title: Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases.
abstract: 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.
authors: 1] Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA [2] Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: J
authors: J
authors: Ngo
authors: Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: M
authors: M
authors: Matsuyama
authors: Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: C
authors: C
authors: Kim
authors: Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: I
authors: I
authors: Poventud-Fuentes
authors: Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: A
authors: A
authors: Bates
authors: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: S L
authors: SL
authors: Siedlak
authors: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: H-G
authors: HG
authors: Lee
authors: Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: Y Q
authors: YQ
authors: Doughman
authors: 1] Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA [2] Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: M
authors: M
authors: Watanabe
authors: Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: A
authors: A
authors: Liner
authors: Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: B
authors: B
authors: Hoit
authors: Pulmonary and Critical Care Medicine Division and Victoria Johnson Center for Pulmonary Obstructive Research, Virginia Commonwealth University, Richmond, VA, USA.
authors: N
authors: N
authors: Voelkel
authors: 1] Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA [2] Department of Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: S
authors: S
authors: Gerson
authors: Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, TX, USA.
authors: P
authors: P
authors: Hasty
authors: 1] Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA [2] Department of Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: S
authors: S
authors: Matsuyama
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006331:Heart Diseases / Q000235:genetics / Q000473:pathology; D006801:Humans; D000072200:Ku Autoantigen; D008171:Lung Diseases / Q000235:genetics* / Q000473:pathology; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D051028:bcl-2-Associated X Protein; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen