Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 210029, People's Republic of China.
BMC Neurosci. 2013 Jan 2;14:1. doi: 10.1186/1471-2202-14-1.
The inactivation of c-Jun N-terminal kinase (JNK) is associated with anti-apoptotic and anti-inflammatory effects in cerebral ischemia, which can be induced by an imbalance between upstream phosphatases and kinases.
Mitogen-activated protein kinase phosphatase 7 (MKP-7) was upregulated significantly at 4 h of reperfusion postischemia in rat hippocampi. By administration of cycloheximide or siRNA against mitogen-activated protein kinase phosphatase 7 (MKP-7) in a rat model of ischemia/reperfusion, an obvious enhancement of JNK activity was observed in 4 h of reperfusion following ischemia, suggesting MKP-7 was involved in JNK inactivation after ischemia. The subcellular localization of MKP-7 altered after ischemia, and the inhibition of MKP-7 nuclear export by Leptomycin B up-regulated JNK activity. Although PI3K/Akt inhibition could block downregulation of JNK activity through SEK1 and MKK-7 activation, PI3K/Akt activity was not associated with the regulation of JNK by MKP-7.
MKP-7, independently of PI3K/Akt pathway, played a key role in downregulation of JNK activity after ischemia in the rat hippocampus, and the export of MKP-7 from the nucleus was involved in downregulation of cytoplasmic JNK activity in response to ischemic stimuli.
c-Jun N 端激酶（JNK）的失活与脑缺血中的抗细胞凋亡和抗炎作用有关，这种失活可由上游磷酸酶和激酶之间的失衡引起。
在缺血后再灌注 4 小时的大鼠海马中，丝裂原活化蛋白激酶磷酸酶 7（MKP-7）显著上调。在缺血/再灌注大鼠模型中，通过给予环己酰亚胺或针对丝裂原活化蛋白激酶磷酸酶 7（MKP-7）的 siRNA，在缺血后再灌注 4 小时观察到 JNK 活性明显增强，表明 MKP-7 参与了缺血后的 JNK 失活。MKP-7 的亚细胞定位在缺血后发生改变，莱普霉素 B 抑制 MKP-7 核输出可上调 JNK 活性。尽管 PI3K/Akt 抑制可通过 SEK1 和 MKK-7 激活阻断 JNK 活性的下调，但 PI3K/Akt 活性与 MKP-7 对 JNK 的调节无关。
MKP-7 独立于 PI3K/Akt 途径，在大鼠海马中缺血后 JNK 活性的下调中发挥关键作用，MKP-7 从核内输出参与了对缺血刺激的细胞质 JNK 活性的下调。
