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首页> 外文期刊>Molecular and Cellular Biology >Mutually Exclusive Subsets of BH3-Only Proteins Are Activated by the p53 and c-Jun N-Terminal Kinase/c-Jun Signaling Pathways during Cortical Neuron Apoptosis Induced by Arsenite
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Mutually Exclusive Subsets of BH3-Only Proteins Are Activated by the p53 and c-Jun N-Terminal Kinase/c-Jun Signaling Pathways during Cortical Neuron Apoptosis Induced by Arsenite

机译：仅BH3蛋白质的互斥子集被亚砷酸盐诱导的皮质神经元凋亡过程中的p53和c-Jun N末端激酶/ c-Jun信号通路激活。

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The c-Jun N-terminal protein kinase (JNK)/c-Jun and p53 pathways form distinct death-signaling modules in neurons that culminate in Bax-dependent apoptosis. To investigate whether this signaling autonomy is due to recruitment of particular BH3-only proteins, we searched for a toxic signal that would activate both pathways in the same set of neurons. We show that arsenite activates both the JNK/c-Jun and p53 pathways in cortical neurons, which together account for >95% of apoptosis, as determined by using the mixed-lineage kinase (JNK/c-Jun) pathway inhibitor CEP11004 and p53-null mice. Despite the coexistence of both pathways in at least 30% of the population, Bim mRNA and protein expression was increased only by the JNK/c-Jun signaling pathway, whereas Noxa and Puma mRNA and Puma protein expression was entirely JNK/c-Jun independent. About 50% of Puma/Noxa expression was p53 dependent, with the remaining signal being independent of both pathways and possibly facilitated by arsenite-induced reduction in P-Akt. However, functionally, Puma was predominant in mediating Bax-dependent apoptosis, as evidenced by the fact that more than 90% of apoptosis was prevented in Puma-null neurons, although Bim was still upregulated, while Bim- and Noxa-null neurons died similarly to wild-type neurons. Thus, the p53 and JNK/c-Jun pathways can activate mutually exclusive subclasses of BH3-only proteins in the same set of neurons. However, other factors besides expression may determine which BH3-only proteins mediate apoptosis.
机译：c-Jun N末端蛋白激酶（JNK）/ c-Jun和p53通路在神经元中形成独特的死亡信号传导模块，最终导致Bax依赖性细胞凋亡。为了研究这种信号自主性是否归因于特定的仅BH3蛋白的募集，我们搜索了一种毒性信号，该信号将激活同一组神经元中的两条途径。我们显示亚砷酸盐激活皮层神经元中的JNK / c-Jun和p53途径，二者合计占细胞凋亡的95％以上，这是通过使用混合谱系激酶（JNK / c-Jun）途径抑制剂CEP11004和p53确定的-空小鼠。尽管这两种途径在至少30％的人口中共存，但 Bim mRNA和蛋白质表达仅通过JNK / c-Jun信号途径增加，而 Noxa 和 Puma mRNA和Puma蛋白表达完全独立于JNK / c-Jun。大约50％的 Puma / Noxa 表达是p53依赖性的，其余信号独立于两种途径，并且可能由砷诱导的P-Akt降低促进。然而，从功能上讲，Puma在介导Bax依赖的凋亡中起主要作用，这一事实证明，尽管Bim仍被上调，但阻止Puma无效的神经元凋亡的90％以上，而Bim和Noxa无效的神经元死亡相似。野生型神经元。因此，p53和JNK / c-Jun途径可以激活同一组神经元中仅BH3蛋白的互斥子类。但是，除表达外，其他因素可能决定了哪些仅BH3蛋白介导凋亡。

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