Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death.
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.
Hashimoto
Yuichi
Y
Departments of Pharmacology and Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan.
Tsuji
Osahiko
O
Niikura
Takako
T
Yamagishi
Yohichi
Y
Ishizaka
Miho
M
Kawasumi
Masaoki
M
Chiba
Tomohiro
T
Kanekura
Kohsuke
K
Yamada
Marina
M
Tsukamoto
Emi
E
Kouyama
Keisuke
K
Terashita
Kenzo
K
Aiso
Sadakazu
S
Lin
Anning
A
Nishimoto
Ikuo
I
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
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