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J. Biol. Chem., Vol. 277, Issue 23, 20783-20793, June 7, 2002
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From the Department of Anatomy and Cell Biology, University of
Bergen, Bergen, 5009 Norway
A number of cyclin-dependent protein
kinase (CDK) inhibitors were tested for the ability to protect IPC-81
rat leukemic cells against cAMP-induced apoptosis. A near perfect
proportionality was observed between inhibitor potency to protect
against cAMP-induced apoptosis and to antagonize CDK5, and to a
lesser extent, CDK2 and CDK1. Enforced expression of dominant negative
CDK5 (but not CDK1-dn or CDK2-dn) protected against death, indicating
that CDK5 activity was necessary for cAMP-induced apoptosis. The CDK
inhibitors failed to protect the cells against daunorubicine-,
staurosporine-, or okadaic acid-induced apoptosis. The inhibition of
CDK5 prevented the cleavage of pro-caspase-3 in cAMP-treated cells. The
cells could be saved closer to the moment of their onset of
death by inhibitors of caspases than by inhibitors of CDK5. This
suggested that the action of CDK5 was upstream of caspase activation.
The cAMP treatment resulted in a moderate increase of the level of CDK5
mRNA and protein in IPC-81 wild-type cells. Such cAMP induction of
CDK5 was not observed in cells expressing the inducible cAMP early
repressor. The cAMP-induced increase of CDK5 contributed to apoptosis
since cells overexpressing CDK5-wt were more sensitive for
cAMP-induced death. These results demonstrate the first example of a
proapoptotic CDK action upstream of caspase activation and of an
extra-neuronal effect of CDK5.
A Novel, Extraneuronal Role for Cyclin-dependent
Protein Kinase 5 (CDK5)
MODULATION OF cAMP-INDUCED APOPTOSIS IN RAT LEUKEMIA CELLS*
*
This work was supported by grants from the Norwegian
Cancer Society (to T. S., S. D., and L. H.), from the Novo Nordic
Insulin Foundation (to S. D.), and from Grethe Harbitz legate (to
L. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 47-55586375;
Fax: 47-55586360; E-mail: stein.doskeland@iac.uib.no.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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