Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene induction by tumor necrosis factor-alpha (TNFalpha) or interleukin-1beta (IL-1beta) is mediated in part by activation of the transcription factor nuclear factor kappaB (NF-kappaB), and requires signal adaptor molecules such as TNF receptor-associated factor (TRAFs). The latter interact with the NF-kappaB-inducing kinase (NIK), which is believed to be part of the IkappaB kinase complex. Although the precise mechanism is to be elucidated, it is well-known that antioxidant treatments inhibit the inflammatory cytokine-induced NF-kappaB activation. Thioredoxin (TRX) is a 12-kDa endogenous protein that regulates various cellular functions by modulating the redox state of proteins, overexpression of this molecule inhibits NF-kappaB activation. To elucidate the roles of TRX in the signal transduction of the cytokines, we investigated the effects of TRX on NF-kappaB activation induced by cytokine treatment or by overexpression of the signaling molecules. Our data show that TRX treatment inhibits NF-kappaB-dependent transcription at the level of downstream of TRAFs and upstream of NIK: TRX inhibited TRAF2-, TRAF5-, and TRAF6-induced NF-kappaB activation but does not inhibit NIK-, IKKalpha-, and MEKK-induced activation. In addition, we show that TRX inhibits NF-kappaB activation in a manner different from that for SAPK (stress activated protein kinase) inhibition.
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PMID:Thioredoxin inhibits tumor necrosis factor- or interleukin-1-induced NF-kappaB activation at a level upstream of NF-kappaB-inducing kinase. 1123 4

Increasing evidence places the epithelial cell at the centre of inflammatory processes in human airways. Crucial to this function and the maintenance of inflammatory homoeostasis is a balanced oxidant-antioxidant status in the airway, in part controlled by thioredoxin and thioredoxin reductase, which together can alter the NF-kappaB pathway. PMX464, a thiol-reactive quinol and putative thioredoxin inhibitor, has been investigated in endothelial cells, fibroblasts and colorectal cancer cell lines but in the present issue of the BJP, these investigations were extended to A549 airway epithelial cells. Thioredoxin inhibition was confirmed as was NF-kappaB and IKK suppression but siRNA knockdown of thioredoxin did not alter inflammatory marker expression or activity, suggesting that PMX464 has targets other than thioredoxin. Future consolidation of this evidence will involve concomitant knockdown of thioredoxin reductase, the use of primary airway epithelial cells and, potentially, the employment of three-dimensional (3D) culture systems for both A549 and primary cells.
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PMID:Targeting airway inflammation: PMX464 and the epithelial bulls eye. 1858 24

Thioredoxin-related protein 14 (TRP14) is a novel 14-kDa disulfide reductase with two active site Cys residues in its WCPDC motif, which is comparable to the WCGPC motif of thioredoxin (Trx). Although the active site cysteine of TRP14 is sufficiently nucleophilic, its redox potential is similar to that of Trx1, and it receives the electrons from Trx reductase 1 (TrxR1) as does Trx1. TRP14 does not target the same substrate as Trx1, suggesting that TRP14 and Trx1 might act on distinct substrate proteins. Comparison of the crystal structures of TRP14 and Trx1 reveals distinct surface structures in the vicinity of their active sites. Both TRP14 and Trx1 inhibit the pathways of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinases, and apoptosis in cells stimulated with tumor necrosis factor-alpha (TNF-alpha), but they appear to do so by acting on target proteins, some of which do not overlap. TRP14 inhibits the TNF-alpha-induced NF-kappaB activation to a greater extent than Trx1. The dynein light chain LC8 was identified as a new target of disulfide reductase activity of TRP14, and LC8 was shown to bind IkappaBalpha in a redox-dependent manner, thereby preventing its phosphorylation by IkappaB kinase. These findings elucidate the molecular mechanism by which NF-kappaB activation is regulated through TRP14.
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PMID:Thioredoxin-related protein 14, a new member of the thioredoxin family with disulfide reductase activity: implication in the redox regulation of TNF-alpha signaling. 1962 32