Role and regulation of Cdc25A phosphatase in neuron death induced by NGF deprivation or β-amyloid.
Role and regulation of Cdc25A phosphatase in neuron death induced by NGF deprivation or β-amyloid.
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DOI：
10.1038/cddiscovery.2016.83
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发表时间：
2016
影响因子：
7
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中科院分区：
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发育过程中和阿尔茨海默病（AD）中的神经元死亡与细胞周期蛋白的异常调节/诱导有关。然而，在这个过程中的近端事件是未知的。细胞周期的启动需要细胞分裂周期25 A（Cdc 25 A）的细胞周期蛋白依赖性激酶的去磷酸化。在这里，我们表明，Cdc 25 A是神经元死亡所必需的神经生长因子剥夺或β-淀粉样蛋白（Aβ）的治疗，并描述了在这些范例中，它是由调节机制。NGF剥夺和Aβ处理可诱导Cdc 25 A mRNA、蛋白和Cdc 25 A磷酸酶活性的升高。在注入Aβ的大鼠脑和Aβ过表达的Aβ PPswe-PS1 dE 9小鼠中也观察到Cdc 25 A表达增强。在培养的神经元中，通过化学抑制剂或shRNA抑制Cdc 25 A可以防止由NGF剥夺或Aβ引起的细胞死亡和神经突变性。此外，Cdc 25 A抑制减少了远端信号传导事件，包括Cdk依赖的磷酸化pRb升高和随后的caspase-3激活。机制研究表明，通过NGF剥夺和Aβ介导的Cdc 25 A诱导是通过激活叉头转录因子介导的，叉头转录因子反过来抑制Cdc 25 A的负调控因子miR-21。因此，我们的研究将Cdc 25 A确定为凋亡细胞周期途径的必需上游元件，其是响应营养因子剥夺和Aβ暴露的神经元死亡所必需的，因此作为抑制病理性神经元死亡的潜在靶点。
Neuron death during development and in Alzheimer’s disease (AD) is associated with aberrant regulation/induction of cell cycle proteins. However, the proximal events in this process are unknown. Cell cycle initiation requires dephosphorylation of cyclin-dependent kinases by cell division cycle 25A (Cdc25A). Here, we show that Cdc25A is essential for neuronal death in response to NGF deprivation or β-amyloid (Aβ) treatment and describe the mechanisms by which it is regulated in these paradigms. Cdc25A mRNA, protein and Cdc25A phosphatase activity were induced by NGF deprivation and Aβ treatment. Enhanced Cdc25A expression was also observed in rat brains infused with Aβ and in Aβ-overexpressing AβPPswe-PS1dE9 mice. In cultured neurons Cdc25A inhibition by chemical inhibitors or shRNA prevented cell death and neurite degeneration caused by NGF deprivation or Aβ. Additionally, Cdc25A inhibition diminished distal signaling events including Cdk-dependent elevation of phospho-pRb and subsequent caspase-3 activation. Mechanism studies revealed that Cdc25A induction by NGF deprivation and Aβ is mediated by activation of Forkhead transcription factors that in turn suppress miR-21, a negative regulator of Cdc25A. Our studies thus identify Cdc25A as a required upstream element of the apoptotic cell cycle pathway that is required for neuron death in response to trophic factor deprivation and to Aβ exposure and therefore as a potential target to suppress pathologic neuron death.