The limited role of NH2-terminal c-Jun phosphorylation in neuronal apoptosis:: Identification of the nuclear pore complex as a potential target of the JNK pathway
The limited role of NH2-terminal c-Jun phosphorylation in neuronal apoptosis:: Identification of the nuclear pore complex as a potential target of the JNK pathway
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DOI：
10.1083/jcb.200501138
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发表时间：
2005-08-01
影响因子：
7.8
通讯作者：
Johnson, EM
中科院分区：
文献类型：
--
作者：
Besirli, CG;Wagner, EF;Johnson, EM
C-Jun 在许多神经元死亡范例中被诱导。 c-Jun 调节的关键步骤涉及位于 NH2 末端反式激活结构域的 Ser63/Ser73 的磷酸化。为了确定这种磷酸化对神经元凋亡的重要性，我们分析了携带缺乏 Ser63/Ser73 磷酸化位点 (jun aa) 的突变 c-Jun 基因的小鼠的交感神经元。 jun aa/aa 神经元中营养因子剥夺或 DNA 损伤诱导的死亡显着延迟。神经元 c-Jun 诱导仅部分受到抑制，表明 Ser63/73 的磷酸化不是 c-Jun 激活所必需的。仅促凋亡 BH3 蛋白 Bim 和 PUMA/Bbc3 的诱导在突变神经元的神经元凋亡过程中被延迟。这些结果表明，NH2 末端 c-Jun 磷酸化对于诱导促凋亡基因和神经元凋亡很重要，但不是必需的。因此，额外的 JNK 底物可能对神经元死亡至关重要。作为潜在的介质，我们确定了其他核 MLK/JNK 底物，包括核孔复合物的 Nup214 亚基。
C-Jun is induced in many neuronal death paradigms. A critical step in c-Jun regulation involves phosphorylation of Ser63/Ser73 located in the NH2-terminal transactivation domain. To determine the importance of this phosphorylation for neuronal apoptosis, we analyzed the sympathetic neurons of mice carrying a mutant c-Jun gene that lacks Ser63/Ser73 phosphorylation sites (jun aa). Trophic factor-deprivation or DNA damage-induced death was significantly delayed in jun aa/aa neurons. Neuronal c-Jun induction was only partially inhibited, demonstrating that phosphorylation of Ser63/73 is not required for c-Jun activation. The inductions of proapoptotic BH3-only proteins, Bim and PUMA/Bbc3, were delayed during neuronal apoptosis in mutant neurons. These results demonstrate that NH2-terminal c-Jun phosphorylation is important, but not necessary, for the induction of proapoptotic genes and neuronal apoptosis. Thus, additional JNK substrates may be critical for neuronal death. As potential mediators, we identified additional nuclear MLK/JNK substrates, including Nup214 subunit of the nuclear pore complex.