Salehi Amir H, Xanthoudakis Steven, Barker Philip A
Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 University Avenue, Montreal, Quebec H3A 2B4, Canada.
J Biol Chem. 2002 Dec 13;277(50):48043-50. doi: 10.1074/jbc.M205324200. Epub 2002 Oct 9.
The p75 neurotrophin receptor (p75NTR) mediates signaling events leading to activation of the JNK pathway and cell death in a variety of cell types. We recently identified NRAGE, a protein that directly interacts with the p75NTR cytosolic region and facilitates p75NTR-mediated cell death. For the present study, we developed an inducible recombinant NRAGE adenovirus to dissect the mechanism of NRAGE-mediated apoptosis. Induced NRAGE expression resulted in robust activation of the JNK pathway that was not inhibited by the pharmacological mixed lineage kinase (MLK) inhibitor CEP1347. NRAGE induced cytosolic accumulation of cytochrome c, activation of Caspases-3, -9 and -7, and caspase-dependent cell death. Blocking JNK and c-Jun action by overexpression of the JNK-binding domain of JIP1 or dominant-negative c-Jun ablated NRAGE-mediated caspase activation and NRAGE-induced cell death. These findings identify NRAGE as a p75NTR interactor capable of inducing caspase activation and cell death through a JNK-dependent mitochondrial apoptotic pathway.
p75神经营养因子受体（p75NTR）介导导致多种细胞类型中JNK途径激活和细胞死亡的信号转导事件。我们最近鉴定出NRAGE，一种直接与p75NTR胞质区域相互作用并促进p75NTR介导的细胞死亡的蛋白质。在本研究中，我们构建了一种可诱导的重组NRAGE腺病毒，以剖析NRAGE介导的细胞凋亡机制。诱导的NRAGE表达导致JNK途径的强烈激活，而这种激活不受药理学上的混合谱系激酶（MLK）抑制剂CEP1347的抑制。NRAGE诱导细胞色素c的胞质积累、半胱天冬酶-3、-9和-7的激活以及半胱天冬酶依赖性细胞死亡。通过过表达JIP1的JNK结合结构域或显性负性c-Jun来阻断JNK和c-Jun的作用，可消除NRAGE介导的半胱天冬酶激活和NRAGE诱导的细胞死亡。这些发现表明NRAGE是一种能够通过JNK依赖性线粒体凋亡途径诱导半胱天冬酶激活和细胞死亡的p75NTR相互作用蛋白。
