title: Involvement of the dual-specificity phosphatase M3/6 in c-Jun N-terminal kinase inactivation following cerebral ischemia in the rat hippocampus.
abstract: The c-Jun N-terminal kinase (JNK) undergoes complete inactivation following the intense activation induced by cerebral ischemia and reperfusion in rat hippocampi. This study examines the molecular mechanism underlying JNK dephosphorylation and inactivation evoked by dual-specificity phosphates following cerebral ischemia. The results revealed upregulation of dual-specificity phosphatase M3/6 (DUSP8) activity at 4 h of reperfusion in rat hippocampi. This was accompanied by the dephosphorylation of JNK. The M3/6 inhibitor, anisomycin, was found to enhance JNK activity following postischemic reperfusion, suggesting that M3/6 is closely associated with JNK inactivation following cerebral ischemia. Cerebral ischemia also induced an increase in heat shock protein (HSP70) levels, which is involved in the upregulation of soluble cytoplasmic M3/6 levels. The inhibition of HSP70 using quercetin resulted in an elevation of JNK activity by decreasing the cytoplasmic solubility of M3/6. The findings of the current study suggest that M3/6 is implicated in the inactivation of JNK in response to cerebral ischemia, which requires the molecular chaperone HSP70 to facilitate the correction of folding defects.
authors.affiliation: 1Laboratory Center for Basic Medical Sciences, Nanjing Medical University , Nanjing , P.R. China.
authors.forename: Zheren
authors.initials: Z
authors.lastname: Huang
authors.forename: Yunzi
authors.initials: Y
authors.lastname: Liu
authors.forename: Jianxi
authors.initials: J
authors.lastname: Zhu
authors.forename: Huiwen
authors.initials: H
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
mesh_terms: D000818:Animals; D000841:Anisomycin / Q000494:pharmacology / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology*; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000841:Anisomycin; D048031:JNK Mitogen-Activated Protein Kinases; C517038:DUSP8 protein, human; D054637:Dual-Specificity Phosphatases