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: 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, Dong-Gyu Jo
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 80 Issue 1 Pg. 23-31 (Jul 2011) ISSN: 1521-0111 [Electronic] United States
• PMID: 21450930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Notch
• Amyloid Precursor Protein Secretases

Topics

• Amyloid Precursor Protein Secretases (metabolism)
• Animals
• Brain Ischemia (enzymology, metabolism, pathology)
• Cell Death (drug effects, physiology)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Neurons (cytology)
• Proto-Oncogene Proteins c-bcl-2 (physiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Notch (metabolism)
• Signal Transduction
• Stroke (enzymology, metabolism, pathology)