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Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer

Most cancers evolve to disable the p53 pathway, a key tumour suppressor mechanism that prevents transformation and malignant cell growth. However, only ~50% exhibit inactivating mutations of p53, while in the rest its activity is suppressed by changes in the proteins that modulate the pathway. There...

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Autores principales: Falcicchio, Marta, Ward, Jake A., Macip, Salvador, Doveston, Richard G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669891/
https://www.ncbi.nlm.nih.gov/pubmed/33298896
http://dx.doi.org/10.1038/s41420-020-00362-3
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author Falcicchio, Marta
Ward, Jake A.
Macip, Salvador
Doveston, Richard G.
author_facet Falcicchio, Marta
Ward, Jake A.
Macip, Salvador
Doveston, Richard G.
author_sort Falcicchio, Marta
collection PubMed
description Most cancers evolve to disable the p53 pathway, a key tumour suppressor mechanism that prevents transformation and malignant cell growth. However, only ~50% exhibit inactivating mutations of p53, while in the rest its activity is suppressed by changes in the proteins that modulate the pathway. Therefore, restoring p53 activity in cells in which it is still wild type is a highly attractive therapeutic strategy that could be effective in many different cancer types. To this end, drugs can be used to stabilise p53 levels by modulating its regulatory pathways. However, despite the emergence of promising strategies, drug development has stalled in clinical trials. The need for alternative approaches has shifted the spotlight to the 14-3-3 family of proteins, which strongly influence p53 stability and transcriptional activity through direct and indirect interactions. Here, we present the first detailed review of how 14-3-3 proteins regulate p53, with special emphasis on the mechanisms involved in their binding to different members of the pathway. This information will be important to design new compounds that can reactivate p53 in cancer cells by influencing protein–protein interactions. The intricate relationship between the 14-3-3 isoforms and the p53 pathway suggests that many potential drug targets for p53 reactivation could be identified and exploited to design novel antineoplastic therapies with a wide range of applications.
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spelling pubmed-76698912020-11-20 Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer Falcicchio, Marta Ward, Jake A. Macip, Salvador Doveston, Richard G. Cell Death Discov Review Article Most cancers evolve to disable the p53 pathway, a key tumour suppressor mechanism that prevents transformation and malignant cell growth. However, only ~50% exhibit inactivating mutations of p53, while in the rest its activity is suppressed by changes in the proteins that modulate the pathway. Therefore, restoring p53 activity in cells in which it is still wild type is a highly attractive therapeutic strategy that could be effective in many different cancer types. To this end, drugs can be used to stabilise p53 levels by modulating its regulatory pathways. However, despite the emergence of promising strategies, drug development has stalled in clinical trials. The need for alternative approaches has shifted the spotlight to the 14-3-3 family of proteins, which strongly influence p53 stability and transcriptional activity through direct and indirect interactions. Here, we present the first detailed review of how 14-3-3 proteins regulate p53, with special emphasis on the mechanisms involved in their binding to different members of the pathway. This information will be important to design new compounds that can reactivate p53 in cancer cells by influencing protein–protein interactions. The intricate relationship between the 14-3-3 isoforms and the p53 pathway suggests that many potential drug targets for p53 reactivation could be identified and exploited to design novel antineoplastic therapies with a wide range of applications. Nature Publishing Group UK 2020-11-16 /pmc/articles/PMC7669891/ /pubmed/33298896 http://dx.doi.org/10.1038/s41420-020-00362-3 Text en © The Author(s) 2020 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/.
spellingShingle Review Article
Falcicchio, Marta
Ward, Jake A.
Macip, Salvador
Doveston, Richard G.
Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer
title Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer
title_full Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer
title_fullStr Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer
title_full_unstemmed Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer
title_short Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer
title_sort regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669891/
https://www.ncbi.nlm.nih.gov/pubmed/33298896
http://dx.doi.org/10.1038/s41420-020-00362-3
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