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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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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. |
format | Online Article Text |
id | pubmed-6792016 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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