Abstract
Amyloid precursor protein (APP), the precursor of Abeta, has been shown to function as a cell surface receptor that mediates neuronal cell death by anti-APP antibody. The c-Jun N-terminal kinase (JNK) can mediate various neurotoxic signals, including Abeta neurotoxicity. However, the relationship of APP-mediated neurotoxicity to JNK is not clear, partly because APP cytotoxicity is Abeta independent. Here we examined whether JNK is involved in APP-mediated neuronal cell death and found that: (i) neuronal cell death by antibody-bound APP was inhibited by dominant-negative JNK, JIP-1b and SP600125, the specific inhibitor of JNK, but not by SB203580 or PD98059; (ii) constitutively active (ca) JNK caused neuronal cell death and (iii) the pharmacological profile of caJNK-mediated cell death closely coincided with that of APP-mediated cell death. Pertussis toxin (PTX) suppressed APP-mediated cell death but not caJNK-induced cell death, which was suppressed by Humanin, a newly identified neuroprotective factor which inhibits APP-mediated cytotoxicity. In the presence of PTX, the PTX-resistant mutant of Galphao, but not that of Galphai, recovered the cytotoxic action of APP. These findings demonstrate that JNK is involved in APP-mediated neuronal cell death as a downstream signal transducer of Go.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Amyloid beta-Protein Precursor / antagonists & inhibitors
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Anthracenes / pharmacology
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Antibodies / pharmacology
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Carrier Proteins / pharmacology
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Cell Death / drug effects
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Cell Death / physiology*
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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GTP-Binding Protein alpha Subunits, Gi-Go
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Genes, Dominant
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Heterotrimeric GTP-Binding Proteins / genetics
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Heterotrimeric GTP-Binding Proteins / metabolism
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Hybrid Cells
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Intracellular Signaling Peptides and Proteins
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JNK Mitogen-Activated Protein Kinases
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Mice
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Neuroprotective Agents / pharmacology
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Pertussis Toxin / pharmacology
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Proteins / pharmacology
Substances
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Adaptor Proteins, Signal Transducing
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Amyloid beta-Protein Precursor
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Anthracenes
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Antibodies
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Carrier Proteins
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Mapk8ip protein, mouse
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Neuroprotective Agents
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Proteins
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humanin
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pyrazolanthrone
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Pertussis Toxin
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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GTP-Binding Protein alpha Subunits, Gi-Go
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Heterotrimeric GTP-Binding Proteins