title: Evidence that neuronal Notch-1 promotes JNK/c-Jun activation and cell death following ischemic stress.
abstract: Notch signaling is a highly conserved pathway that regulates cell fate decisions during embryonic development. We have recently identified that in ischemic stroke, activity of γ-secretase and the resulting Notch activation may endanger neurons by modulating NF-κB and HIF-1α pathways. Notch signaling can also modulate MAPK-related pathways. However, the role of γ-secretase-mediated Notch signaling in activating MAPK following ischemic stroke has not been investigated. We used control and NICD1-overexpressing HEK and SH-SY5Y cell lines, and inhibitors of γ-secretase and JNK, to explore novel roles of Notch in modulating cell death following ischemic stress in vitro. Our findings indicate that expression of NICD1, JNK/cJun, p38-MAPK and the pro-apoptotic marker, cleaved caspase-3, increased during ischemic conditions. γ-Secretase inhibitors reduced ischemia-induced increase in NICD1 and JNK/p-cJun. Furthermore, NICD overexpression augmented JNK/cJun levels and cell death under these conditions. These results suggest that Notch signaling contributes to the pathogenesis of ischemic stroke, in part by promoting JNK/cJun signaling. These results provide further support for the potential use of γ-secretase inhibitors as therapy for ischemic stroke.
authors.affiliation: Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, 117597 Singapore; School of Biomedical Sciences, The University of Queensland, St Lucia QLD 4072, Australia.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, 117597 Singapore.
authors.forename: Wei Lun
authors.initials: WL
authors.lastname: Seow
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia QLD 4072, Australia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Manzanero
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: jodg@skku.edu.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, 117597 Singapore; School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: phstva@nus.edu.sg.
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D051881:Receptor, Notch1; D048670:MAP Kinase Kinase 4; D005947:Glucose
keywords: Ischemic stroke; MAPK; Notch; γ-Secretase