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

Eleanor T Coffey; Giedre Smiciene; Vesa Hongisto; Jiong Cao; Stephan Brecht; Thomas Herdegen; Michael J Courtney

doi:10.1523/JNEUROSCI.22-11-04335.2002

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

J Neurosci. 2002 Jun 1;22(11):4335-45. doi: 10.1523/JNEUROSCI.22-11-04335.2002.

Authors

Eleanor T Coffey¹, Giedre Smiciene, Vesa Hongisto, Jiong Cao, Stephan Brecht, Thomas Herdegen, Michael J Courtney

Affiliation

¹ Department of Biochemistry and Pharmacy Abo Akademi University, Biocity, Turku, FIN 20521, Finland.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Compartmentation
Cells, Cultured
Cerebellum / cytology
Cerebellum / drug effects
Cerebellum / enzymology
Dose-Response Relationship, Drug
Enzyme Activation / drug effects
Enzyme Activation / physiology
Enzyme Inhibitors / pharmacology
Genes, Reporter
Growth Substances / pharmacology
Imidazoles / pharmacology
Isoenzymes / antagonists & inhibitors
Isoenzymes / genetics
Isoenzymes / metabolism
JNK Mitogen-Activated Protein Kinases
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 10
Mitogen-Activated Protein Kinase 8
Mitogen-Activated Protein Kinase 9
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / genetics
Mitogen-Activated Protein Kinases / metabolism*
Neurons / cytology
Neurons / drug effects
Neurons / enzymology*
Phosphorylation / drug effects
Promoter Regions, Genetic
Protein-Tyrosine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / metabolism
Pyridines / pharmacology
Rats
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Stress, Physiological / enzymology*
p38 Mitogen-Activated Protein Kinases

Substances

Enzyme Inhibitors
Growth Substances
Imidazoles
Isoenzymes
Pyridines
Recombinant Fusion Proteins
Mitogen-Activated Protein Kinase 10
Mitogen-Activated Protein Kinase 9
Protein-Tyrosine Kinases
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 8
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
SB 203580