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PMID:15504737

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Citation

Eminel, S, Klettner, A, Roemer, L, Herdegen, T and Waetzig, V (2004) JNK2 translocates to the mitochondria and mediates cytochrome c release in PC12 cells in response to 6-hydroxydopamine. J. Biol. Chem. 279:55385-92

Abstract

6-Hydroxydopamine (6-OHDA) causes death of dopaminergic neurons by mitochondrial dysfunction with JNKs as central mediators. Here we provide novel insights into specific actions of JNK isoforms in 6-OHDA-induced death of PC12 cells. Twenty five mum 6-OHDA enhanced total JNK activity in the cytoplasm, nucleus, and at the mitochondria. Inhibition of JNKs by 2 mum SP600125 or transfection with dominant-negative JNK2 (dnJNK2) rescued more than 60% of the otherwise dying PC12 cells after 24 h, whereas transfection with dnJNK1 had no protective effects. In contrast to constitutively present JNK1, JNK2 amounts increased in the nucleus and at the mitochondria after 6-OHDA stimulation. JNK inhibition by SP600125 or transfection of dnJNK2 reduced the pool of active JNKs in the nucleus, the release of cytochrome c, as well as the cleavage of caspase-3 and its substrate poly(ADP-ribose) polymerase-1. Transfection with dnJNK1, however, had no effects on the translocation of JNKs to the mitochondria or the release of cytochrome c. Our data provide novel functional insights into the pathological role of individual JNK isoforms, the signalosome at the mitochondria, and the mode of JNK-induced release of cytochrome c.

Links

PubMed Online version:10.1074/jbc.M405858200

Keywords

Animals; Anthracenes/pharmacology; Apoptosis; Blotting, Western; Caspase 3; Caspases/metabolism; Cell Nucleus/metabolism; Cytochromes c/metabolism; Cytoplasm/metabolism; DNA, Complementary/metabolism; Databases as Topic; Genes, Dominant; JNK Mitogen-Activated Protein Kinases/metabolism; MAP Kinase Kinase 4; Mitochondria/metabolism; Mitogen-Activated Protein Kinase 9/metabolism; Mitogen-Activated Protein Kinase Kinases/metabolism; Oxidopamine/chemistry; Oxidopamine/pharmacology; PC12 Cells; Phosphorylation; Plasmids/metabolism; Poly(ADP-ribose) Polymerases/metabolism; Protein Isoforms; Protein Transport; Rats; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; Transfection; Trypan Blue/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:MK08

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MK08

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MK08

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MK09

involved_in

GO:0009636: response to toxic substance

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MK09

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MK09

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MK09

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MK09

involved_in

GO:0006626: protein targeting to mitochondrion

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MK09

involved_in

GO:0043065: positive regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MK09

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MK09

involved_in

GO:0001836: release of cytochrome c from mitochondria

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MK08

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MK08

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:MK08

part_of

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

See also

References

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