Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases

被引：19

作者：

Ngo, J. ^{[1
,2
]}

Matsuyama, M. ^{[1
]}

Kim, C. ^{[1
]}

Poventud-Fuentes, I. ^{[1
]}

Bates, A. ^{[1
]}

Siedlak, S. L. ^{[3
]}

Lee, H-g ^{[3
]}

Doughman, Y. Q. ^{[4
]}

Watanabe, M. ^{[2
,4
]}

Liner, A. ^{[1
]}

Hoit, B. ^{[1
]}

Voelkel, N. ^{[5
,6
]}

Gerson, S. ^{[1
,7
]}

Hasty, P. ^{[8
,9
]}

Matsuyama, S. ^{[1
,7
]}

机构：

[1] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA

[4] Case Western Reserve Univ, Sch Med, Dept Pediat, Cleveland, OH 44106 USA

[5] Virginia Commonwealth Univ, Div Pulm & Crit Care Med, Richmond, VA USA

[6] Virginia Commonwealth Univ, Victoria Johnson Ctr Pulm Obstruct Res, Richmond, VA USA

[7] Case Western Reserve Univ, Sch Med, Dept Case Comprehens, Ctr Canc, Cleveland, OH 44106 USA

[8] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA

[9] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, San Antonio, TX 78229 USA

来源：

CELL DEATH & DISEASE | 2015年 / 6卷

基金：

美国国家卫生研究院;

关键词：

EMBRYONIC STEM-CELLS; DNA-REPAIR; MEDIATED APOPTOSIS; PROAPOPTOTIC BAX; PROTECTS CELLS; MOUSE MODELS; CYCLIN-E; DEATH; KU80; ACETYLATION;

D O I：

10.1038/cddis.2015.11

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1 / 12

页数：12

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