title: Over-expression of map kinase phosphatase-1 (MKP-1) suppresses neuronal death through regulating JNK signaling in hypoxia/re-oxygenation.
abstract: A pivotal role of c-jun N-terminal kinase (JNK) on neuronal apoptosis has been demonstrated in a rodent stroke model. MAP kinase phosphatase 1 (MKP-1) is an archetypal member of the dual-specificity protein phosphatase (DUSP) family, which inactivates mitogen-activated protein kinase (MAPK) including JNK through dephosphorylation. MKP-1, one of immediate early genes in stress conditions, was induced at transcriptional level in hypoxia/re-oxygenation (H/R) in neuroblastoma N1E115 cells, however the activation of JNK was not suppressed in the acute phase of re-oxygenation. Small interference RNA-mediated knock-down of MKP-1 enhanced phospho-JNK and neuronal death that is rescued by JNK inhibitor in H/R. Conversely, conditional over-expression of MKP-1 suppressed phospho-JNK, the expression of proapoptotic genes, and neuronal death in H/R. Further the immunoreactivity of MKP-1 was detected in the neurons and partially co-localized with that of phospho-JNK in the surrounding zone of ischemia in rat MCA-O (middle cerebral artery occlusion) reperfusion model. These findings indicate that over-expression of MKP-1 could suppress neuronal death possibly through regulating JNK signaling in vitro and be a prominent neuroprotective target for the treatment of acute cerebral infarction.
authors.affiliation: Department of Neurobiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Koga
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kojima
authors.forename: Takashi
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwabara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics; D000860:Hypoxia / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D020521:Stroke / Q000378:metabolism*
chemical_list: D048670:MAP Kinase Kinase 4; D054638:Dual Specificity Phosphatase 1; D010100:Oxygen