title: Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons.
abstract: c-Jun N-terminal kinases (JNKs) typically respond strongly to stress, are implicated in brain development, and are believed to mediate neuronal apoptosis. Surprisingly, however, JNK does not respond characteristically to stress in cultured cerebellar granule (CBG) neurons, a widely exploited CNS model for studies of death and development, despite the regulation of its substrate c-Jun. To understand this anomaly, we characterized JNK regulation in CBG neurons. We find that the specific activity of CBG JNK is elevated considerably above that from neuron-like cell lines (SH-SY5Y, PC12); however, similar elevated activities are found in brain extracts. This activity does not result from cellular stress because the stress-activated protein kinase p38 is not activated. We identify a minor stress-sensitive pool of JNK that translocates with mitogen-activated protein kinase kinase-4 (MKK4) into the nucleus. However, the major pool of total activity is cytoplasmic, residing largely in the neurites, suggesting a non-nuclear role for JNK in neurons. A third JNK pool is colocalized with MKK7 in the nucleus, and specific activities of both increase during neuritogenesis, nuclear JNK activity increasing 10-fold, whereas c-Jun expression and activity decrease. A role for JNK during differentiation is supported by modulation of neuritic architecture after expression of dominant inhibitory regulators of the JNK pathway. Channeling of JNK signaling away from c-Jun during differentiation is consistent with the presence in the nucleus of the JNK/MKK7 scaffold protein JNK-interacting protein, which inhibits JNK-c-Jun interaction. We propose a model in which distinct pools of JNK serve different functions, providing a basis for understanding multifunctional JNK signaling in differentiating neurons.
authors.affiliation: Turku Centre for Biotechnology, Abo Akademi University and University of Turku, BioCity, FIN-20521 Turku, Finland. ecoffey@aton.abo.fi.
authors.forename: E T
authors.initials: ET
authors.lastname: Coffey
authors.forename: V
authors.initials: V
authors.lastname: Hongisto
authors.forename: M
authors.initials: M
authors.lastname: Dickens
authors.forename: R J
authors.initials: RJ
authors.lastname: Davis
authors.forename: M J
authors.initials: MJ
authors.lastname: Courtney
mesh_terms: D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016548:Prosencephalon / Q000166:cytology / Q000201:enzymology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000201:enzymology*; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016895:Culture Media, Serum-Free; D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D000841:Anisomycin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases