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Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells
The molecular mechanism responsible that determines cell fate after mitotic slippage is unclear. Here we investigate the post-mitotic effects of different mitotic aberrations—misaligned chromosomes produced by CENP-E inhibition and monopolar spindles resulting from Eg5 inhibition. Eg5 inhibition in...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Pub. Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506520/ https://www.ncbi.nlm.nih.gov/pubmed/26144554 http://dx.doi.org/10.1038/ncomms8668 |
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author | Ohashi, Akihiro Ohori, Momoko Iwai, Kenichi Nakayama, Yusuke Nambu, Tadahiro Morishita, Daisuke Kawamoto, Tomohiro Miyamoto, Maki Hirayama, Takaharu Okaniwa, Masanori Banno, Hiroshi Ishikawa, Tomoyasu Kandori, Hitoshi Iwata, Kentaro |
author_facet | Ohashi, Akihiro Ohori, Momoko Iwai, Kenichi Nakayama, Yusuke Nambu, Tadahiro Morishita, Daisuke Kawamoto, Tomohiro Miyamoto, Maki Hirayama, Takaharu Okaniwa, Masanori Banno, Hiroshi Ishikawa, Tomoyasu Kandori, Hitoshi Iwata, Kentaro |
author_sort | Ohashi, Akihiro |
collection | PubMed |
description | The molecular mechanism responsible that determines cell fate after mitotic slippage is unclear. Here we investigate the post-mitotic effects of different mitotic aberrations—misaligned chromosomes produced by CENP-E inhibition and monopolar spindles resulting from Eg5 inhibition. Eg5 inhibition in cells with an impaired spindle assembly checkpoint (SAC) induces polyploidy through cytokinesis failure without a strong anti-proliferative effect. In contrast, CENP-E inhibition causes p53-mediated post-mitotic apoptosis triggered by chromosome missegregation. Pharmacological studies reveal that aneuploidy caused by the CENP-E inhibitor, Compound-A, in SAC-attenuated cells causes substantial proteotoxic stress and DNA damage. Polyploidy caused by the Eg5 inhibitor does not produce this effect. Furthermore, p53-mediated post-mitotic apoptosis is accompanied by aneuploidy-associated DNA damage response and unfolded protein response activation. Because Compound-A causes p53 accumulation and antitumour activity in an SAC-impaired xenograft model, CENP-E inhibitors could be potential anticancer drugs effective against SAC-impaired tumours. |
format | Online Article Text |
id | pubmed-4506520 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Pub. Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-45065202015-07-21 Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells Ohashi, Akihiro Ohori, Momoko Iwai, Kenichi Nakayama, Yusuke Nambu, Tadahiro Morishita, Daisuke Kawamoto, Tomohiro Miyamoto, Maki Hirayama, Takaharu Okaniwa, Masanori Banno, Hiroshi Ishikawa, Tomoyasu Kandori, Hitoshi Iwata, Kentaro Nat Commun Article The molecular mechanism responsible that determines cell fate after mitotic slippage is unclear. Here we investigate the post-mitotic effects of different mitotic aberrations—misaligned chromosomes produced by CENP-E inhibition and monopolar spindles resulting from Eg5 inhibition. Eg5 inhibition in cells with an impaired spindle assembly checkpoint (SAC) induces polyploidy through cytokinesis failure without a strong anti-proliferative effect. In contrast, CENP-E inhibition causes p53-mediated post-mitotic apoptosis triggered by chromosome missegregation. Pharmacological studies reveal that aneuploidy caused by the CENP-E inhibitor, Compound-A, in SAC-attenuated cells causes substantial proteotoxic stress and DNA damage. Polyploidy caused by the Eg5 inhibitor does not produce this effect. Furthermore, p53-mediated post-mitotic apoptosis is accompanied by aneuploidy-associated DNA damage response and unfolded protein response activation. Because Compound-A causes p53 accumulation and antitumour activity in an SAC-impaired xenograft model, CENP-E inhibitors could be potential anticancer drugs effective against SAC-impaired tumours. Nature Pub. Group 2015-07-06 /pmc/articles/PMC4506520/ /pubmed/26144554 http://dx.doi.org/10.1038/ncomms8668 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Ohashi, Akihiro Ohori, Momoko Iwai, Kenichi Nakayama, Yusuke Nambu, Tadahiro Morishita, Daisuke Kawamoto, Tomohiro Miyamoto, Maki Hirayama, Takaharu Okaniwa, Masanori Banno, Hiroshi Ishikawa, Tomoyasu Kandori, Hitoshi Iwata, Kentaro Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells |
title | Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells |
title_full | Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells |
title_fullStr | Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells |
title_full_unstemmed | Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells |
title_short | Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells |
title_sort | aneuploidy generates proteotoxic stress and dna damage concurrently with p53-mediated post-mitotic apoptosis in sac-impaired cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506520/ https://www.ncbi.nlm.nih.gov/pubmed/26144554 http://dx.doi.org/10.1038/ncomms8668 |
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