J Biol Chem 2002,
PMID: 12221085
Li, Xiang; Massa, Paul E; Hanidu, Adedayo; Peet, Gregory W; Aro, Patrick; Savitt, Ann; Mische, Sheenah; Li, Jun; Marcu, Kenneth B
The IKKbeta and NEMO/IKKgamma subunits of the NF-kappaB-activating signalsome complex are known to be essential for activating NF-kappaB by inflammatory and other stress-like stimuli. However, the IKKalpha subunit is believed to be dispensable for the latter responses and instead functions as an in vivo mediator of other novel NF-kappaB-dependent and -independent functions. In contrast to this generally accepted view of IKKalpha's physiological functions, we demonstrate in mouse embryonic fibroblasts (MEFs) that, akin to IKKbeta and NEMO/IKKgamma, IKKalpha is also a global regulator of tumor necrosis factor alpha- and IL-1-responsive IKK signalsome-dependent target genes including many known NF-kappaB targets such as serum amyloid A3, C3, interleukin (IL)-6, IL-11, IL-1 receptor antagonist, vascular endothelial growth factor, Ptx3, beta(2)-microglobulin, IL-1alpha, 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-kappaB-dependent target genes were preferentially dependent on IKKalpha or IKKbeta. Constitutive expression of a trans-dominant IkappaBalpha superrepressor (IkappaBalphaSR) in wild type MEFs confirmed that these signalsome-dependent target genes were also dependent on NF-kappaB. A subset of NF-kappaB 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-kappaB in established MEFs. Overall, a sizable number of novel NF-kappaB/IKK-dependent genes were identified including Secreted Frizzled, cadherin 13, protocadherin 7, CCAAT/enhancer-binding protein-beta and -delta, osteoprotegerin, FOXC2 and FOXF2, BMP-2, p75 neurotrophin receptor, caspase-11, guanylate-binding proteins 1 and 2, ApoJ/clusterin, interferon (alpha and beta) 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-kappaB/IKK-induced gene, suggesting that IKK-mediated NF-kappaB activation can coordinately illicit negative effects on STAT signaling.
Diseases/Pathways annotated by Medline MESH: Inflammation
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Text Mining Data
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Manually curated Databases
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Reactome Reaction:
CHUK
→
RNF135
(reaction)
-
Reactome Reaction:
IKBKG
→
RNF135
(reaction)
-
Reactome Reaction:
IKBKB
→
MAVS
(reaction)
-
Reactome Reaction:
IKBKB
→
IKBKG
(direct_complex)
-
Reactome Reaction:
IKBKG
→
TRIM25
(reaction)
-
Reactome Reaction:
CHUK
→
TRAF6
(reaction)
-
Reactome Reaction:
IKBKB
→
TRAF2
(reaction)
-
Reactome Reaction:
CHUK
→
MAP3K1
(reaction)
-
Reactome Reaction:
MAP3K1
→
IKBKG
(reaction)
-
Reactome Reaction:
IKBKG
→
IFIH1
(reaction)
-
Reactome Reaction:
IKBKG
→
TRAF6
(reaction)
-
Reactome Reaction:
IKBKB
→
DDX58
(reaction)
-
Reactome Reaction:
CHUK
→
IFIH1
(reaction)
-
Reactome Reaction:
CHUK
→
IKBKB
(direct_complex)
-
Reactome Reaction:
IKBKG
→
DDX58
(reaction)
-
Reactome Reaction:
CHUK
→
DDX58
(reaction)
-
Reactome Reaction:
IKBKB
→
MAP3K1
(reaction)
-
Reactome Reaction:
CHUK
→
TRIM25
(reaction)
-
Reactome Reaction:
IKBKB
→
TRAF6
(reaction)
-
Reactome Reaction:
IKBKB
→
IFIH1
(reaction)
-
Reactome Reaction:
CHUK
→
IKBKG
(direct_complex)
-
Reactome Reaction:
IKBKB
→
TRIM25
(reaction)
-
Reactome Reaction:
CHUK
→
MAVS
(reaction)
-
Reactome Reaction:
IKBKG
→
MAVS
(reaction)
-
Reactome Reaction:
CHUK
→
TRAF2
(reaction)
-
Reactome Reaction:
IKBKG
→
TRAF2
(reaction)
-
Reactome Reaction:
IKBKB
→
RNF135
(reaction)
In total, 27 gene pairs are associated to this article in curated databases