Chatterjee Nandini, Sanphui Priyankar, Kemeny Stav, Greene Lloyd A, Biswas Subhas C
Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology , 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
Department of Pathology and Cell Biology, Columbia University Medical Center , New York, NY 10032, USA.
Cell Death Discov. 2016 Dec 12;2:16083. doi: 10.1038/cddiscovery.2016.83. eCollection 2016.
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 -amyloid (A) 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 A treatment. Enhanced Cdc25A expression was also observed in rat brains infused with A and in A-overexpressing APPswe-PS1dE9 mice. In cultured neurons Cdc25A inhibition by chemical inhibitors or shRNA prevented cell death and neurite degeneration caused by NGF deprivation or A. 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 A 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 A exposure and therefore as a potential target to suppress pathologic neuron death.
在发育过程以及阿尔茨海默病（AD）中，神经元死亡与细胞周期蛋白的异常调控/诱导有关。然而，这一过程中的近端事件尚不清楚。细胞周期启动需要细胞分裂周期25A（Cdc25A）使细胞周期蛋白依赖性激酶去磷酸化。在此，我们表明Cdc25A对于响应神经生长因子（NGF）剥夺或β-淀粉样蛋白（Aβ）处理时的神经元死亡至关重要，并描述了在这些范式中其受到调控的机制。NGF剥夺和Aβ处理可诱导Cdc25A mRNA、蛋白质以及Cdc25A磷酸酶活性。在注入Aβ的大鼠脑以及过表达Aβ的APPswe-PS1dE9小鼠中也观察到Cdc25A表达增强。在培养的神经元中，化学抑制剂或短发夹RNA（shRNA）对Cdc25A的抑制可防止因NGF剥夺或Aβ引起的细胞死亡和神经突退化。此外，Cdc25A抑制减少了远端信号事件，包括依赖细胞周期蛋白依赖性激酶（Cdk）的磷酸化视网膜母细胞瘤蛋白（pRb）升高以及随后的半胱天冬酶-3激活。机制研究表明，NGF剥夺和Aβ诱导Cdc25A是由叉头转录因子的激活介导的，叉头转录因子进而抑制Cdc25A的负调节因子miR-21。因此，我们的研究确定Cdc25A是凋亡细胞周期途径中必需的上游元件，是响应营养因子剥夺和Aβ暴露时神经元死亡所必需的，因此是抑制病理性神经元死亡的潜在靶点。
