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J. Biol. Chem., Vol. 277, Issue 35, 31918-31928, August 30, 2002
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From the We demonstrate here a novel role for
the I
A Novel Specific Role for I
B Kinase Complex-associated Protein
in Cytosolic Stress Signaling*
§,,,
, and**
Apoptosis Laboratory, Danish Cancer Society,
Strandboulevarden 49, DK-2100 Copenhagen, Denmark, ¶ Department of
Molecular Genetics and the Rappaport Family Institute for Research in
the Medical Sciences, Technion-Israel Institute of Technology, 7th
Efron St. Bat Galim P. O. Box 9649, Haifa, Israel 31096, and
§ Klinikum der Christian-Albrechts University of Kiel,
Institute of Pharmacology, Hospitalstrasse 4, D-24105 Kiel, Germany
B kinase complex-associated protein (IKAP) in the regulation of
activation of the mammalian stress response via the c-Jun N-terminal
kinase (JNK)-signaling pathway. We cloned IKAP as a JNK-associating
protein using the Ras recruitment yeast two-hybrid system. IKAP
efficiently and specifically enhanced JNK activation induced by ectopic
expression of MEKK1 and ASK1, upstream activators of JNK.
Importantly, IKAP also enhanced JNK activation induced by ultraviolet
light irradiation as well as treatments with tumor necrosis factor or
epidermal growth factor. The JNK association site in IKAP was mapped to the C-terminal part of IKAP. Interestingly, this region is deleted from
IKAP expressed in the autonomous nervous system of the patients affected by familial dysautonomia. Ectopic expression of this C-terminal fragment of IKAP was sufficient to support JNK activation. Taken together, our data demonstrate a novel role for IKAP in the
regulation of the JNK-mediated stress signaling. Additionally, our
results point to a role of JNK signaling in familial dysautonomia and,
thus, further support the involvement of JNK signaling in the
development, survival, and degeneration of the sensory and autonomic
nervous system.
*
This project was funded by grants from Novo Foundation,
Danish Cancer Society, Danish Cancer Research Foundation, Research Foundation of Leo Pharmaceuticals (all to T. K.), Danish Medical Research Council (to M. J.), International Union Against Cancer Grant
UICC-ICRETT-1999 1091 (to T. K.), European Community Training Program
on Biomedicine and Health Contract BMH4-98-514 (to T. K.), the
Henselt Foundation of the University of Kiel (to C. H. and T. H.),
and the Deutsche Forschungsgemeinschaft-supported SFB 415 (to
C. H. and T. H.). This research was also supported in part by Israel
Science Foundation Grant 534/01-1).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 may be addressed. E-mail:
aronheim@techunix.technion.ac.il.
**
To whom correspondence may be addressed. Tel.: 45-35-25-73-45; Fax:
45-35-25-77-21; E-mail: tk@cancer.dk.
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