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Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53 (R178E) mice show no detectable target...

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Autores principales: Timofeev, Oleg, Klimovich, Boris, Schneikert, Jean, Wanzel, Michael, Pavlakis, Evangelos, Noll, Julia, Mutlu, Samet, Elmshäuser, Sabrina, Nist, Andrea, Mernberger, Marco, Lamp, Boris, Wenig, Ulrich, Brobeil, Alexander, Gattenlöhner, Stefan, Köhler, Kernt, Stiewe, Thorsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792016/
https://www.ncbi.nlm.nih.gov/pubmed/31483066
http://dx.doi.org/10.15252/embj.2019102096
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author Timofeev, Oleg
Klimovich, Boris
Schneikert, Jean
Wanzel, Michael
Pavlakis, Evangelos
Noll, Julia
Mutlu, Samet
Elmshäuser, Sabrina
Nist, Andrea
Mernberger, Marco
Lamp, Boris
Wenig, Ulrich
Brobeil, Alexander
Gattenlöhner, Stefan
Köhler, Kernt
Stiewe, Thorsten
author_facet Timofeev, Oleg
Klimovich, Boris
Schneikert, Jean
Wanzel, Michael
Pavlakis, Evangelos
Noll, Julia
Mutlu, Samet
Elmshäuser, Sabrina
Nist, Andrea
Mernberger, Marco
Lamp, Boris
Wenig, Ulrich
Brobeil, Alexander
Gattenlöhner, Stefan
Köhler, Kernt
Stiewe, Thorsten
author_sort Timofeev, Oleg
collection PubMed
description Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53 (R178E) mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53 (−/−) mice. Surprisingly, stabilization of p53(R178E) in Mdm2 (−/−) mice nevertheless triggers extensive apoptosis, indicative of residual wild‐type activities. Although this apoptotic activity suffices to trigger lethality of Trp53 (R178E) ;Mdm2 (−/−) embryos, it proves insufficient for suppression of spontaneous and oncogene‐driven tumorigenesis. Trp53 (R178E) mice develop tumors indistinguishably from Trp53 (−/−) mice and tumors retain and even stabilize the p53(R178E) protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53 (R178E) tumors exhibit remarkably better chemotherapy responses than Trp53 (−/−) ones, resulting in enhanced eradication of p53‐mutated tumor cells. Together, this provides genetic proof‐of‐principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy.
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spelling pubmed-67920162019-10-21 Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses Timofeev, Oleg Klimovich, Boris Schneikert, Jean Wanzel, Michael Pavlakis, Evangelos Noll, Julia Mutlu, Samet Elmshäuser, Sabrina Nist, Andrea Mernberger, Marco Lamp, Boris Wenig, Ulrich Brobeil, Alexander Gattenlöhner, Stefan Köhler, Kernt Stiewe, Thorsten EMBO J Articles Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53 (R178E) mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53 (−/−) mice. Surprisingly, stabilization of p53(R178E) in Mdm2 (−/−) mice nevertheless triggers extensive apoptosis, indicative of residual wild‐type activities. Although this apoptotic activity suffices to trigger lethality of Trp53 (R178E) ;Mdm2 (−/−) embryos, it proves insufficient for suppression of spontaneous and oncogene‐driven tumorigenesis. Trp53 (R178E) mice develop tumors indistinguishably from Trp53 (−/−) mice and tumors retain and even stabilize the p53(R178E) protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53 (R178E) tumors exhibit remarkably better chemotherapy responses than Trp53 (−/−) ones, resulting in enhanced eradication of p53‐mutated tumor cells. Together, this provides genetic proof‐of‐principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy. John Wiley and Sons Inc. 2019-09-04 2019-10-15 /pmc/articles/PMC6792016/ /pubmed/31483066 http://dx.doi.org/10.15252/embj.2019102096 Text en © 2019 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Timofeev, Oleg
Klimovich, Boris
Schneikert, Jean
Wanzel, Michael
Pavlakis, Evangelos
Noll, Julia
Mutlu, Samet
Elmshäuser, Sabrina
Nist, Andrea
Mernberger, Marco
Lamp, Boris
Wenig, Ulrich
Brobeil, Alexander
Gattenlöhner, Stefan
Köhler, Kernt
Stiewe, Thorsten
Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses
title Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses
title_full Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses
title_fullStr Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses
title_full_unstemmed Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses
title_short Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses
title_sort residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792016/
https://www.ncbi.nlm.nih.gov/pubmed/31483066
http://dx.doi.org/10.15252/embj.2019102096
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