bcl-2/Adenovirus E1B 19-kd Interacting Protein 3 (BNIP3) Regulates Hypoxia-Induced Neural Precursor Cell Death

被引:46
作者
Walls, K. C. [1 ,2 ]
Ghosh, Arindam P. [1 ,3 ]
Ballestas, Mary E. [4 ]
Klocke, Barbara J. [1 ]
Roth, Kevin A. [1 ]
机构
[1] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA
[2] Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA
[3] Univ Alabama, Dept Genet, Birmingham, AL 35294 USA
[4] Univ Alabama, Dept Pediat & Infect Dis, Birmingham, AL 35294 USA
关键词
Apoptosis; Apoptosis-inducing factor; BNIP3; Hypoxia; INDUCIBLE FACTOR 1-ALPHA; MALIGNANT GLIOMA-CELLS; UP-REGULATION; TRANSCRIPTIONAL ACTIVITY; PROLYL HYDROXYLATION; SUBVENTRICULAR ZONE; HIF-ALPHA; MITOCHONDRIAL; APOPTOSIS; HIF-1-ALPHA;
D O I
10.1097/NEN.0b013e3181c3b9be
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Perinatal hypoxia-ischemia may result in long-term neurological deficits. In addition to producing neuron death, HI causes death of neural precursor cells (NPCs) in the developing brain. To characterize the molecular pathways that regulate hypoxia-induced death of NPCs, we treated a mouse neural stein cell line (C 17.2 cells) and fibroblastic growth factor II-expanded primary NPCs derived from wild-type or gene-disrupted mice, with oxygen glucose deprivation or the hypoxia mimetics desferrioxamine or cobalt chloride. Neural precursor cells undergoing hypoxia exhibited time- and concentration-dependent caspase-3 activation and cell death, which was significantly reduced by treatment with a broad caspase inhibitor or protein synthesis inhibition. Bax/Bak-deficient NPCs were protected from desferrioxamine-induced death and exhibited minimal caspase-3 activation. Oxygen glucose deprivation or hypoxia-mimetic exposure also resulted in increased hypoxia-inducible factor (x and bcl-2/adenovirus E1B 19-kd interacting protein 3 (BNIP3) expression. BNIP3 shRNA treatment failed to affect hypoxia-induced caspase-3 activation but inhibited cell death and nuclear translocation of apoptosis-inducing factor, indicating that BNIP3 is an important regulator of caspase-independent NPC death after hypoxia. These studies demonstrate that hypoxia activates both caspase-dependent and -independent NPC death pathways that are critically regulated by multiple Bcl-2 family members.
引用
收藏
页码:1326 / 1338
页数:13
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