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The Journal of Neuroscience, June 1, 2002, 22(11):4335-4345
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.
Coffey1, 2,
Giedre
Smiciene1, 2,
Vesa
Hongisto1, 2,
Jiong
Cao4,
Stephan
Brecht3,
Thomas
Herdegen3, and
Michael J.
Courtney1, 2, 4
1 Department of Biochemistry and Pharmacy Abo Akademi
University, Biocity, Turku, FIN 20521, Finland, and 2 Turku
Center for Biotechnology, Åbo Akademi University and University of
Turku, BioCity, Turku, FIN-20521 Finland, 3 Institute of
Pharmacology, Christian-Albrechts University, Kiel, 24105 Germany, and
4 Department of Neurobiology, A. I. Virtanen
Institute, University of Kuopio, Kuopio, FIN-70211 Finland
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 µM
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.
Key words:
JNK; isoforms; c-Jun; stress; cerebellar granule neurons; p38
Copyright © 2002 Society for Neuroscience 0270-6474/02/22114335-11$05.00/0
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