Gene network revealed involvements of Birc2, Birc3 and Tnfrsf1a in anti-apoptosis of injured peripheral nerves.
Gene network revealed involvements of Birc2, Birc3 and Tnfrsf1a in anti-apoptosis of injured peripheral nerves.
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基因网络揭示 Birc2、Birc3 和 Tnfrsf1a 参与损伤周围神经的抗凋亡
DOI：
10.1371/journal.pone.0043436
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gu X
中科院分区：
文献类型：
--
作者：
Wang Y;Tang X;Yu B;Gu Y;Yuan Y;Yao D;Ding F;Gu X
周围神经的挤压伤或轴索切断导致炎性细胞因子的快速产生，这些炎性细胞因子在各种模型中被证实在一定程度上对髓鞘或雪旺细胞（Schwann cells，SC）有害。TNF-α是炎性级联反应的主要引发剂之一，并通过与其I型（TNFRI）和II型（TNFRII）受体结合在生理条件下发挥多效性功能。信号通路分子TNFRI、Birc 2和Birc 3在信号传导的激活过程中起关键作用。损伤的周围神经，阻止它们从TNF-α介导的破坏和进行到成功的再生，可能启动抗凋亡机制。为了确定TNFRI，Birc 2和Birc 3的确切功能，以及其参与的细胞事件的途径，我们推断一个动态的基因调控网络从短时间序列测量的近端神经节段的cDNA微阵列大鼠坐骨神经横断。TNFRI家族成员Tnfrsf 1a、Birc 2和Birc 3被挖掘出来整合作为主调节因子介导炎症反应。实验结果表明，Tnfrsf 1a、Birc 2和Birc 3蛋白在大鼠周围神经组织中与S100共定位，且表达水平随时间延长而增加。敲低的蛋白质诱导凋亡形成的原代培养的干细胞的半胱天冬酶3和半胱天冬酶6的上调。我们的系统分析表明，Tnfrsf 1a，Birc 2和Birc 3的SC，最初被认为是XIAP，主要负责炎症介导的周围神经的抗凋亡。Birc 2和Birc 3可能是炎症细胞因子介导的抗凋亡保护作用的最有潜力的靶点。
Crush injury or axotomy of peripheral nerves results in the rapid production of the inflammatory cytokines, which were confirmed in various models, to some extent, to be noxious to the myelin sheath or Schwann cells (SCs). TNF-α is one of the primary initiators of the inflammatory cascade and exerts pleiotropic functions in the physiological conditions by binding to its receptors, type I (TNFRI) and type II (TNFRII). The pathway molecules TNFRI, Birc2 and Birc3 play key roles during the activation of the signaling. Injured peripheral nerves, preventing them from TNF-α-mediated destruction and proceeding to successful regeneration, might initiate an anti-apoptotic mechanism. To identity the exact functions of TNFRI, Birc2 and Birc3, as well as its involved pathways in the cellular events, we inferred a dynamic gene regulatory network from short time-series measurements of the proximal nerve segment cDNA microarray following rat sciatic nerve transection. TNFRI family member Tnfrsf1a, Birc2 and Birc3 were mined out integrating as master regulators to mediate inflammatory responses. Experiments revealed that Tnfrsf1a, Birc2 and Birc3 proteins colocalized with S100 in the rat peripheral nerve tissues, and the expression levels increased with the time extension. Knockdown of the proteins induced the apoptotic formation of primary cultured SCs by upregulation of caspase 3 and caspase 6. Our systematic analysis indicated that Tnfrsf1a, Birc2 and Birc3 of SCs, not originally regarded as XIAP, were mainly responsible for the inflammation-mediated anti-apoptosis of peripheral nerves. Birc2 and Birc3 might be the most potential targets for anti-apoptotic protection mediated by inflammatory cytokines.
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影响因子：
4.8
作者：
Eckelman, BP;Salvesen, GS
通讯作者：
Salvesen, GS
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Moretto, G