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Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart

The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two r...

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Autores principales: Huang, Shibo, Cao, Bo, Wang, Jieqiong, Zhang, Yiwei, Ledet, Elisa, Sartor, Oliver, Xiong, Yuqin, Zeng, Shelya X, Lu, Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964174/
https://www.ncbi.nlm.nih.gov/pubmed/34918105
http://dx.doi.org/10.1093/jmcb/mjab078
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author Huang, Shibo
Cao, Bo
Wang, Jieqiong
Zhang, Yiwei
Ledet, Elisa
Sartor, Oliver
Xiong, Yuqin
Zeng, Shelya X
Lu, Hua
author_facet Huang, Shibo
Cao, Bo
Wang, Jieqiong
Zhang, Yiwei
Ledet, Elisa
Sartor, Oliver
Xiong, Yuqin
Zeng, Shelya X
Lu, Hua
author_sort Huang, Shibo
collection PubMed
description The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named ‘p53-374*48’ and ‘p53-393*78’) as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity.
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spelling pubmed-89641742022-03-30 Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart Huang, Shibo Cao, Bo Wang, Jieqiong Zhang, Yiwei Ledet, Elisa Sartor, Oliver Xiong, Yuqin Zeng, Shelya X Lu, Hua J Mol Cell Biol Article The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named ‘p53-374*48’ and ‘p53-393*78’) as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity. Oxford University Press 2021-12-16 /pmc/articles/PMC8964174/ /pubmed/34918105 http://dx.doi.org/10.1093/jmcb/mjab078 Text en © The Author(s) (2021). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Huang, Shibo
Cao, Bo
Wang, Jieqiong
Zhang, Yiwei
Ledet, Elisa
Sartor, Oliver
Xiong, Yuqin
Zeng, Shelya X
Lu, Hua
Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart
title Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart
title_full Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart
title_fullStr Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart
title_full_unstemmed Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart
title_short Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart
title_sort cancer-derived c-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964174/
https://www.ncbi.nlm.nih.gov/pubmed/34918105
http://dx.doi.org/10.1093/jmcb/mjab078
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