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Title: Knock-down of POSH expression is neuroprotective through down-regulating activation of the MLK3-MKK4-JNK pathway following cerebral ischaemia in the rat hippocampal CA1 subfield
Author: Zhang, QG ; Wang, RM ; Yin, XH ; Pan, J ; Xu, TL(徐天乐) ; Zhang, GY
Source: JOURNAL OF NEUROCHEMISTRY
Issued Date: 2005
Volume: 95, Issue:3, Pages:784-795
Keyword: antisense oligodeoxynucleotides ; hippocampus ; c-Jun N-terminal kinase ; mixed lineage kinase 3 ; MAP kinase kinase 4 ; neuronal death ; MIXED-LINEAGE KINASE-3 ; TRANSIENT FOREBRAIN ISCHEMIA ; D-ASPARTATE RECEPTOR ; PROTEIN-KINASES ; C-JUN ; SCAFFOLD PROTEIN ; GLOBAL-ISCHEMIA ; CYTOCHROME-C ; BRAIN-INJURY ; JNK
Subject: Biochemistry & Molecular Biology ; Neurosciences & Neurology
Corresponding Author: Zhang, QG (reprint author), Xuzhou Med Coll, Res Ctr Biochem & Mol Biol, 84 W Hua Hai Rd, Xuzhou 221002, Jiangsu, Peoples R China,gyzhang@xzmc.edu.cn
English Abstract: We investigated the expression and subcellular localization of the multidomain protein POSH (plenty of SH3s) by immunohistochemistry and western blot analysis, as well as its role in the selective activation of mixed-lineage kinases (MLKs) 3, MAP kinase kinase (MKK) 4, c-Jun N-terminal kinases (JNKs) and the c-Jun signalling cascade in the rat hippocampal CA1 region following cerebral ischaemia. Our results indicated that the cytosol immunoreactivity of POSH was strong in the CA1-CA3 pyramidal cell but weak in the DG granule cell of the rat hippocampus both in sham control and after reperfusion. Co-immunoprecipitation experiments showed that the interactions of MLK3, MKK4 and phospho-JNKs with POSH were persistently enhanced during the early (30 min) and the later reperfusion period (from 1 to 3 days) compared with sham controls. Consistently, MLK3-MKK4-JNK activation was rapidly increased with peaks both at 30 min and 3 days of reperfusion. Intracerebroventricular infusion of POSH antisense oligodeoxynucleotides (AS-ODNs) not only significantly reduced the protein level of POSH, markedly decreased its interactions with MLK3, MKK4 and phospho-JNKs, but also attenuated the activation of the JNK signalling pathway. In addition, infusion of POSH AS-ODNs significantly increased the neuronal density in the CA1 region at 5 days of reperfusion. Our results suggest that POSH might serve as a scaffold mediating JNK signalling activation in the hippocampal CA1 region following cerebral ischaemia, and POSH AS-ODNs exerts its protective effects on ischaemic injury through a mechanism of inhibition of the MLK3-MKK4-JNK signalling pathway, involving c-Jun and caspase 3 activation.
Indexed Type: SCI
Language: 英语
Content Type: 期刊论文
URI: http://ir.sibs.ac.cn/handle/331001/1873
Appears in Collections:神经所(总)_期刊论文

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Zhang, QG; Wang, RM; Yin, XH; Pan, J; Xu, TL; Zhang, GY.Knock-down of POSH expression is neuroprotective through down-regulating activation of the MLK3-MKK4-JNK pathway following cerebral ischaemia in the rat hippocampal CA1 subfield,JOURNAL OF NEUROCHEMISTRY,2005,95(3):784-795
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