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Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress

We previously reported that p53-mediated apoptosis is determined by severity of DNA damage, not by the level of p53, in doxorubicin-treated prostate cancer cells. In addition to doxorubicin, our results here indicated that camptothecin and bortezomib, which are a topoisomerase 1 poison and a 26 S pr...

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Autores principales: Ho, Cheng-Jung, Lin, Ru-Wei, Zhu, Wei-Hua, Wen, Tsung-Kai, Hu, Chieh-Ju, Lee, Yi-Lin, Hung, Ta-I, Wang, Chihuei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711993/
https://www.ncbi.nlm.nih.gov/pubmed/31482012
http://dx.doi.org/10.1038/s41420-019-0211-5
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author Ho, Cheng-Jung
Lin, Ru-Wei
Zhu, Wei-Hua
Wen, Tsung-Kai
Hu, Chieh-Ju
Lee, Yi-Lin
Hung, Ta-I
Wang, Chihuei
author_facet Ho, Cheng-Jung
Lin, Ru-Wei
Zhu, Wei-Hua
Wen, Tsung-Kai
Hu, Chieh-Ju
Lee, Yi-Lin
Hung, Ta-I
Wang, Chihuei
author_sort Ho, Cheng-Jung
collection PubMed
description We previously reported that p53-mediated apoptosis is determined by severity of DNA damage, not by the level of p53, in doxorubicin-treated prostate cancer cells. In addition to doxorubicin, our results here indicated that camptothecin and bortezomib, which are a topoisomerase 1 poison and a 26 S proteasome inhibitor, respectively, could also induce apoptosis in a p53-dependent manner in prostate cancer. Then, we examined whether p53-mediated apoptosis induced by genotoxic and non-genotoxic stress occur in the same or a different way. By using dominant negative p53 to compete with wild-type p53 in transcription activity, we demonstrated that p53-mediated apoptosis in response to doxorubicin- or camptothecin-induced genotoxic stress is transcription-independent. In contrast, p53-mediated apoptosis from bortezomib-induced stress is transcription-dependent. Interestingly, we also found that doxorubicin-induced p21 expression is activated by p53 in transcription-dependent manner, while camptothecin-induced p21 expression is p53-independent. We then investigated the p53 ratio of nucleus to cytosol corresponding to low and high dose doxorubicin, camptothecin, or bortezomib treatment. The results suggested that p53 translocation from cytoplasm to nucleus actively drives cells toward apoptosis in either transcription-dependent or -independent manner for responding to non-genotoxic or genotoxic stress, respectively.
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spelling pubmed-67119932019-09-03 Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress Ho, Cheng-Jung Lin, Ru-Wei Zhu, Wei-Hua Wen, Tsung-Kai Hu, Chieh-Ju Lee, Yi-Lin Hung, Ta-I Wang, Chihuei Cell Death Discov Article We previously reported that p53-mediated apoptosis is determined by severity of DNA damage, not by the level of p53, in doxorubicin-treated prostate cancer cells. In addition to doxorubicin, our results here indicated that camptothecin and bortezomib, which are a topoisomerase 1 poison and a 26 S proteasome inhibitor, respectively, could also induce apoptosis in a p53-dependent manner in prostate cancer. Then, we examined whether p53-mediated apoptosis induced by genotoxic and non-genotoxic stress occur in the same or a different way. By using dominant negative p53 to compete with wild-type p53 in transcription activity, we demonstrated that p53-mediated apoptosis in response to doxorubicin- or camptothecin-induced genotoxic stress is transcription-independent. In contrast, p53-mediated apoptosis from bortezomib-induced stress is transcription-dependent. Interestingly, we also found that doxorubicin-induced p21 expression is activated by p53 in transcription-dependent manner, while camptothecin-induced p21 expression is p53-independent. We then investigated the p53 ratio of nucleus to cytosol corresponding to low and high dose doxorubicin, camptothecin, or bortezomib treatment. The results suggested that p53 translocation from cytoplasm to nucleus actively drives cells toward apoptosis in either transcription-dependent or -independent manner for responding to non-genotoxic or genotoxic stress, respectively. Nature Publishing Group UK 2019-08-27 /pmc/articles/PMC6711993/ /pubmed/31482012 http://dx.doi.org/10.1038/s41420-019-0211-5 Text en © The Author(s) 2019 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 Article
Ho, Cheng-Jung
Lin, Ru-Wei
Zhu, Wei-Hua
Wen, Tsung-Kai
Hu, Chieh-Ju
Lee, Yi-Lin
Hung, Ta-I
Wang, Chihuei
Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress
title Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress
title_full Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress
title_fullStr Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress
title_full_unstemmed Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress
title_short Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress
title_sort transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711993/
https://www.ncbi.nlm.nih.gov/pubmed/31482012
http://dx.doi.org/10.1038/s41420-019-0211-5
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