title: Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death.
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.
authors.affiliation: Departments of Pharmacology and Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Osahiko
authors.initials: O
authors.lastname: Tsuji
authors.forename: Takako
authors.initials: T
authors.lastname: Niikura
authors.forename: Yohichi
authors.initials: Y
authors.lastname: Yamagishi
authors.forename: Miho
authors.initials: M
authors.lastname: Ishizaka
authors.forename: Masaoki
authors.initials: M
authors.lastname: Kawasumi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Chiba
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kanekura
authors.forename: Marina
authors.initials: M
authors.lastname: Yamada
authors.forename: Emi
authors.initials: E
authors.lastname: Tsukamoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kouyama
authors.forename: Kenzo
authors.initials: K
authors.lastname: Terashita
authors.forename: Sadakazu
authors.initials: S
authors.lastname: Aiso
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nishimoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D005799:Genes, Dominant; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006822:Hybrid Cells; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D000873:Anthracenes; D000906:Antibodies; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C490665:Mapk8ip protein, mouse; D018696:Neuroprotective Agents; D011506:Proteins; C427211:humanin; C432165:pyrazolanthrone; D037342:Pertussis Toxin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins