Mitogen- and Stress-Activated Protein Kinase 1 Regulates Status Epilepticus-Evoked Cell Death in the Hippocampus.
Mitogen- and Stress-Activated Protein Kinase 1 Regulates Status Epilepticus-Evoked Cell Death in the Hippocampus.
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DOI：
10.1177/1759091417726607
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发表时间：
2017-09
期刊：
影响因子：
4.7
通讯作者：
Obrietan K
中科院分区：
文献类型：
--
作者：
Choi YS;Horning P;Aten S;Karelina K;Alzate-Correa D;Arthur JSC;Hoyt KR;Obrietan K
有丝分裂原活化蛋白激酶（MAPK）信号转导已涉及广泛的神经过程，包括发育，可塑性和活力。细胞外信号调节激酶/MAPK途径和p38 MAPK途径的主要下游靶标之一是促分裂原和应激活化蛋白激酶1（MSK 1）。在这里，我们试图了解的作用，MSK 1在海马神经保护兴奋性毒性刺激。为此，我们利用免疫组织化学标记，一个MSK 1空小鼠系，细胞活力测定，和基于阵列的分析方法。最初，我们发现，MSK 1广泛表达的主要神经元细胞层的海马和癫痫持续状态驱动急性诱导MSK 1激活。在癫痫持续状态的范例，MSK 1基因敲除小鼠表现出显着增加的脆弱性毛果芸香碱诱发的细胞死亡内的CA 1和CA 3细胞层。此外，培养的MSK 1空神经元表现出相对于野生型神经元的N-甲基-D-天冬氨酸诱发的兴奋性毒性水平升高，如使用乳酸脱氢酶测定所评估的。鉴于这些发现，我们研究了MSK 1基因敲除小鼠的海马转录谱。亲和阵列分析显示，MSK 1缺失导致130个基因的显著（>1.25倍）下调和145个基因的上调。值得注意的是，功能分析表明，这些基因的子集有助于神经保护信号网络。总之，这些数据提供了重要的新的见解MAPK/MSK 1信号盒赋予神经保护免受兴奋性毒性损伤的机制。旨在上调或模拟MSK 1的功能作用的方法可能证明对兴奋性毒性损伤引起的一系列退行性过程有益。
Mitogen-activated protein kinase (MAPK) signaling has been implicated in a wide range of neuronal processes, including development, plasticity, and viability. One of the principal downstream targets of both the extracellular signal-regulated kinase/MAPK pathway and the p38 MAPK pathway is Mitogen- and Stress-activated protein Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized immunohistochemical labeling, a MSK1 null mouse line, cell viability assays, and array-based profiling approaches. Initially, we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus drives acute induction of MSK1 activation. In response to the status epilepticus paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of N-methyl-D-aspartate-evoked excitotoxicity relative to wild-type neurons, as assessed using the lactate dehydrogenase assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that MSK1 deletion led to the significant (>1.25-fold) downregulation of 130 genes and an upregulation of 145 genes. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults.
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影响因子：
5.3
作者：
Borges, K;Gearing, M;Dingledine, R
通讯作者：
Dingledine, R
影响因子：
3.5
作者：
Arthur, JSC;Cohen, P
通讯作者：
Cohen, P
影响因子：
3.8
作者：
Garrido, YCS;Sanabria, ERG;Naffah-Mazzacoratti, MG
通讯作者：
Naffah-Mazzacoratti, MG
DOI：
10.1073/pnas.96.22.12866
发表时间：
1999-10-26
影响因子：
11.1
作者：
Alessandrini, A;Namura, S;Bonventre, JV
通讯作者：
Bonventre, JV
影响因子：
4.1
作者：
Curia G;Lucchi C;Vinet J;Gualtieri F;Marinelli C;Torsello A;Costantino L;Biagini G
通讯作者：
Biagini G