Death-signalling cascade in mouse cerebellar granule neurons.
Molecular mechanisms of neuronal cell death are still largely unknown. In the present study, the signal transduction pathway of cell death in cerebellar granule neurons was examined by employing various death-preventative agents. When death was induced by the depletion of serum and a depolarizing level of potassium, transient increase in active c-Jun, mitochondrial membrane potential (deltapsi) loss, activation of caspase-3 (-like) proteases, and nuclear condensation and fragmentation were observed. The protein synthesis inhibitor cycloheximide blocked all these phenomena, whereas RNA synthesis inhibitor actinomycin-D, survival factor such as insulin-like growth factor-1, brain-derived neurotrophic factor, high K+ (25 mM) and overproduced antiapoptotic protein Bcl-2, prevented deltapsi, loss, caspase activation, and nuclear change, but not an increase in active c-Jun. The caspase inhibitor z-Asp-CH2-DCB (carbobenzoxy-L-aspartyl-alpha-[(2,6-dichlorobenzoyl) oxy]methane) only inhibited activation of caspases and nuclear change. These results suggest that the death signal in cerebellar granule neurons is sequentially transduced in the order of c-Jun activation, de novo RNA synthesis, mitochondrial deltapsi loss, activation of caspase-3 (-like) proteases and nuclear change.
Tanabe
H
H
Department of Molecular Genetics, Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Eguchi
Y
Y
Shimizu
S
S
Martinou
J C
JC
Tsujimoto
Y
Y
D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology*; D016895:Culture Media, Serum-Free; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010766:Phosphorylation; D011188:Potassium / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis
D016895:Culture Media, Serum-Free; D009419:Nerve Tissue Proteins; D011500:Protein Synthesis Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D003609:Dactinomycin; D007334:Insulin-Like Growth Factor I; D003513:Cycloheximide; D011188:Potassium