c-Jun N-Terminal Protein Kinase (JNK) 2/3 Is Specifically Activated by Stress, Mediating c-Jun Activation, in the Presence of Constitutive JNK1 Activity in Cerebellar Neurons
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c-Jun is considered a major regulator of both neuronal death and regeneration. Stress in primary cultured CNS neurons induces phosphorylation of c-Jun serines 63 and 73 and increased c-Jun protein. However, total c-Jun N-terminal protein kinase (JNK) activity does not increase, and no satisfactory explanation for this paradox has been available. Here we demonstrate that neuronal stress induces strong activation of JNK2/3 in the presence of constitutively and highly active JNK1. Correspondingly, neurons from JNK1(-/-) mice show lower constitutive activity and considerably higher responsiveness to stress. p38 activity can be completely inhibited without effect on c-Jun phosphorylation, whereas 10 micrometer SB203580 strongly inhibits neuronal JNK2/3, stress-induced c-Jun phosphorylation, induced c-Jun activity, and neuronal death in response to trophic withdrawal stress. Neither constitutive JNK1 activity nor total neuronal JNK activity were significantly affected by this concentration of drug. Thus, neuronal stress selectively activates JNK2/3 in the presence of mechanisms maintaining constitutive JNK1 activity, and this JNK2/3 activity selectively targets c-Jun, which is isolated from constitutive JNK1 activity.
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The point-of-no-return for CGN apoptosis takes place within the first 6 h of deprivation, and onset of apoptosis can be observed at 6 h post-deprivation by phosphorylation of c-Jun and activation of caspase-3.
“The point-of-no-return for the CGN apoptosis takes place within the first 6 h of deprivation, and the onset of apoptosis can be observed at 6 h postdeprivation by phosphorylation of c-Jun, the central transcription factor required for JNK-dependent apoptosis, and activation of caspase-3, a major executioner of apoptosis [22,26,27].”
From PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling (2012) · cites this paper as [26]
The section on withdrawal of trophic support reports c-Jun phosphorylation within 15 minutes in cerebellar granule neurons, supporting that part of the claim. The section on c-jun promoter activation describes the resulting neuronal death as caspase-dependent, but the passages found do not establish a point of no return within 6 hours or caspase-3 activation at 6 hours (pages not available in our copy). (LLM, conf=0.87)
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A Mammalian Scaffold Complex That Selectively Mediates MAP Kinase Activation
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JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis
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- Authors
- Coffey, E. T., Smiciene, G., Hongisto, V., Cao, J., Brecht, S., Herdegen, T., & Courtney, M. J.
- Affiliations
- Åbo Akademi University (FI)
- University of Eastern Finland (FI)
- Christian-Albrechts-Universität zu Kiel (DE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-06-01
- Volume
- 22
- Issue
- 11
- Pages
- 4335-4345
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758801
- OpenAlex
- W2128994713
- Cited by
- 184
- References
- 2
- Citations by year
- 2026: 1 · 2025: 5 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 8 · 2019: 2 · 2018: 2 · 2017: 10 · 2016: 3 · 2015: 2 · 2014: 6 · 2013: 13 · 2012: 4
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Åbo Akademi University Research Portal (submittedVersion)
- Funders
- University of Leicester
- Academy of Finland
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- c-Jun N-terminal kinase, JNK1, c-Jun phosphorylation, neuronal stress, cerebellar neurons, constitutive kinase activity, p38 MAPK, SB203580, neuronal cell death
- MeSH terms
- Animals, Cell Compartmentation, Cells, Cultured, Cerebellum, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Growth Substances, Imidazoles, Isoenzymes, Neurons, Phosphorylation, Promoter Regions, Genetic, Protein-Tyrosine Kinases, Pyridines, Recombinant Fusion Proteins, Stress, Physiological, Genes, Reporter, Mice, Knockout, Mitogen-Activated Protein Kinases, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Mitogen-Activated Protein Kinase 10, Mice, Rats
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