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Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons

Item Type:Article
Title:Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons
Creators Name:Kenchappa, R.S. and Zampieri, N. and Chao, M.V. and Barker, P.A. and Teng, H.K. and Hempstead, B.L. and Carter, B.D.
Abstract:The p75 neurotrophin receptor regulates neuronal survival, promoting it in some contexts yet activating apoptosis in others. The mechanism by which the receptor elicits these differential effects is poorly understood. Here, we demonstrate that p75 is cleaved by gamma-secretase in sympathetic neurons, specifically in response to proapoptotic ligands. This cleavage resulted in ubiquitination and subsequent nuclear translocation of NRIF, a DNA binding protein essential for p75-mediated apoptosis. Inhibition of gamma-secretase or expression of a mutant p75 resistant to this protease prevented receptor proteolysis, blocked NRIF nuclear entry, and prevented apoptosis. In contrast, overexpression of the p75 ICD resulted in NRIF nuclear accumulation and apoptosis. The receptor proteolysis and NRIF nuclear localization were also observed in vivo during naturally occurring cell death in the superior cervical ganglia. These results indicate that p75-mediated apoptosis requires gamma-secretase dependent release of its ICD, which facilitates nuclear translocation of NRIF.
Keywords:Amyloid Precursor Protein Secretases, Apoptosis, Brain-Derived Neurotrophic Factor, Cell Nucleus, Cultured Cells, Endopeptidases, Enzyme Inhibitors, Immunohistochemistry, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Ligands, Nerve Growth Factor Receptor, Neurons, Protein Transport, Sympathetic Nervous System, Western Blotting, Animals, Rats
Source:Neuron
ISSN:0896-6273
Publisher:Cell Press (U.S.A.)
Volume:50
Number:2
Page Range:219-232
Date:20 April 2006
Official Publication:https://doi.org/10.1016/j.neuron.2006.03.011
PubMed:View item in PubMed

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