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Research ArticleArticle

Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke

Thiruma V. Arumugam, Yi-Lin Cheng, Yuri Choi, Yun-Hyung Choi, Sunghee Yang, Young-Kwang Yun, Jong-Sung Park, Dong Kwon Yang, John Thundyil, Mathias Gelderblom, Vardan T. Karamyan, Sung-Chun Tang, Sic L. Chan, Tim Magnus, Christopher G. Sobey and Dong-Gyu Jo
Molecular Pharmacology July 2011, 80 (1) 23-31; DOI: https://doi.org/10.1124/mol.111.071076
Thiruma V. Arumugam
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Yi-Lin Cheng
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Yuri Choi
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Yun-Hyung Choi
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Sunghee Yang
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Young-Kwang Yun
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Jong-Sung Park
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Dong Kwon Yang
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John Thundyil
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Mathias Gelderblom
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Vardan T. Karamyan
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Sung-Chun Tang
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Sic L. Chan
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Tim Magnus
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Christopher G. Sobey
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Dong-Gyu Jo
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This article has a correction. Please see:

  • Correction to “Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke” - September 01, 2011

Abstract

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 γ-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, γ-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-κB (NF-κB), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a γ-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, γ-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-κB, pro-death protein Bim, and caspase pathways.

Footnotes

  • This work was supported by the National Research Foundation of Korea [Grant 2010-0016953]; the Korea Healthcare Technology R&D Project [Grant A092042]; the National Heart Foundation of Australia [Grant G-09B-4272]; and an Australian Research Council Future Fellowship [FT100100427].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071076.

  • ABBREVIATIONS:

    NICD
    Notch intracellular domain
    Bim
    Bcl-2-interacting mediator of cell death
    GD
    glucose deprivation
    DAPT
    N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester
    DBZ
    ((S,S)-2-[2-(3,5-difluorophenyl) acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7yl)propionamide)
    JAK
    Janus kinase
    NF-κB
    nuclear factor κB
    NaCN
    sodium cyanide
    siRNA
    small interfering RNA
    GFP
    green fluorescent protein
    ICA
    internal carotid artery
    Z-VAD
    N-benzyloxycarbonyl-valyl-alanyl-aspartyl-[O-methyl]-
    AG490
    α-cyano-(3,4-dihydroxy)-N-benzylcinnamide
    A23187
    calcimycin
    BAPTA/AM
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid/acetoxymethyl ester
    TK
    thymidine kinase
    NES
    nuclear export signal
    NLS
    nuclear localization signal.

  • Received January 14, 2011.
  • Accepted March 29, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke

Thiruma V. Arumugam, Yi-Lin Cheng, Yuri Choi, Yun-Hyung Choi, Sunghee Yang, Young-Kwang Yun, Jong-Sung Park, Dong Kwon Yang, John Thundyil, Mathias Gelderblom, Vardan T. Karamyan, Sung-Chun Tang, Sic L. Chan, Tim Magnus, Christopher G. Sobey and Dong-Gyu Jo
Molecular Pharmacology July 1, 2011, 80 (1) 23-31; DOI: https://doi.org/10.1124/mol.111.071076

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Research ArticleArticle

Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke

Thiruma V. Arumugam, Yi-Lin Cheng, Yuri Choi, Yun-Hyung Choi, Sunghee Yang, Young-Kwang Yun, Jong-Sung Park, Dong Kwon Yang, John Thundyil, Mathias Gelderblom, Vardan T. Karamyan, Sung-Chun Tang, Sic L. Chan, Tim Magnus, Christopher G. Sobey and Dong-Gyu Jo
Molecular Pharmacology July 1, 2011, 80 (1) 23-31; DOI: https://doi.org/10.1124/mol.111.071076
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