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首页> 外文期刊>Biochemical Pharmacology >The neurotoxicant PCB-95 by increasing the neuronal transcriptional. repressor REST down-regulates caspase-8 and increases Ripk1, Ripk3 and MLKL expression determining necroptotic neuronal death
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The neurotoxicant PCB-95 by increasing the neuronal transcriptional. repressor REST down-regulates caspase-8 and increases Ripk1, Ripk3 and MLKL expression determining necroptotic neuronal death

机译：通过增加神经元转录的神经毒剂PCB-95。 阻遏物休息次调节Caspase-8并增加RIPK1，RIPK3和MLK1表达，确定恶臭神经元死亡

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摘要

Our previous study showed that the environmental neurotoxicant non-dioxin-like polychlorinated biphenyl (PCB)-95 increases REI-silencing transcription factor (REST) expression, which is related to necrosis, but not apoptosis, of neurons. Meanwhile, necroptosis is a type of a programmed necrosis that is positively regulated by receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL) and negatively regulated by caspase-8. Here we evaluated whether necroptosis contributes to PCB-95-induced neuronal death through REST up-regulation. Our results demonstrated that in cortical neurons PCB -95 increased RIPK1, RIPK3, and MLKL expression and decreased caspase-8 at the gene and protein level. Furthermore, the RIPK1 inhibitor necrostatin-1 or siRNA-mediated RIPK1, RIPK3 and MLKL expression knockdown significantly reduced PCB-95-induced neuronal death. Intriguingly, PCB-95-induced increases in RIPK1, RIPK3, MLKL expression and decreases in caspase-8 expression were reversed by knockdown of REST expression with a REST-specific siRNA (siREST). Notably, in silico analysis of the rat genome identified a REST consensus sequence in the caspase-8 gene promoter (Casp8-RE1), but not the RIPK1, RIPK3 and MLKL promoters. Interestingly, in PCB-95-treated neurons, REST binding to the Casp8-RE1 sequence increased in parallel with a reduction in its promoter activity, whereas under the same experimental conditions, transfection of siREST or mutation of the Casp8-RE1 sequence blocked PCB-95-induced caspase-8 reduction. Since RIPK1, RIPK3 and MLKL rat genes showed no putative REST binding site, we assessed whether the transcription factor cAMP Responsive Element Binding Protein (CREB), which has a consensus sequence in all three genes, affected neuronal death. In neurons treated with PCB -95, CREB protein expression decreased in parallel with a reduction in binding to the RIPKI, RIPK3 and MLKL gene promoter sequence. Furthermore, CREB overexpression was associated with reduced promoter activity of the RIPK1, RIPK3 and MLKL genes. Collectively, these results indicate that PCB -95 was associated with REST-induced necroptotic cell death by increasing RIPK1, RIPK3 and MLKL expression and reducing caspase-8 levels. In addition, since REST is involved in several neurological disorders, therapies that block REST-induced necroptosis could be a new strategy to revert the neurodetrimental effects associated to its overexpression. (C) 2017 Elsevier Inc. All rights reserved.
机译：我们以前的研究表明，环境神经毒剂非二恶蛋白样多氯联苯（PCB）-95增加了REI沉默转录因子（REST）表达，其与神经元的坏死，但不是细胞凋亡。同时，肮脏是一种编程的坏死的类型，其被受体相互作用蛋白激酶1（RIPK1），RIPK3和混合谱系激酶畴样（MLK1）正面调节，并通过Caspase-8负调节。在这里，我们通过休息预定调节，评估是否有助于PCB-95诱导的神经元死亡。我们的结果表明，在皮质神经元PCB -95中，在基因和蛋白质水平上增加了RIPK1，RIPK3和MLK1表达和降低的Caspase-8。此外，RIPK1抑制剂Necroderatin-1或siRNA介导的ripk1，ripk3和MLK1表达敲低显着降低了PCB-95诱导的神经元死亡。可感染的PCB-95诱导的RIPK1，RIPK3，MLK1表达和Caspase-8表达中的减少通过休息表达与静物特异性siRNA（最初）来反转。值得注意的是，在大鼠基因组的硅分析中，在Caspase-8基因启动子（Casp8-Re1）中鉴定了RIPK1，RIPK3和MLKL启动子的休息共有序列。有趣的是，在PCB-95处理的神经元中，与CasP8-RE1序列的静止结合随着其启动子活性的降低并行增加，而在相同的实验条件下，CasP8-Re1序列的转染或突变被阻塞的PCB- 95诱导的Caspase-8减少。由于RIPK1，RIPK3和MLKL大鼠GAT基因显示出备向休息结合位点，我们评估了在所有三种基因中具有共有序列的转录因子阵营响应因子结合蛋白（CREB）是否影响了神经元死亡。在用PCB -95处理的神经元中，CREB蛋白表达与ripki，RIPK3和MLKL基因启动子序列的结合还原下降。此外，CREB过表达与RIPK1，RIPK3和MLKL基因的启动子活性降低相关。总的来说，这些结果表明PCB -95通过增加RIPK1，RIPK3和MLK1表达和减少胱天蛋白酶-8水平，PCB-95与休息诱导的恶臭细胞死亡相关。此外，由于休息涉及几种神经系统疾病，因此阻止休息诱导的死亡症的疗法可以是改复与其过度表达相关的神经重育效应的新策略。 （c）2017年Elsevier Inc.保留所有权利。

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  • 来源
    《Biochemical Pharmacology》 |2017年第2017期|共13页
  • 作者

    Guida Natascia; Laudati Giusy; Serani Angelo; Mascolo Luigi; Molinaro Pasquale; Montuori Paolo; Di Renzo Gianfranco; Canzoniero Lorella M. T.; Formisano Luigi;

  • 作者单位

    IRCCS SDN I-80143 Naples Italy;

    Federico II Univ Naples Div Pharmacol Dept Neurosci Reprod &

    Dent Sci Sch Med I-80131 Naples;

    Federico II Univ Naples Div Pharmacol Dept Neurosci Reprod &

    Dent Sci Sch Med I-80131 Naples;

    Federico II Univ Naples Div Pharmacol Dept Neurosci Reprod &

    Dent Sci Sch Med I-80131 Naples;

    Federico II Univ Naples Div Pharmacol Dept Neurosci Reprod &

    Dent Sci Sch Med I-80131 Naples;

    Univ Federico II Dept Prevent Med Sci Via Pansini 5 I-80131 Naples Italy;

    Federico II Univ Naples Div Pharmacol Dept Neurosci Reprod &

    Dent Sci Sch Med I-80131 Naples;

    Federico II Univ Naples Div Pharmacol Dept Neurosci Reprod &

    Dent Sci Sch Med I-80131 Naples;

    Federico II Univ Naples Div Pharmacol Dept Neurosci Reprod &

    Dent Sci Sch Med I-80131 Naples;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    PCB-95; REST; Necroptosis; Neuronal cell death;

    机译：PCB-95;休息;坏凋亡;神经元细胞死亡;

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