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Correlation between structure of Bcl-2 and its inhibitory function of JNK and caspase activity in dopaminergic neuronal apoptosis.

Authors
Choi, WS; Yoon, SY; Chang, II; Choi, EJ; Rhim, H; Jin, BK; Oh, TH; Krajewski, S; Reed, JC; Oh, YJ
Citation
Journal of neurochemistry, 74(4):1621-1626, 2000
Journal Title
Journal of neurochemistry
ISSN
0022-30421471-4159
Abstract
To examine the correlation between the structure of Bcl-2 and its inhibitory function of c-Jun N-terminal kinase (JNK) and caspase activity, we established a dopaminergic neuronal cell line, MN9D overexpressing Bcl-2 (MN9D/Bcl-2) or its structural mutants. The mutants comprised a point mutation in the BH1 (G145A; MN9D/BH1) or BH2 (W188A; MN9D/BH2) domain and a deletion mutation in the C-terminal (MN9D/C22), BH3 (MN9D/BH3), or BH4 (MN9D/BH4) domain. As determined by the TUNEL (terminal deoxynucleotidyltransferase nick end-labeling) and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] reduction assay, apoptotic death of MN9D/Neo cells reached 80-90% within 24 h in response to 1 microM staurosporine. Upon staurosporine treatment, JNK activity increased six- to sevenfold over the basal level within 2-4 h. Treatment of MN9D/Neo with both staurosporine and a caspase inhibitor, Z-VAD, attenuated cell death without suppressing JNK activation. Both staurosporine-induced cell death and JNK activation were attenuated in MN9D/Bcl-2. As determined by cleavage of poly(ADP-ribose) polymerase into 85 kDa, Bcl-2 blocked caspase activity as well. When cells overexpressing one of the Bcl-2 mutants were treated with staurosporine, death was attenuated in MN9D/BH1, MN9D/BH2, and MN9D/C22 but not in MN9D/BH3 and MN9D/BH4. Similarly, both JNK and caspase activation were blocked in MN9D/BH1, MN9D/BH2, and MN9D/C22, whereas they were not suppressed in MN9D/BH3 and MN9D/BH4. Taken together, our data indicate that there exists a close structural and functional correlation of Bcl-2 to JNK and caspase activity in staurosporine-induced dopaminergic neuronal cell death.
MeSH terms
Apoptosis/drug effects/*physiologyCaspases/*metabolismCells, CulturedDopamine/physiologyEnzyme Inhibitors/pharmacologyHumansIn Situ Nick-End LabelingJNK Mitogen-Activated Protein KinasesMitogen-Activated Protein Kinases/*metabolismMutation/physiologyNeurons/*cytology/*enzymologyParkinson Disease/metabolismProtein Structure, TertiaryProto-Oncogene Proteins c-bcl-2/chemistry/genetics/*metabolismStaurosporine/pharmacologyStructure-Activity RelationshipTransfection
PMID
10737620
Appears in Collections:
Journal Papers > Research Organization > Institute for Medical Sciences
AJOU Authors
진, 병관
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