JNK3 contributes to c-Jun activation and apoptosis but not oxidative stress in nerve growth factor-deprived sympathetic neurons.
The stress activated protein kinase pathway culminates in c-Jun phosphorylation mediated by the Jun Kinases (JNKs). The role of the JNK pathway in sympathetic neuronal death is unclear in that apoptosis is not inhibited by a dominant negative protein of one JNK kinase, SEK1, but is inhibited by CEP-1347, a compound known to inhibit this overall pathway but not JNKs per se. To evaluate directly the apoptotic role of the JNK isoform that is selectively expressed in neurons, JNK3, we isolated sympathetic neurons from JNK3-deficient mice and quantified nerve growth factor (NGF) deprivation-induced neuronal death, oxidative stress, c-Jun phosphorylation, and c-jun induction. Here, we report that oxidative stress in neurons from JNK3-deficient mice is normal after NGF deprivation. In contrast, NGF-deprivation-induced increases in the levels of phosphorylated c-Jun, c-jun, and apoptosis are each inhibited in JNK3-deficient mice. Overall, these results indicate that JNK3 plays a critical role in activation of c-Jun and apoptosis in a classic model of cell-autonomous programmed neuron death.
Bruckner
S R
SR
Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
Tammariello
S P
SP
Kuan
C Y
CY
Flavell
R A
RA
Rakic
P
P
Estus
S
S
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D016758:Genes, jun; D005838:Genotype; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000502:physiology*
D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D016755:Proto-Oncogene Proteins c-jun; D020932:Nerve Growth Factor; D048057:Mitogen-Activated Protein Kinase 10; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases