NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation
NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation
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DOI：
10.1016/j.yexcr.2016.07.004
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发表时间：
2016-09-10
影响因子：
3.7
通讯作者：
Mo, Shi-Jing
中科院分区：
文献类型：
--
作者：
Chen, Zhi-Dong;Xu, Liang;Mo, Shi-Jing
神经细胞凋亡是缺氧缺血性脑损伤的主要病理特征之一。核因子-κ B（nuclear factor-kappa B，NF-κ B）可能是缺氧/缺血性脑损伤的潜在治疗靶点，因为NF-κ B在缺氧暴露后被发现失活，但NF-κ B失活的潜在分子机制在很大程度上尚不清楚。在这里，我们报告，表皮生长因子受体（EGFR）的激活防止神经元样PC 12细胞凋亡，在缺氧反应通过恢复NF-κ B依赖的转录上调细胞周期蛋白D1。在功能上，表皮生长因子刺激表皮生长因子受体激活减轻缺氧诱导的PC 12细胞凋亡的剂量和时间依赖性的方式。值得注意的是，EGFR活化提高IKK β磷酸化，增加I κ B α泛素化，促进P65核转位和在细胞周期蛋白D1基因启动子处的募集，以及上调细胞周期蛋白D1表达。EGFR激活还消除了缺氧诱导的IKK β磷酸化的减少、I κ B α泛素化的减少、P65核转位的阻断和cyclin D1基因启动子的募集以及cyclin D1表达的下调。此外，NF-κ B依赖性细胞周期蛋白D1的上调有助于EGFR介导的细胞保护作用对抗缺氧性细胞凋亡。此外，由EGF siRNA转染或抗HB-EGF中和抗体处理诱导的EGFR去磷酸化增强缺氧细胞毒性，其被EGF施用减弱。我们的研究结果强调了NF-κ B依赖的细胞周期蛋白D1的转录上调在缺氧预处理下EGFR介导的细胞保护作用中的重要作用，并支持EGF在缺氧/缺血性脑损伤患者临床试验中的进一步研究。(C)2016由Elsevier Inc.出版
Apoptosis of neural cells is one of the main pathological features in hypoxic/ischemic brain injury. Nuclear factor-kappa B (NF-kappa B) might be a potential therapeutic target for hypoxic/ischemic brain injury since NF-kappa B has been found to be inactivated after hypoxia exposure, yet the underlying molecular mechanisms of NF-kappa B inactivation are largely unknown. Here we report that epidermal growth factor receptor (EGFR) activation prevents neuron-like PC12 cells apoptosis in response to hypoxia via restoring NF-kappa B-dependent transcriptional upregulation of cyclin D1. Functionally, EGFR activation by EGF stimulation mitigates hypoxia-induced PC12 cells apoptosis in both dose- and time-dependent manner. Of note, EGFR activation elevates IKK beta phosphorylation, increases I kappa B alpha ubiquitination, promotes P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as upregulates cyclin Dl expression. EGFR activation also abrogates the decrease of IKK beta phosphorylation, reduction of I kappa B alpha ubiquitination, blockade of P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as down regulation of cyclin D1 expression induced by hypoxia. Furthermore, NF-kappa B-dependent upregulation of cyclin Dl is instrumental for the EGFR-mediated cytoprotection against hypoxic apoptosis. In addition, the dephosphorylation of EGFR induced by either EGF siRNA transfection or anti-HB-EGF neutralization antibody treatment enhances hypoxic cytotoxicity, which are attenuated by EGF administration. Our results highlight the essential role of NF-kappa B-dependent transcriptional upregulation of cyclin D1 in EGFR-mediated cytoprotective effects under hypoxic preconditioning and support further investigation of EGF in clinical trials of patients with hypoxic/ischemic brain injury. (C) 2016 Published by Elsevier Inc.