Abstract
Excitotoxic insults induce c-Jun N-terminal kinase (JNK) activation, which leads to neuronal death and contributes to many neurological conditions such as cerebral ischemia and neurodegenerative disorders. The action of JNK can be inhibited by the D-retro-inverso form of JNK inhibitor peptide (D-JNKI1), which totally prevents death induced by N-methyl-D-aspartate (NMDA) in vitro and strongly protects against different in vivo paradigms of excitotoxicity. To obtain optimal neuroprotection, it is imperative to elucidate the prosurvival action of D-JNKI1 and the death pathways that it inhibits. In cortical neuronal cultures, we first investigate the pathways by which NMDA induces JNK activation and show a rapid and selective phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7), whereas the only other known JNK activator, mitogen-activated protein kinase kinase 4 (MKK4), was unaffected. We then analyze the action of D-JNKI1 on four JNK targets containing a JNK-binding domain: MAPK-activating death domain-containing protein/differentially expressed in normal and neoplastic cells (MADD/DENN), MKK7, MKK4 and JNK-interacting protein-1 (IB1/JIP-1).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / isolation & purification
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Calcium / metabolism
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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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Cycloheximide / pharmacology
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Death Domain Receptor Signaling Adaptor Proteins
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Electrophoresis, Gel, Two-Dimensional
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Fluorescent Antibody Technique
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Guanine Nucleotide Exchange Factors / metabolism
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism*
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MAP Kinase Kinase 4 / metabolism
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MAP Kinase Kinase 7 / metabolism
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N-Methylaspartate / toxicity*
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Neurons / cytology
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Neurons / drug effects*
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Neurons / enzymology*
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Neurons / pathology
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Neurotoxins / toxicity*
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Phosphorylation / drug effects
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Proteomics
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Rats
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Signal Transduction / drug effects
Substances
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Adaptor Proteins, Signal Transducing
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Death Domain Receptor Signaling Adaptor Proteins
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Enzyme Inhibitors
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Guanine Nucleotide Exchange Factors
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Madd protein, rat
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Mapk8ip1 protein, rat
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Neurotoxins
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N-Methylaspartate
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Cycloheximide
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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MAP Kinase Kinase 7
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Calcium