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J. Biol. Chem., Vol. 277, Issue 47, 45129-45140, November 22, 2002
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From the The IKK
IKK
, IKK
, and NEMO/IKK
Are Each Required for the
NF-
B-mediated Inflammatory Response Program*
§,
,,,,,, and**§§¶¶
Department of Biology, Boehringer Ingelheim
Pharmaceuticals, Ridgefield, Connecticut 06877-0368, the
¶ Genetics Graduate Program, Department of Biochemistry and
Cell Biology, and ** Department of Microbiology, State
University of New York, Stony Brook, New York 11794-5215, and the
§§ Center for Applied Biomedical Research,
S. Orsola University Hospital, Via Massarenti 9, Bologna 40138, Italy
and NEMO/IKK
subunits
of the NF-
B-activating signalsome complex are known to be essential
for activating NF-B by inflammatory and other stress-like stimuli.
However, the IKK
subunit is believed to be dispensable for the
latter responses and instead functions as an in vivo
mediator of other novel NF-B-dependent and -independent
functions. In contrast to this generally accepted view of IKK's
physiological functions, we demonstrate in mouse embryonic fibroblasts
(MEFs) that, akin to IKK and NEMO/IKK, IKK is also a global
regulator of tumor necrosis factor - and IL-1-responsive IKK
signalsome-dependent target genes including many known
NF-B targets such as serum amyloid A3, C3, interleukin (IL)-6,
IL-11, IL-1 receptor antagonist, vascular endothelial growth factor,
Ptx3, 2-microglobulin, IL-1, Mcp-1 and -3, RANTES (regulated on activation normal T cell expressed and secreted), Fas
antigen, Jun-B, c-Fos, macrophage colony-stimulating factor, and
granulocyte-macrophage colony-stimulating factor. Only a small number
of NF-B-dependent target genes were preferentially
dependent on IKK or IKK. Constitutive expression of a
trans-dominant IB superrepressor (IBSR) in wild
type MEFs confirmed that these signalsome-dependent target
genes were also dependent on NF-B. A subset of NF-B target genes
were IKK-dependent in the absence of exogenous stimuli,
suggesting that the signalsome was also required to regulate basal
levels of activated NF-B in established MEFs. Overall, a sizable
number of novel NF-B/IKK-dependent genes were identified
including Secreted Frizzled, cadherin 13, protocadherin 7, CCAAT/enhancer-binding protein- and -
, osteoprotegerin, FOXC2 and
FOXF2, BMP-2, p75 neurotrophin receptor, caspase-11, guanylate-binding proteins 1 and 2, ApoJ/clusterin, interferon ( and ) receptor 2, decorin, osteoglycin, epiregulin, proliferins 2 and 3, stromal cell-derived factor, and cathepsins B, F, and Z. SOCS-3, a negative effector of STAT3 signaling, was found to be an NF-B/IKK-induced gene, suggesting that IKK-mediated NF-B activation can coordinately illicit negative effects on STAT signaling.
*
This work was supported in part by National Institutes of
Health Grant GM26939 (to K. B. M.).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. Tel.: 203-798-5714;
Fax: 203-791-6906; E-mail: jli@rdg.boehringer-ingelheim.com.
¶¶
To whom correspondence may be addressed. Tel.:
631-632-8553; Fax: 631-632-9730; E-mail:
kmarcu@ms.cc.sunysb.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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