title: Carboxypeptidase E/NFα1: a new neurotrophic factor against oxidative stress-induced apoptotic cell death mediated by ERK and PI3-K/AKT pathways.
abstract: Mice lacking Carboxypeptidase E (CPE) exhibit degeneration of hippocampal neurons caused by stress at weaning while over-expression of CPE in hippocampal neurons protect them against hydrogen peroxide-induced cell death. Here we demonstrate that CPE acts as an extracellular trophic factor to protect neurons. Rat hippocampal neurons pretreated with purified CPE protected the cells against hydrogen peroxide-, staurosporine- and glutamate-induced cell death. This protection was observed even when hippocampal neurons were treated with an enzymatically inactive mutant CPE or with CPE in the presence of its inhibitor, GEMSA. Purified CPE added to the culture medium rescued CPE knock-out hippocampal neurons from cell death. Both ERK and AKT were phosphorylated within 15 min after CPE treatment of hippocampal neurons and, using specific inhibitors, both signaling pathways were shown to be required for the neuroprotective effect. The expression of the anti-apoptotic protein, B-cell lymphoma 2 (BCL-2), was up-regulated after hippocampal neurons were treated with CPE. Furthermore, hydrogen peroxide induced down-regulation of BCL-2 protein and subsequent activation of caspase-3 were inhibited by CPE treatment. Thus, this study has identified CPE as a new neurotrophic factor that can protect neurons against degeneration through the activation of ERK and AKT signaling pathways to up-regulate expression of BCL-2.
authors: Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Yong
authors: Y
authors: Cheng
authors: Niamh X
authors: NX
authors: Cawley
authors: Y Peng
authors: YP
authors: Loh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D043423:Carboxypeptidase H / Q000378:metabolism* / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology; D006624:Hippocampus / Q000473:pathology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D061945:Caspase Inhibitors; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D043423:Carboxypeptidase H; D053148:Caspase 3
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