Evidence that gamma-secretase-mediated Notch signaling induces neuronal cell death via the nuclear factor-kappaB-Bcl-2-interacting mediator of cell death pathway in ischemic stroke.
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Evidence that gamma-secretase-mediated Notch signaling induces neuronal cell death via the nuclear factor-kappaB-Bcl-2-interacting mediator of cell death pathway in ischemic stroke. / Arumugam, Thiruma V; Cheng, Yi-Lin; Choi, Yuri; Choi, Yun-Hyung; Yang, Sunghee; Yun, Young-Kwang; Park, Jong-Sung; Yang, Dong Kwon; Thundyil, John; Gelderblom, Mathias; Karamyan, Vardan T; Tang, Sung-Chun; Chan, Sic L; Magnus, Tim; Sobey, Christopher G; Jo, Dong-Gyu.
In: MOL PHARMACOL, Vol. 80, No. 1, 1, 2011, p. 23-31.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Evidence that gamma-secretase-mediated Notch signaling induces neuronal cell death via the nuclear factor-kappaB-Bcl-2-interacting mediator of cell death pathway in ischemic stroke.
AU - Arumugam, Thiruma V
AU - Cheng, Yi-Lin
AU - Choi, Yuri
AU - Choi, Yun-Hyung
AU - Yang, Sunghee
AU - Yun, Young-Kwang
AU - Park, Jong-Sung
AU - Yang, Dong Kwon
AU - Thundyil, John
AU - Gelderblom, Mathias
AU - Karamyan, Vardan T
AU - Tang, Sung-Chun
AU - Chan, Sic L
AU - Magnus, Tim
AU - Sobey, Christopher G
AU - Jo, Dong-Gyu
PY - 2011
Y1 - 2011
N2 - Notch-1 (Notch) is a cell surface receptor that regulates cell-fate decisions in the developing nervous system, and it may also have roles in synaptic plasticity in the adult brain. Binding of its ligands results in the proteolytic cleavage of Notch by the ?-secretase enzyme complex, thereby causing the release of a Notch intracellular domain (NICD) that translocates to the nucleus, in which it regulates transcription. Here we show that activation of Notch modulates ischemic neuronal cell death in vitro and in vivo. Specifically, our findings from the use of Notch-1 siRNA or the overexpression of NICD indicate that Notch activation contributes to cell death. Using modified NICD, we demonstrate an apoptosis-inducing function of NICD in both the nucleus and the cytosol. NICD transfection-induced cell death was reduced by blockade of calcium signaling, caspase activation, and Janus kinase signaling. Inhibition of the Notch-activating enzyme, ?-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-?B (NF-?B), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a ?-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, ?-secretase inhibition reduced NICD, p-p65, and Bim levels in vivo. These findings suggest that Notch signaling endangers neurons after ischemic stroke by modulating the NF-?B, pro-death protein Bim, and caspase pathways.
AB - Notch-1 (Notch) is a cell surface receptor that regulates cell-fate decisions in the developing nervous system, and it may also have roles in synaptic plasticity in the adult brain. Binding of its ligands results in the proteolytic cleavage of Notch by the ?-secretase enzyme complex, thereby causing the release of a Notch intracellular domain (NICD) that translocates to the nucleus, in which it regulates transcription. Here we show that activation of Notch modulates ischemic neuronal cell death in vitro and in vivo. Specifically, our findings from the use of Notch-1 siRNA or the overexpression of NICD indicate that Notch activation contributes to cell death. Using modified NICD, we demonstrate an apoptosis-inducing function of NICD in both the nucleus and the cytosol. NICD transfection-induced cell death was reduced by blockade of calcium signaling, caspase activation, and Janus kinase signaling. Inhibition of the Notch-activating enzyme, ?-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-?B (NF-?B), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a ?-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, ?-secretase inhibition reduced NICD, p-p65, and Bim levels in vivo. These findings suggest that Notch signaling endangers neurons after ischemic stroke by modulating the NF-?B, pro-death protein Bim, and caspase pathways.
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Rats
KW - Rats, Sprague-Dawley
KW - Cell Line, Tumor
KW - Signal Transduction
KW - Amyloid Precursor Protein Secretases/metabolism
KW - Brain Ischemia/enzymology/metabolism/pathology
KW - Cell Death/drug effects/physiology
KW - Enzyme Inhibitors/pharmacology
KW - NF-kappa B/metabolism
KW - Neurons/cytology
KW - Proto-Oncogene Proteins c-bcl-2/physiology
KW - Receptors, Notch/metabolism
KW - Stroke/enzymology/metabolism/pathology
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Rats
KW - Rats, Sprague-Dawley
KW - Cell Line, Tumor
KW - Signal Transduction
KW - Amyloid Precursor Protein Secretases/metabolism
KW - Brain Ischemia/enzymology/metabolism/pathology
KW - Cell Death/drug effects/physiology
KW - Enzyme Inhibitors/pharmacology
KW - NF-kappa B/metabolism
KW - Neurons/cytology
KW - Proto-Oncogene Proteins c-bcl-2/physiology
KW - Receptors, Notch/metabolism
KW - Stroke/enzymology/metabolism/pathology
M3 - SCORING: Journal article
VL - 80
SP - 23
EP - 31
JO - MOL PHARMACOL
JF - MOL PHARMACOL
SN - 0026-895X
IS - 1
M1 - 1
ER -
