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: Yi-Lin Cheng, Yuri Choi, Wei Lun Seow, Silvia Manzanero, Christopher G Sobey, Dong-Gyu Jo, Thiruma V Arumugam
• Journal: Brain research (Brain Res) Vol. 1586 Pg. 193-202 (Oct 24 2014) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 25168760 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Proto-Oncogene Proteins c-jun
• Receptor, Notch1
• MAP Kinase Kinase 4
• Glucose

Topics

• Cell Death (drug effects, physiology)
• Cell Hypoxia
• Cell Line
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation (drug effects, physiology)
• Glucose (deficiency)
• Humans
• Hypoxia (metabolism)
• MAP Kinase Kinase 4 (metabolism)
• Proto-Oncogene Proteins c-jun (metabolism)
• Receptor, Notch1 (genetics, metabolism)
• Signal Transduction (drug effects, physiology)
• Time Factors
• Transfection