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

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 activit...

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Autores principales: Walerych, Dawid, Pruszko, Magdalena, Zyla, Lukasz, Wezyk, Michalina, Gaweda-Walerych, Katarzyna, Zylicz, Alicja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112834/
https://www.ncbi.nlm.nih.gov/pubmed/30174797
http://dx.doi.org/10.18632/oncotarget.25944
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author Walerych, Dawid
Pruszko, Magdalena
Zyla, Lukasz
Wezyk, Michalina
Gaweda-Walerych, Katarzyna
Zylicz, Alicja
author_facet Walerych, Dawid
Pruszko, Magdalena
Zyla, Lukasz
Wezyk, Michalina
Gaweda-Walerych, Katarzyna
Zylicz, Alicja
author_sort Walerych, Dawid
collection PubMed
description 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.
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spelling pubmed-61128342018-08-31 Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a “dominant-positive” mechanism Walerych, Dawid Pruszko, Magdalena Zyla, Lukasz Wezyk, Michalina Gaweda-Walerych, Katarzyna Zylicz, Alicja Oncotarget Research Paper 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. Impact Journals LLC 2018-08-10 /pmc/articles/PMC6112834/ /pubmed/30174797 http://dx.doi.org/10.18632/oncotarget.25944 Text en Copyright: © 2018 Walerych et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Walerych, Dawid
Pruszko, Magdalena
Zyla, Lukasz
Wezyk, Michalina
Gaweda-Walerych, Katarzyna
Zylicz, Alicja
Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a “dominant-positive” mechanism
title Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a “dominant-positive” mechanism
title_full Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a “dominant-positive” mechanism
title_fullStr Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a “dominant-positive” mechanism
title_full_unstemmed Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a “dominant-positive” mechanism
title_short Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a “dominant-positive” mechanism
title_sort wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a “dominant-positive” mechanism
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112834/
https://www.ncbi.nlm.nih.gov/pubmed/30174797
http://dx.doi.org/10.18632/oncotarget.25944
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