Comparing effects of CDK inhibition and E2F1/2 ablation on neuronal cell death pathways in vitro and after traumatic brain injury.
Comparing effects of CDK inhibition and E2F1/2 ablation on neuronal cell death pathways in vitro and after traumatic brain injury.
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DOI：
10.1038/s41419-018-1156-y
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发表时间：
2018-11-06
影响因子：
9
通讯作者：
Stoica BA
中科院分区：
文献类型：
--
作者：
Aubrecht TG;Faden AI;Sabirzhanov B;Glaser EP;Roelofs BA;Polster BM;Makarevich O;Stoica BA
创伤性脑损伤可激活多种神经细胞死亡机制，导致创伤后神经元丢失和神经功能障碍。脑损伤诱导有丝分裂后神经元的细胞周期激活(CCA)导致细胞死亡，包括细胞周期蛋白依赖性激酶(CDK)的激活和E2F转录因子介导的促凋亡程序的启动。在这里，我们研究了体外培养的原代神经元和暴露于受控皮质冲击(CCI)的小鼠中依赖CCA的神经元凋亡的机制。与我们之前的工作显示CDK抑制剂对脑损伤后强大的神经保护作用不同，在CCI后对E2F1−/−/E2F2−/−或E2F2−/−转基因小鼠的神经细胞凋亡机制的检测表明，E2F1和/或E2F2在脑创伤后神经细胞丢失中可能只起到很小的作用。为了阐明CCA参与创伤后神经细胞死亡的更多关键分子通路，我们在原代皮质神经元细胞死亡的DNA损伤模型中研究了强有力的CDK抑制剂CR8的神经保护作用和机制。CR8处理显著降低了caspase的激活和caspase底物的裂解，减轻了神经细胞的死亡。CR8的神经保护作用似乎反映了抑制汇聚到线粒体的多条途径，包括损伤诱导促凋亡的Bcl2同源区3(BH3)蛋白PUMA和NOXA的增加，从而减弱线粒体的通透性和细胞色素c和AIF的释放，减少caspase依赖和非依赖的细胞凋亡。CR8的应用也限制了损伤诱导的线粒体呼吸缺陷。这些神经保护作用可能是通过CR8介导的抑制关键的上游损伤反应来解释的，包括减弱c-jun的磷酸化/激活以及抑制仅BH3靶点的p53反式激活。
Traumatic brain injury (TBI) activates multiple neuronal cell death mechanisms, leading to post-traumatic neuronal loss and neurological deficits. TBI-induced cell cycle activation (CCA) in post-mitotic neurons causes regulated cell death involving cyclin-dependent kinase (CDK) activation and initiation of an E2F transcription factor-mediated pro-apoptotic program. Here we examine the mechanisms of CCA-dependent neuronal apoptosis in primary neurons in vitro and in mice exposed to controlled cortical impact (CCI). In contrast to our prior work demonstrating robust neuroprotective effects by CDK inhibitors after TBI, examination of neuronal apoptotic mechanisms in E2F1−/−/E2F2−/− or E2F2−/− transgenic mice following CCI suggests that E2F1 and/or E2F2 likely play only a modest role in neuronal cell loss after brain trauma. To elucidate more critical CCA molecular pathways involved in post-traumatic neuronal cell death, we investigated the neuroprotective effects and mechanisms of the potent CDK inhibitor CR8 in a DNA damage model of cell death in primary cortical neurons. CR8 treatment significantly reduced caspase activation and cleavage of caspase substrates, attenuating neuronal cell death. CR8 neuroprotective effects appeared to reflect inhibition of multiple pathways converging on the mitochondrion, including injury-induced elevation of pro-apoptotic Bcl-2 homology region 3 (BH3)-only proteins Puma and Noxa, thereby attenuating mitochondrial permeabilization and release of cytochrome c and AIF, with reduction of both caspase-dependent and -independent apoptosis. CR8 administration also limited injury-induced deficits in mitochondrial respiration. These neuroprotective effects may be explained by CR8-mediated inhibition of key upstream injury responses, including attenuation of c-Jun phosphorylation/activation as well as inhibition of p53 transactivation of BH3-only targets.
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影响因子：
9.3
作者：
Byrnes KR;Loane DJ;Stoica BA;Zhang J;Faden AI
通讯作者：
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影响因子：
4.2
作者：
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影响因子：
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作者：
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DOI：
10.1080/15384101.2015.1004937
发表时间：
2015
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
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通讯作者：
Ovejero-Benito MC
影响因子：
7.8
作者：
Besirli, CG;Wagner, EF;Johnson, EM
通讯作者：
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