Linked Life Data

16286467

Source:http://linkedlifedata.com/resource/pubmed/id/16286467

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2006-1-17
pubmed:abstractText
Reactive oxygen species (ROS) have been demonstrated to act as second messengers in a number of signal transduction pathways, including NFkappaB. However, the mechanism(s) by which ROS regulate NFkappaB remain unclear and controversial. In the present report, we describe a mechanism whereby interleukin-1beta (IL-1beta) stimulation of NFkappaB is partially regulated by H2O2-mediated activation of NIK and subsequent NIK-mediated phosphorylation of IKKalpha. IL-1beta induced H2O2 production in MCF-7 cells and clearance of this ROS through the expression of GPx-1 reduced NFkappaB transcriptional activation by inhibiting NIK-mediated phosphorylation of IKKalpha. Although IKKalpha and IKKbeta were both involved in IL-1beta-mediated activation of NFkappaB, only the IKKalpha-dependent component was modulated by changes in H2O2 levels. Interestingly, in vitro reconstitution experiments demonstrated that NIK was activated by a very narrow range of H2O2 (1-10 microM), whereas higher concentrations (100 microM to 1 mM) inhibited NIK activity. Treatment of cells with the general Ser/Thr phosphatase inhibitor (okadaic acid) lead to activation of NFkappaB and enhanced NIK activity as a IKKalpha kinase, suggesting that ROS may directly regulate NIK through the inhibition of phosphatases. Recruitment of NIK to TRAF6 following IL-1beta stimulation was inhibited by H2O2 clearance and Rac1 siRNA, suggesting that Rac-dependent NADPH oxidase may be a source of ROS required for NIK activation. In summary, our studies have demonstrated that redox regulation of NIK by H2O2 is mechanistically important in IL-1beta induction of NFkappaB activation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
20
pubmed:volume
281
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1495-505
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Interleukin-1beta induction of NFkappaB is partially regulated by H2O2-mediated activation of NFkappaB-inducing kinase.
pubmed:affiliation
Department of Anatomy & Cell Biology, College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural