title: 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.
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.
authors: School of Biomedical Sciences, the University of Queensland, St Lucia, QLD 4072, Australia.
authors: Thiruma V
authors: TV
authors: Arumugam
authors: Yi-Lin
authors: YL
authors: Cheng
authors: Yuri
authors: Y
authors: Choi
authors: Yun-Hyung
authors: YH
authors: Choi
authors: Sunghee
authors: S
authors: Yang
authors: Young-Kwang
authors: YK
authors: Yun
authors: Jong-Sung
authors: JS
authors: Park
authors: Dong Kwon
authors: DK
authors: Yang
authors: John
authors: J
authors: Thundyil
authors: Mathias
authors: M
authors: Gelderblom
authors: Vardan T
authors: VT
authors: Karamyan
authors: Sung-Chun
authors: SC
authors: Tang
authors: Sic L
authors: SL
authors: Chan
authors: Tim
authors: T
authors: Magnus
authors: Christopher G
authors: CG
authors: Sobey
authors: Dong-Gyu
authors: DG
authors: Jo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D020521:Stroke / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases