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p53 partial loss-of-function mutations sensitize to chemotherapy

The tumor suppressive transcription factor p53 is frequently inactivated in cancer cells by missense mutations that cluster in the DNA binding domain. 30% hit mutational hotspot residues, resulting in a complete loss of transcriptional activity and mutant p53-driven chemotherapy resistance. Of the r...

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Autores principales: Klimovich, Boris, Merle, Nastasja, Neumann, Michelle, Elmshäuser, Sabrina, Nist, Andrea, Mernberger, Marco, Kazdal, Daniel, Stenzinger, Albrecht, Timofeev, Oleg, Stiewe, Thorsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837531/
https://www.ncbi.nlm.nih.gov/pubmed/34907344
http://dx.doi.org/10.1038/s41388-021-02141-5
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author Klimovich, Boris
Merle, Nastasja
Neumann, Michelle
Elmshäuser, Sabrina
Nist, Andrea
Mernberger, Marco
Kazdal, Daniel
Stenzinger, Albrecht
Timofeev, Oleg
Stiewe, Thorsten
author_facet Klimovich, Boris
Merle, Nastasja
Neumann, Michelle
Elmshäuser, Sabrina
Nist, Andrea
Mernberger, Marco
Kazdal, Daniel
Stenzinger, Albrecht
Timofeev, Oleg
Stiewe, Thorsten
author_sort Klimovich, Boris
collection PubMed
description The tumor suppressive transcription factor p53 is frequently inactivated in cancer cells by missense mutations that cluster in the DNA binding domain. 30% hit mutational hotspot residues, resulting in a complete loss of transcriptional activity and mutant p53-driven chemotherapy resistance. Of the remaining 70% of non-hotspot mutants, many are partial loss-of-function (partial-LOF) mutants with residual transcriptional activity. The therapeutic consequences of a partial-LOF have remained largely elusive. Using a p53 mutation engineered to reduce DNA binding, we demonstrate that partial-LOF is sufficient to enhance oncogene-driven tumorigenesis in mouse models of lung and pancreatic ductal adenocarcinoma and acute myeloid leukemia. Interestingly, mouse and human tumors with partial-LOF mutations showed mutant p53 protein accumulation similar as known for hotspot mutants. Different from the chemotherapy resistance caused by p53-loss, the partial-LOF mutant sensitized to an apoptotic chemotherapy response and led to a survival benefit. Mechanistically, the pro-apoptotic transcriptional activity of mouse and human partial-LOF mutants was rescued at high mutant protein levels, suggesting that accumulation of partial-LOF mutants enables the observed apoptotic chemotherapy response. p53 non-hotspot mutants with partial-LOF, therefore, represent tumorigenic p53 mutations that need to be distinguished from other mutations because of their beneficial impact on survival in a therapy context.
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spelling pubmed-88375312022-02-24 p53 partial loss-of-function mutations sensitize to chemotherapy Klimovich, Boris Merle, Nastasja Neumann, Michelle Elmshäuser, Sabrina Nist, Andrea Mernberger, Marco Kazdal, Daniel Stenzinger, Albrecht Timofeev, Oleg Stiewe, Thorsten Oncogene Article The tumor suppressive transcription factor p53 is frequently inactivated in cancer cells by missense mutations that cluster in the DNA binding domain. 30% hit mutational hotspot residues, resulting in a complete loss of transcriptional activity and mutant p53-driven chemotherapy resistance. Of the remaining 70% of non-hotspot mutants, many are partial loss-of-function (partial-LOF) mutants with residual transcriptional activity. The therapeutic consequences of a partial-LOF have remained largely elusive. Using a p53 mutation engineered to reduce DNA binding, we demonstrate that partial-LOF is sufficient to enhance oncogene-driven tumorigenesis in mouse models of lung and pancreatic ductal adenocarcinoma and acute myeloid leukemia. Interestingly, mouse and human tumors with partial-LOF mutations showed mutant p53 protein accumulation similar as known for hotspot mutants. Different from the chemotherapy resistance caused by p53-loss, the partial-LOF mutant sensitized to an apoptotic chemotherapy response and led to a survival benefit. Mechanistically, the pro-apoptotic transcriptional activity of mouse and human partial-LOF mutants was rescued at high mutant protein levels, suggesting that accumulation of partial-LOF mutants enables the observed apoptotic chemotherapy response. p53 non-hotspot mutants with partial-LOF, therefore, represent tumorigenic p53 mutations that need to be distinguished from other mutations because of their beneficial impact on survival in a therapy context. Nature Publishing Group UK 2021-12-14 2022 /pmc/articles/PMC8837531/ /pubmed/34907344 http://dx.doi.org/10.1038/s41388-021-02141-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Klimovich, Boris
Merle, Nastasja
Neumann, Michelle
Elmshäuser, Sabrina
Nist, Andrea
Mernberger, Marco
Kazdal, Daniel
Stenzinger, Albrecht
Timofeev, Oleg
Stiewe, Thorsten
p53 partial loss-of-function mutations sensitize to chemotherapy
title p53 partial loss-of-function mutations sensitize to chemotherapy
title_full p53 partial loss-of-function mutations sensitize to chemotherapy
title_fullStr p53 partial loss-of-function mutations sensitize to chemotherapy
title_full_unstemmed p53 partial loss-of-function mutations sensitize to chemotherapy
title_short p53 partial loss-of-function mutations sensitize to chemotherapy
title_sort p53 partial loss-of-function mutations sensitize to chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837531/
https://www.ncbi.nlm.nih.gov/pubmed/34907344
http://dx.doi.org/10.1038/s41388-021-02141-5
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