Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke
Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke
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DOI：
10.1124/mol.111.071076
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发表时间：
2011-07-01
影响因子：
3.6
通讯作者：
Jo, Dong-Gyu
中科院分区：
文献类型：
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作者：
Arumugam, Thiruma V.;Cheng, Yi-Lin;Jo, Dong-Gyu
Notch-1 (Notch) 是一种细胞表面受体，可调节发育中的神经系统的细胞命运决定，并且它还可能在成人大脑的突触可塑性中发挥作用。其配体的结合导致γ-分泌酶复合物对Notch进行蛋白水解切割，从而导致Notch胞内结构域(NICD)释放，该结构域易位至细胞核，在细胞核中调节转录。在这里，我们表明Notch的激活在体外和体内调节缺血性神经元细胞死亡。具体来说，我们使用 Notch-1 siRNA 或 NICD 过表达的结果表明，Notch 激活会导致细胞死亡。使用改良的 NICD，我们证明了 NICD 在细胞核和细胞质中的凋亡诱导功能。通过阻断钙信号传导、半胱天冬酶激活和 Janus 激酶信号传导，可以减少 NICD 转染诱导的细胞死亡。通过靶向凋亡蛋白酶、裂解的 caspase-3、核因子 kappa B (NF-kappa B) 和仅促死亡的 BH3 蛋白、Bcl-2 相互作用的细胞死亡介质 (Bim)，抑制 Notch 激活酶、γ-分泌酶，防止缺血性神经元细胞死亡。在局灶性缺血性中风模型中，用γ-分泌酶抑制剂化合物E治疗小鼠，可减少梗塞面积并改善功能结果。此外，γ-分泌酶抑制降低了体内 NICD、p-p65 和 Bim 水平。这些发现表明，Notch 信号传导通过调节 NF-kappa B、促死亡蛋白 Bim 和 caspase 通路，危及缺血性中风后的神经元。
Notch-1 (Notch) is a cell surface receptor that regulates cell-fate decisions in the developing nervous system, and it may also have roles in synaptic plasticity in the adult brain. Binding of its ligands results in the proteolytic cleavage of Notch by the gamma-secretase enzyme complex, thereby causing the release of a Notch intracellular domain (NICD) that translocates to the nucleus, in which it regulates transcription. Here we show that activation of Notch modulates ischemic neuronal cell death in vitro and in vivo. Specifically, our findings from the use of Notch-1 siRNA or the overexpression of NICD indicate that Notch activation contributes to cell death. Using modified NICD, we demonstrate an apoptosis-inducing function of NICD in both the nucleus and the cytosol. NICD transfection-induced cell death was reduced by blockade of calcium signaling, caspase activation, and Janus kinase signaling. Inhibition of the Notch-activating enzyme, gamma-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-kappa B (NF-kappa B), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a gamma-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, gamma-secretase inhibition reduced NICD, p-p65, and Bim levels in vivo. These findings suggest that Notch signaling endangers neurons after ischemic stroke by modulating the NF-kappa B, pro-death protein Bim, and caspase pathways.