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Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases
Ku70 (Lupus Ku autoantigen p70) is essential in nonhomologous end joining DNA double-strand break repair, and ku70(−/−) mice age prematurely because of increased genomic instability and DNA damage responses. Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis. We hypothesiz...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385910/ https://www.ncbi.nlm.nih.gov/pubmed/25811803 http://dx.doi.org/10.1038/cddis.2015.11 |
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author | Ngo, J Matsuyama, M Kim, C Poventud-Fuentes, I Bates, A Siedlak, S L Lee, H-g Doughman, Y Q Watanabe, M Liner, A Hoit, B Voelkel, N Gerson, S Hasty, P Matsuyama, S |
author_facet | Ngo, J Matsuyama, M Kim, C Poventud-Fuentes, I Bates, A Siedlak, S L Lee, H-g Doughman, Y Q Watanabe, M Liner, A Hoit, B Voelkel, N Gerson, S Hasty, P Matsuyama, S |
author_sort | Ngo, J |
collection | PubMed |
description | Ku70 (Lupus Ku autoantigen p70) is essential in nonhomologous end joining DNA double-strand break repair, and ku70(−/−) mice age prematurely because of increased genomic instability and DNA damage responses. Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis. We hypothesized that Bax-mediated apoptosis would be enhanced in the absence of Ku70 and contribute to premature death observed in ku70(−/−) mice. Here, we show that ku70(−/−) bax(+/−) and ku70(−/−) bax(−/−) mice have better survival, especially in females, than ku70(−/−) mice, even though Bax deficiency did not decrease the incidence of lymphoma observed in a Ku70-null background. Moreover, we found that ku70(−/−) mice develop lung diseases, like emphysema and pulmonary arterial (PA) occlusion, by 3 months of age. These lung abnormalities can trigger secondary health problems such as heart failure that may account for the poor survival of ku70(−/−) mice. Importantly, Bax deficiency appeared to delay the development of emphysema. This study suggests that enhanced Bax activity exacerbates the negative impact of Ku70 deletion. Furthermore, the underlying mechanisms of emphysema and pulmonary hypertension due to PA occlusion are not well understood, and therefore ku70(−/−) and Bax-deficient ku70(−/−) mice may be useful models to study these diseases. |
format | Online Article Text |
id | pubmed-4385910 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-43859102015-04-07 Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases Ngo, J Matsuyama, M Kim, C Poventud-Fuentes, I Bates, A Siedlak, S L Lee, H-g Doughman, Y Q Watanabe, M Liner, A Hoit, B Voelkel, N Gerson, S Hasty, P Matsuyama, S Cell Death Dis Original Article Ku70 (Lupus Ku autoantigen p70) is essential in nonhomologous end joining DNA double-strand break repair, and ku70(−/−) mice age prematurely because of increased genomic instability and DNA damage responses. Previously, we found that Ku70 also inhibits Bax, a key mediator of apoptosis. We hypothesized that Bax-mediated apoptosis would be enhanced in the absence of Ku70 and contribute to premature death observed in ku70(−/−) mice. Here, we show that ku70(−/−) bax(+/−) and ku70(−/−) bax(−/−) mice have better survival, especially in females, than ku70(−/−) mice, even though Bax deficiency did not decrease the incidence of lymphoma observed in a Ku70-null background. Moreover, we found that ku70(−/−) mice develop lung diseases, like emphysema and pulmonary arterial (PA) occlusion, by 3 months of age. These lung abnormalities can trigger secondary health problems such as heart failure that may account for the poor survival of ku70(−/−) mice. Importantly, Bax deficiency appeared to delay the development of emphysema. This study suggests that enhanced Bax activity exacerbates the negative impact of Ku70 deletion. Furthermore, the underlying mechanisms of emphysema and pulmonary hypertension due to PA occlusion are not well understood, and therefore ku70(−/−) and Bax-deficient ku70(−/−) mice may be useful models to study these diseases. Nature Publishing Group 2015-03 2015-03-26 /pmc/articles/PMC4385910/ /pubmed/25811803 http://dx.doi.org/10.1038/cddis.2015.11 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0 |
spellingShingle | Original Article Ngo, J Matsuyama, M Kim, C Poventud-Fuentes, I Bates, A Siedlak, S L Lee, H-g Doughman, Y Q Watanabe, M Liner, A Hoit, B Voelkel, N Gerson, S Hasty, P Matsuyama, S Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases |
title | Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases |
title_full | Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases |
title_fullStr | Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases |
title_full_unstemmed | Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases |
title_short | Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases |
title_sort | bax deficiency extends the survival of ku70 knockout mice that develop lung and heart diseases |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385910/ https://www.ncbi.nlm.nih.gov/pubmed/25811803 http://dx.doi.org/10.1038/cddis.2015.11 |
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