title: The p38/CYLD Pathway is Involved in Necroptosis Induced by Oxygen-glucose Deprivation Combined with ZVAD in Primary Cortical Neurons.
abstract: Recently, necroptosis, a form of programmed necrosis, has been widely studied. It has previously been shown that knockout of lysine 63 deubiquitinase CYLD significantly inhibits necroptosis in other cell lines, and serum response factor (SRF) could regulate CYLD gene expression through p38 mitogen-activated protein kinase (p38 MAPK). In the following study, we show oxygen-glucose deprivation (OGD) combined with a caspase inhibitor, ZVAD (OGD/ZVAD), induced CYLD protein expression in a time-dependent manner. Immunofluorescence studies showed that CYLD was localized strongly to the nucleus and weakly to the cytoplasm of neurons. The expression of CYLD in the cytoplasm, but not in the nucleus, was increased significantly upon OGD treatment. SB203580 (a p38 MAPK inhibitor) protected against neuronal injury induced by OGD/ZVAD treatment. More importantly, SB203580 decreased CYLD protein levels by inhibiting SRF phosphorylation and indirectly prevented SRF from binding to a CYLD promoter. We also found that cells with knockdown of SRF by short interfering RNA in a lentivirus vector tolerated OGD/ZVAD-induced necroptosis, when the expression of CYLD protein decreased. The results show that SB203580 prevented necroptosis induced by OGD/ZVAD injury by blocking a p38/CYLD dependent pathway.
authors.affiliation: Department of Rehabilitation Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Feng
authors.affiliation: Department of Neurology, The Fourth Hospital of Xuzhou, Xuzhou, Jiangsu, China.
authors.forename: WeiWei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, The Eastern Hospital of Xuzhou, Xuzhou, Jiangsu, China.
authors.forename: CaiYi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Rehabilitation Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, 221002, Xuzhou, Jiangsu, China.
authors.forename: HongMei
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: LianLian
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, 221002, Xuzhou, Jiangsu, China. gengdeqin@hotmail.com.
authors.forename: DeQin
authors.initials: D
authors.lastname: Geng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D005947:Glucose / Q000172:deficiency*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000633:toxicity*; D011247:Pregnancy
chemical_list: D009842:Oligopeptides; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases; D005947:Glucose
keywords: CYLD; Necroptosis; Oxygen-glucose deprivation; P38; SRF