Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
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
_version_ 1782365104511123456
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
work_keys_str_mv AT ngoj baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT matsuyamam baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT kimc baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT poventudfuentesi baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT batesa baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT siedlaksl baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT leehg baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT doughmanyq baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT watanabem baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT linera baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT hoitb baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT voelkeln baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT gersons baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT hastyp baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases
AT matsuyamas baxdeficiencyextendsthesurvivalofku70knockoutmicethatdeveloplungandheartdiseases