Downstream targets of Lmo4 are modulated by cisplatin in the inner ear of Wistar rats.
Downstream targets of Lmo4 are modulated by cisplatin in the inner ear of Wistar rats.
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DOI：
10.1371/journal.pone.0115263
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Jamesdaniel S
中科院分区：
文献类型：
--
作者：
Jamesdaniel S
Lmo4是一种转录调节因子，在介导顺铂耳毒性的耳蜗病理过程中似乎是一个关键角色，因为它通过调节转录复合物的形成来控制细胞反应。我们提供了顺铂耳毒性中Lmo4在体内发生硝化作用的首个证据。我们的数据表明，Lmo4的硝化以及其在耳蜗中表达的相关降低可能在顺铂耳毒性中起关键作用。然而，在耳蜗中传递下游事件信号的Lmo4相互作用组却鲜为人知。因此，我们使用定制的基因芯片来评估在接受16mg/kg顺铂处理的Wistar大鼠中Lmo4已知结合伴侣或靶标的调节情况。顺铂处理3天后的逆转录聚合酶链反应（RT - PCR）分析表明，顺铂诱导了多个与Lmo4信号通路相关的耳蜗基因的上调/下调。顺铂处理使Esr1在耳蜗中的表达显著上调，而Stat3的表达则下调。与一种具有耳保护作用的抗氧化剂Trolox共同处理，减弱了顺铂诱导的耳蜗中5个基因的调节。与在基因水平观察到的变化一致，用抗Stat3抗体进行的免疫印迹表明，Trolox共同处理减弱了顺铂诱导的耳蜗蛋白质水平的降低。这些结果表明，顺铂诱导的硝化作用使耳蜗中Lmo4降低，以及其结合伴侣Esr1和Jak1在耳蜗中表达的相关调节，可能促进了Stat3的抑制，Stat3是Lmo4的一个下游靶点，与药物介导的细胞凋亡有关。总之，这些发现为Lmo4的下游事件提供了见解，并表明Jak/Stat转录机制在顺铂诱导的耳毒性中传递Lmo4蛋白信号方面具有潜在作用。
Lmo4, a transcriptional regulator, appears to be a key player in mediating the cochlear pathology in cisplatin ototoxicity, as it controls cellular responses by modulating the formation of transcriptional complexes. We provided the first evidence of in vivo nitration of Lmo4 in cisplatin ototoxicity. Our data suggested that nitration of Lmo4 and associated decrease in its cochlear expression has the potential to play a pivotal role in cisplatin ototoxicity. However, the Lmo4 interactomes that signal the downstream events in the cochlea are poorly understood. Therefore, custom-made gene arrays were employed to evaluate the modulation of known binding partners or targets of Lmo4, in Wistar rats treated with 16 mg/kg cisplatin. RT-PCR analysis, 3 days post cisplatin treatment, indicated that cisplatin induced up/down regulation of multiple cochlear genes associated with Lmo4 signaling. The cochlear expression of Esr1 was significantly up-regulated by cisplatin treatment, while the expression of Stat3 was down-regulated. Co-treatment with Trolox, an otoprotective antioxidant, attenuated the cisplatin-induced modulation of 5 genes in the cochlea. Consistent with the changes observed at the gene level, immunoblots with anti-Stat3 indicated that cisplatin-induced decrease in cochlear protein levels were attenuated by Trolox co-treatment. These results suggest that cisplatin-induced decreases in the cochlear Lmo4 upon nitration, and associated modulation in the cochlear expression of its binding partners Esr1 and Jak1, probably facilitates the repression of Stat3, a downstream target of Lmo4 implicated in drug mediated apoptosis. Collectively, these findings provide insights on Lmo4 downstream events and indicate a potential role of Jak/Stat transcriptional machinery in relaying the Lmo4 protein signaling in cisplatin-induced ototoxicity.
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