Evidence that neuronal Notch-1 promotes JNK/c-Jun activation and cell death following ischemic stress

Yi-Lin Cheng, Yuri Choi, Wei Lun Seow, Silvia Manzanero, Christopher G Sobey, Dong-Gyu Jo, Thiruma V Arumugam

Research output: Contribution to journalArticleResearchpeer-review

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 gamma-secretase and the resulting Notch activation may endanger neurons by modulating NF-kappaB and HIF-1alpha pathways. Notch signaling can also modulate MAPK-related pathways. However, the role of gamma-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 gamma-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. gamma-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 gamma-secretase inhibitors as therapy for ischemic stroke.
Original languageEnglish
Pages (from-to)193 - 202
Number of pages10
JournalBrain Research
Volume1586
DOIs
Publication statusPublished - 2014

Cite this

Cheng, Yi-Lin ; Choi, Yuri ; Seow, Wei Lun ; Manzanero, Silvia ; Sobey, Christopher G ; Jo, Dong-Gyu ; Arumugam, Thiruma V. / Evidence that neuronal Notch-1 promotes JNK/c-Jun activation and cell death following ischemic stress. In: Brain Research. 2014 ; Vol. 1586. pp. 193 - 202.
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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 gamma-secretase and the resulting Notch activation may endanger neurons by modulating NF-kappaB and HIF-1alpha pathways. Notch signaling can also modulate MAPK-related pathways. However, the role of gamma-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 gamma-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. gamma-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 gamma-secretase inhibitors as therapy for ischemic stroke.",
author = "Yi-Lin Cheng and Yuri Choi and Seow, {Wei Lun} and Silvia Manzanero and Sobey, {Christopher G} and Dong-Gyu Jo and Arumugam, {Thiruma V}",
year = "2014",
doi = "10.1016/j.brainres.2014.08.054",
language = "English",
volume = "1586",
pages = "193 -- 202",
journal = "Brain Research",
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Evidence that neuronal Notch-1 promotes JNK/c-Jun activation and cell death following ischemic stress. / Cheng, Yi-Lin; Choi, Yuri; Seow, Wei Lun; Manzanero, Silvia; Sobey, Christopher G; Jo, Dong-Gyu; Arumugam, Thiruma V.

In: Brain Research, Vol. 1586, 2014, p. 193 - 202.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Evidence that neuronal Notch-1 promotes JNK/c-Jun activation and cell death following ischemic stress

AU - Cheng, Yi-Lin

AU - Choi, Yuri

AU - Seow, Wei Lun

AU - Manzanero, Silvia

AU - Sobey, Christopher G

AU - Jo, Dong-Gyu

AU - Arumugam, Thiruma V

PY - 2014

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N2 - 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 gamma-secretase and the resulting Notch activation may endanger neurons by modulating NF-kappaB and HIF-1alpha pathways. Notch signaling can also modulate MAPK-related pathways. However, the role of gamma-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 gamma-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. gamma-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 gamma-secretase inhibitors as therapy for ischemic stroke.

AB - 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 gamma-secretase and the resulting Notch activation may endanger neurons by modulating NF-kappaB and HIF-1alpha pathways. Notch signaling can also modulate MAPK-related pathways. However, the role of gamma-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 gamma-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. gamma-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 gamma-secretase inhibitors as therapy for ischemic stroke.

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