Abstract
Neuroprotective proteins expressed in the fetus play a critical role during early embryonic neurodevelopment, especially during maternal exposure to alcohol and drugs that cause stress, glutamate neuroexcitotoxicity, and damage to the fetal brain, if prolonged. We have identified a novel protein, carboxypeptidase E-ΔN (CPE-ΔN), which is a splice variant of CPE that has neuroprotective effects on embryonic neurons. CPE-ΔN is transiently expressed in mouse embryos from embryonic day 5.5 to postnatal day 1. It is expressed in embryonic neurons, but not in 3 week or older mouse brains, suggesting a function primarily in utero. CPE-ΔN expression was up-regulated in embryonic hippocampal neurons in response to dexamethasone treatment. CPE-ΔN transduced into rat embryonic cortical and hippocampal neurons protected them from glutamate- and H2O2-induced cell death. When transduced into embryonic cortical neurons, CPE-ΔN was found in the nucleus and enhanced the transcription of FGF2 mRNA. Embryonic cortical neurons challenged with glutamate resulted in attenuated FGF2 levels and cell death, but CPE-ΔN transduced neurons treated in the same manner showed increased FGF2 expression and normal viability. This neuroprotective effect of CPE-ΔN was mediated by secreted FGF2. Through receptor signaling, FGF2 activated the AKT and ERK signaling pathways, which in turn increased BCL-2 expression. This led to inhibition of caspase-3 activity and cell survival.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Carboxypeptidase H / genetics*
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Carboxypeptidase H / metabolism
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Death / drug effects
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Survival / drug effects
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Cerebral Cortex / cytology
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Cerebral Cortex / drug effects
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Cerebral Cortex / enzymology
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Embryo, Mammalian
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblast Growth Factor 2 / agonists*
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Fibroblast Growth Factor 2 / genetics
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Fibroblast Growth Factor 2 / metabolism
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Gene Expression Regulation, Developmental
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Glutamic Acid / pharmacology*
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Hippocampus / cytology
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Hippocampus / drug effects
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Hippocampus / enzymology
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Hydrogen Peroxide / pharmacology
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Mice
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Neurons / cytology
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Neurons / drug effects*
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Neurons / enzymology
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Neuroprotective Agents / metabolism*
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Primary Cell Culture
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Proto-Oncogene Proteins c-akt / agonists
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / agonists
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Signal Transduction
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Transduction, Genetic
Substances
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Nerve Tissue Proteins
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Neuroprotective Agents
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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Fibroblast Growth Factor 2
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Bcl2 protein, mouse
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Glutamic Acid
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Hydrogen Peroxide
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Carboxypeptidase H
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Caspase 3