly involves loss of transcription factor activity, and-especially in the case of prevalent missense mutations-dominant-negative effect over WT p53 (DN) in a tetrameric protein and gain-of-function (GOF) which can actively drive neoplasia [11,12]. The details of this last mechanism still spark controversies, although it was directly proven nearly three decades ago [13], followed by key mouse model experiments [14,15] and a spectrum of mechanistic studies [16].…”