Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2007-3-19
pubmed:abstractText
Activation of NF-kappaB by the pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) requires the IkappaB kinase (IKK) complex, which contains two kinases named IKKalpha and IKKbeta and a critical regulatory subunit named NEMO. Although we have previously demonstrated that NEMO associates with both IKKs, genetic studies reveal that only its interaction with IKKbeta is required for TNF-induced NF-kappaB activation. To determine whether NEMO and IKKalpha can form a functional IKK complex capable of activating the classical NF-kappaB pathway in the absence of IKKbeta, we utilized a panel of mouse embryonic fibroblasts (MEFs) lacking each of the IKK complex subunits. This confirmed that TNF-induced IkappaBalpha degradation absolutely requires NEMO and IKKbeta. In contrast, we consistently observed intact IkappaBalpha degradation and NF-kappaB activation in response to IL-1 in two separate cell lines lacking IKKbeta. Furthermore, exogenously expressed, catalytically inactive IKKbeta blocked TNF- but not IL-1-induced IkappaBalpha degradation in wild-type MEFs, and reconstitution of IKKalpha/beta double knockout cells with IKKalpha rescued IL-1- but not TNF-induced NF-kappaB activation. Finally, we have shown that incubation of IKKbeta-deficient MEFs with a cell-permeable peptide that blocks the interaction of NEMO with the IKKs inhibits IL-1-induced NF-kappaB activation. Our results therefore demonstrate that NEMO and IKKalpha can form a functional IKK complex that activates the classical NF-kappaB pathway in response to IL-1 but not TNF. These findings further suggest NEMO differentially regulates the fidelity of the IKK subunits activated by distinct upstream signaling pathways.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10195896, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10195897, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10229185, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10346820, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10359587, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10766741, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10837071, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10898787, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10911991, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10911992, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-10968790, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-11287960, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-11418127, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-11520989, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-11713531, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-11733537, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-11801607, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12138192, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12192055, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12244103, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12352969, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12374738, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12387745, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12556537, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12709443, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12789342, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-12789343, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-14499113, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-14597638, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-14612578, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-14651848, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-15145317, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-15156202, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-15319427, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-15371334, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-15858576, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-16051172, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-16116086, http://linkedlifedata.com/resource/pubmed/commentcorrection/17244613-16410796
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
282
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
8724-33
pubmed:dateRevised
2011-9-26
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Interleukin-1-induced NF-kappaB activation is NEMO-dependent but does not require IKKbeta.
pubmed:affiliation
Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, PA 19104, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural