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Targeting Oncogenic Mutant p53 for Cancer Therapy

Among genetic alterations in human cancers, mutations in the tumor suppressor p53 gene are the most common, occurring in over 50% of human cancers. The majority of p53 mutations are missense mutations and result in the accumulation of dysfunctional p53 protein in tumors. These mutants frequently hav...

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Detalles Bibliográficos
Autores principales: Parrales, Alejandro, Iwakuma, Tomoo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685147/
https://www.ncbi.nlm.nih.gov/pubmed/26732534
http://dx.doi.org/10.3389/fonc.2015.00288
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author Parrales, Alejandro
Iwakuma, Tomoo
author_facet Parrales, Alejandro
Iwakuma, Tomoo
author_sort Parrales, Alejandro
collection PubMed
description Among genetic alterations in human cancers, mutations in the tumor suppressor p53 gene are the most common, occurring in over 50% of human cancers. The majority of p53 mutations are missense mutations and result in the accumulation of dysfunctional p53 protein in tumors. These mutants frequently have oncogenic gain-of-function activities and exacerbate malignant properties of cancer cells, such as metastasis and drug resistance. Increasing evidence reveals that stabilization of mutant p53 in tumors is crucial for its oncogenic activities, while depletion of mutant p53 attenuates malignant properties of cancer cells. Thus, mutant p53 is an attractive druggable target for cancer therapy. Different approaches have been taken to develop small-molecule compounds that specifically target mutant p53. These include compounds that restore wild-type conformation and transcriptional activity of mutant p53, induce depletion of mutant p53, inhibit downstream pathways of oncogenic mutant p53, and induce synthetic lethality to mutant p53. In this review article, we comprehensively discuss the current strategies targeting oncogenic mutant p53 in cancers, with special focus on compounds that restore wild-type p53 transcriptional activity of mutant p53 and those reducing mutant p53 levels.
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spelling pubmed-46851472016-01-05 Targeting Oncogenic Mutant p53 for Cancer Therapy Parrales, Alejandro Iwakuma, Tomoo Front Oncol Oncology Among genetic alterations in human cancers, mutations in the tumor suppressor p53 gene are the most common, occurring in over 50% of human cancers. The majority of p53 mutations are missense mutations and result in the accumulation of dysfunctional p53 protein in tumors. These mutants frequently have oncogenic gain-of-function activities and exacerbate malignant properties of cancer cells, such as metastasis and drug resistance. Increasing evidence reveals that stabilization of mutant p53 in tumors is crucial for its oncogenic activities, while depletion of mutant p53 attenuates malignant properties of cancer cells. Thus, mutant p53 is an attractive druggable target for cancer therapy. Different approaches have been taken to develop small-molecule compounds that specifically target mutant p53. These include compounds that restore wild-type conformation and transcriptional activity of mutant p53, induce depletion of mutant p53, inhibit downstream pathways of oncogenic mutant p53, and induce synthetic lethality to mutant p53. In this review article, we comprehensively discuss the current strategies targeting oncogenic mutant p53 in cancers, with special focus on compounds that restore wild-type p53 transcriptional activity of mutant p53 and those reducing mutant p53 levels. Frontiers Media S.A. 2015-12-21 /pmc/articles/PMC4685147/ /pubmed/26732534 http://dx.doi.org/10.3389/fonc.2015.00288 Text en Copyright © 2015 Parrales and Iwakuma. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Parrales, Alejandro
Iwakuma, Tomoo
Targeting Oncogenic Mutant p53 for Cancer Therapy
title Targeting Oncogenic Mutant p53 for Cancer Therapy
title_full Targeting Oncogenic Mutant p53 for Cancer Therapy
title_fullStr Targeting Oncogenic Mutant p53 for Cancer Therapy
title_full_unstemmed Targeting Oncogenic Mutant p53 for Cancer Therapy
title_short Targeting Oncogenic Mutant p53 for Cancer Therapy
title_sort targeting oncogenic mutant p53 for cancer therapy
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685147/
https://www.ncbi.nlm.nih.gov/pubmed/26732534
http://dx.doi.org/10.3389/fonc.2015.00288
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