Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis
Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis
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DOI：
10.1523/jneurosci.2953-04.2004
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发表时间：
2004-10-06
影响因子：
5.3
通讯作者：
Bonni, A
中科院分区：
文献类型：
--
作者：
Becker, EBE;Howell, J;Bonni, A
c-Jun N-末端激酶（JNK）信号通路在神经系统中介导细胞凋亡中起着关键作用;然而，JNK触发神经元凋亡的机制仍不完全清楚。最近的研究表明，除了诱导促凋亡基因的转录外，JNK还直接激活细胞死亡机制。在这里，我们报告说，JNK催化磷酸化的BH 3-唯一的蛋白Bcl-2相互作用的细胞死亡介质（Bim（EL））在丝氨酸65，在体外和体内。JNK诱导的Bim（EL）丝氨酸65位磷酸化促进了Bim（EL）对原代小脑颗粒神经元的凋亡作用。我们还表征了JNK-Bim（EL）信号通路在p75神经营养因子受体（p75（NTR））过表达引发的细胞凋亡中的作用。我们发现，激活p75（NTR）诱导JNK依赖性磷酸化内源性Bim（EL）在丝氨酸65在细胞中。通过RNA干扰或Bim（EL）的显性干扰形式的表达的Bim（EL）的遗传敲低显著损害了激活的p75（NTR）诱导凋亡的能力。总之，这些结果表明JNK诱导的Bim（EL）在丝氨酸65处的磷酸化介导p75（NTR）诱导的细胞凋亡。我们的研究结果定义了一种新的机制，死亡受体途径直接激活线粒体凋亡机制。
The c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in mediating apoptosis in the nervous system; however, the mechanisms by which JNK triggers neuronal apoptosis remain incompletely understood. Recent studies suggest that in addition to inducing transcription of pro-apoptotic genes, JNK also directly activates the cell death machinery. Here, we report that JNK catalyzed the phosphorylation of the BH3-only protein Bcl-2 interacting mediator of cell death (Bim(EL)) at serine 65, both in vitro and in vivo. The JNK-induced phosphorylation of Bim(EL) at serine 65 promoted the apoptotic effect of Bim(EL) in primary cerebellar granule neurons. We also characterized the role of the JNK-Bim(EL) signaling pathway in apoptosis that was triggered by overexpression of the p75 neurotrophin receptor (p75(NTR)). We found that activation of p75(NTR) induced the JNK-dependent phosphorylation of endogenous Bim(EL) at serine 65 in cells. The genetic knockdown of Bim(EL) by RNA interference or the expression of a dominant interfering form of Bim(EL) significantly impaired the ability of activated p75(NTR) to induce apoptosis. Together, these results suggest that JNK-induced phosphorylation of Bim(EL) at serine 65 mediates p75(NTR)-induced apoptosis. Our findings define a novel mechanism by which a death-receptor pathway directly activates the mitochondrial apoptotic machinery.