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)

Activation of transcription factor NF-kappaB, the major regulator of the inflammatory response, depends on the inhibitor of NF-kappaB kinase (IKK) complex, which is composed of 2 catalytic subunits, IKK1 and IKK2 (also known as IKKalpha and IKKbeta), and a regulatory subunit, IKKgamma (also known as NEMO). In this issue of the JCI, Mourkioti et al. show that muscle-specific disruption in mice of the gene encoding IKK2 prevents NF-kappaB activation in response to denervation or toxin-induced injury (see the related article beginning on page 2945). Importantly, this genetic manipulation prevents muscle wasting, thereby providing strong evidence in support of a major pathogenic role for inflammation in a variety of muscular dystrophies characterized by progressive muscle fiber degeneration.
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PMID:Role for IKK2 in muscle: waste not, want not. 1708 Jan 95

Deregulation of intestinal immune responses seems to have a principal function in the pathogenesis of inflammatory bowel disease. The gut epithelium is critically involved in the maintenance of intestinal immune homeostasis-acting as a physical barrier separating luminal bacteria and immune cells, and also expressing antimicrobial peptides. However, the molecular mechanisms that control this function of gut epithelial cells are poorly understood. Here we show that the transcription factor NF-kappaB, a master regulator of pro-inflammatory responses, functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial-cell-specific inhibition of NF-kappaB through conditional ablation of NEMO (also called IkappaB kinase-gamma (IKKgamma)) or both IKK1 (IKKalpha) and IKK2 (IKKbeta)-IKK subunits essential for NF-kappaB activation-spontaneously caused severe chronic intestinal inflammation in mice. NF-kappaB deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 prevented the development of intestinal inflammation, demonstrating that Toll-like receptor activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to tumour-necrosis factor (TNF)-induced apoptosis, whereas TNF receptor-1 inactivation inhibited intestinal inflammation, demonstrating that TNF receptor-1 signalling is crucial for disease induction. These findings demonstrate that a primary NF-kappaB signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype. Our results identify NF-kappaB signalling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis, and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease.
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PMID:Epithelial NEMO links innate immunity to chronic intestinal inflammation. 1736 Nov 31

In response to DNA damage, p53 and its homolog p73 have a function antagonistic to NF-kappaB in deciding cell fate. Here, we show for the first time that p73, but not p53, is stabilized by physical interaction with nuclear IkappaB kinase (IKK)-alpha to enhance cisplatin (CDDP)-induced apoptosis. CDDP caused a significant increase in the amounts of nuclear IKK-alpha and p73alpha in human osteosarcoma-derived U2OS cells. Ectopic expression of IKK-alpha prolonged the half-life of p73 by inhibiting its ubiquitination and thereby enhancing its transactivation and pro-apoptotic activities. Consistent with these results, small interfering RNA-mediated knockdown of endogenous IKK-alpha inhibited the CDDP-mediated accumulation of p73alpha. The kinase-deficient mutant form of IKK-alpha interacted with p73alpha, but failed to stabilize it. Furthermore, CDDP-mediated accumulation of endogenous p73alpha was not detected in mouse embryonic fibroblasts (MEFs) prepared from IKK-alpha-deficient mice, and CDDP sensitivity was significantly decreased in IKK-alpha-deficient MEFs compared with wild-type MEFs. Thus, our results strongly suggest that the nuclear IKK-alpha-mediated accumulation of p73alpha is one of the novel molecular mechanisms to induce apoptotic cell death in response to CDDP, which may be particularly important in killing tumor cells with p53 mutation.
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PMID:Stabilization of p73 by nuclear IkappaB kinase-alpha mediates cisplatin-induced apoptosis. 1745 32

A potent and selective series of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta is described. The most potent compounds are 8h, 8r and 8v, with IKK-beta inhibitory potencies of pIC(50) 7.0, 6.8 and 6.8, respectively. The series has excellent selectivity, both within the IKK family over IKK-epsilon, and across a wide variety of kinase assays. The potency of 8h in the IKK-beta enzyme assay translates to significant cellular activity (pIC(50) 5.7-6.1) in assays of functional and mechanistic relevance.
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PMID:The discovery of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta kinases. 1750 44

Constitutive activation of the NF-kappaB pathway by the Tax oncoprotein plays a crucial role in the proliferation and transformation of HTLV-I infected T lymphocytes. We have previously shown that Tax ubiquitylation on C-terminal lysines is critical for binding of Tax to IkappaB kinase (IKK) and its subsequent activation. Here, we report that ubiquitylated Tax is not associated with active cytosolic IKK subunits, but binds endogenous IKK-alpha, -beta, -gamma, targeting them to the centrosome. K63-ubiquitylated Tax colocalizes at the centrosome with IKK-gamma, while K48-ubiquitylated Tax is stabilized upon proteasome inhibition. Altogether, these results support a model in which K63-ubiquitylated Tax activates IKK in a centrosome-associated signalosome, leading to the production of Tax-free active cytoplasmic IKK. These observations highlight an unsuspected link between Tax-induced IKK activation and the centrosome.
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PMID:Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome. 1789 Nov 79

Apoptosis is mediated by cysteine-dependent, aspartate-directed proteases of the caspase family that proteolyse strategic intracellular substrates to induce cell suicide. We describe here that engagement of apoptotic processes by Fas triggering or by staurosporine stimulation leads to the caspase-dependent inactivation of the nuclear factor kappa B (NF-kappaB) pathway after cleavage of IKK1 (IkappaB kinase 1) and NEMO (NF-kappaB essential modulator), which are needed to transduce NF-kappaB activation signals. In this study, we have analyzed in more detail, the role of NEMO cleavage, as NEMO, but not IKK1, is important for the pro-survival actions of NF-kappaB. We demonstrate that NEMO is cleaved after Asp355 to remove the last 64 C-terminal amino acids. This short form was unable to rescue NF-kappaB activation by tumor necrosis factor-alpha (TNF-alpha) when transfected in NEMO-deficient cells. Consequently, inactivation of NEMO resulted in an inhibition of the expression of antiapoptotic NF-kappaB-target genes coding for caspase inhibitors (cIAP-1, cIAP-2) or adaptors of the TNF receptor family. NEMO-deficient Jurkat cells transiently expressing a non-cleavable mutant of NEMO were less sensitive to TNF-alpha-induced apoptosis. Therefore, downmodulation of NF-kappaB activation via the proteolytic cleavage of NEMO could represent an amplification loop for apoptosis.
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PMID:Inhibition of the NF-kappaB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-kappaB essential modulator NEMO. 1793 97

The severity of chronic obstructive pulmonary disease correlates with increased numbers of cytotoxic CD8(+) T lymphocytes in the lung parenchyma. CD8(+) T lymphocytes release IFN-gamma which stimulates airway epithelial cells to produce CXCR3 chemokines leading to further recruitment of CD8(+) T lymphocytes. To evaluate the signaling pathways involved in regulation of CXCR3 ligands, the human bronchial epithelial cell line BEAS-2B was stimulated with IFN-gamma and the release of the CXCR3 ligands was measured by ELISA. The release of CXCL9, CXCL10, and CXCL11 was inhibited by an IkappaB kinase 2 (IKK2) selective inhibitor 2-[(Aminocarbonyl)amino]-5-[4-fluorophenyl]-3-thiophenecarboxamide (TPCA-1) (EC(50) values were 0.50 +/- 0.03, 0.17 +/- 0.06, and 0.45 +/- 0.10 microM, respectively (n = 6)) and an IKK1/2 selective inhibitor 2-amino-6-(2'cyclopropylemethoxy-6'-hydroxy-phenyl)-4-piperidin-3-yl-pyridine-3-carbonitrile (EC(50) values 0.74 +/- 0.40, 0.27 +/- 0.06, and 0.88 +/- 0.29 microM, respectively (n = 6)). The glucocorticosteroid dexamethasone had no effect on CXCR3 ligand release. The release of CXCL10 was most sensitive to inhibition by IKK2 and a role for IKK2 in CXCL10 release was confirmed by overexpression of dominant-negative adenoviral constructs to IKK2 (68.2 +/- 8.3% n = 5), but not of IKK1. Neither phosphorylation of IkappaBalpha, translocation of p65 to the nucleus, or activation of a NF-kappaB-dependent reporter (Ad-NF-kappaB-luc) were detected following stimulation of BEAS-2B cells with IFN-gamma. These data suggest that IKK2 is also involved in the IFN-gamma-stimulated release of the CXCR3 ligands through a novel mechanism that is independent NF-kappaB.
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PMID:The role of IkappaB kinase 2, but not activation of NF-kappaB, in the release of CXCR3 ligands from IFN-gamma-stimulated human bronchial epithelial cells. 1794 99

The therapeutic effects of alpha-lipoic acid (alpha-LA) via NF-kappa B down regulation were demonstrated on joint inflammation and erosion in an animal model. In this study, we investigated how alpha-LA inhibits the pathway of NF-kappa B activation by TNF-alpha via the mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis (RA) fibroblast-like synovial cells (FLS). FLS were stimulated with TNF-alpha following pre-treatment with or without alpha-LA. Electrophoretic mobility shift assays (EMSA) revealed that TNF-alpha activates NF-kappa B in FLS. This was inhibited by alpha-LA at concentrations of 1 mM. TNF-alpha induced IKK mediated phosphorylation of GST-I kappa B and pre-treatment with alpha-LA inhibited this pathway. FLS constitutively express MEKK1, MEKK2, MEKK3, and TAK1 and that their levels are unaffected by TNF-alpha or alpha-LA. Immunoprecipitation using anti-MEKK1 antibody phosphorylated GST-I kappa B and pre-treating the cells with alpha-LA could abolish the reaction. FLS were immunoprecipitated using an antibody to MEKK1, and MKK4 was coprecipitated with MEKK1. In addition, immune complexes precipitated with anti-MKK4 antibody phosphorylated GST-I kappa B, and pre-treatment with alpha-LA inhibited the phosphorylation. Immunoprecipitation assay showed that MEKK1, MKK4, IKK-alpha, IKK-beta, I kappa B, and NF-kappa B comprised immunocomplex. It can be concluded that TNF-alpha activates NF-kappa B in FLS through MEKK1-MKK4-IKK signaling complex, and alpha-LA inhibits this signaling at the level of or upstream of IKK-alpha and IKK-beta.
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PMID:Alpha-lipoic acid inhibits TNF-alpha induced NF-kappa B activation through blocking of MEKK1-MKK4-IKK signaling cascades. 1818 52

Although probiotics have been reported to reduce the gastric inflammatory response to Helicobacter pylori infection, little information is available regarding the molecular mechanisms behind this reduction. This study investigates the role of conjugated linoleic acids (CLA) produced by probiotics in interactions of IkappaB kinase (IKK) and heat shock protein 90 (Hsp90) to activate the nuclear factor-kappaB (NF-kappaB) signaling pathway in human gastric epithelial cells infected with H. pylori. Conditioned medium (CM) containing Lactobacillus acidophilus-producing CLA significantly inhibited the activated NF-kappaB signals and the upregulated expression of interleukin-8 (IL-8) in MKN-45 cells infected with H. pylori. Pretreatment with CM with CLA attenuated the increased IKK activity induced by H. pylori. Transfection of siRNA for IKK-beta dramatically reduced H. pylori-induced IkappaBalpha phosphorylation, but siRNA for IKK-alpha had little effect on IkappaBalpha phosphorylation, although the siRNA for IKK-alpha significantly decreased IL-8 production. Furthermore, Hsp90 was associated with IKK-alpha and IKK-gamma in H. pylori-infected cells, and CM with CLA dissociated the complex between Hsp90 and IKK-gamma. These results suggest that CLA produced by probiotics has anti-inflammatory activity in gastric epithelial cells infected with H. pylori via dissociation of the IKK-gamma and Hsp90 complex.
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PMID:Conjugated linoleic acids produced by Lactobacillus dissociates IKK-gamma and Hsp90 complex in Helicobacter pylori-infected gastric epithelial cells. 1834 82

The IkappaB kinases (IKKs) IKK-alpha and IKK-beta, and the IKK-related kinases TBK1 and IKK-epsilon, have essential roles in innate immunity through signal-induced activation of NF-kappaB, IRF3 and IRF7, respectively. Although the signaling events within these pathways have been extensively studied, the mechanisms of IKK and IKK-related complex assembly and activation remain poorly defined. Recent data provide insight into the requirement for scaffold proteins in complex assembly; NF-kappaB essential modulator coordinates some IKK complexes, whereas TANK, NF-kappaB-activating kinase-associated protein 1 (NAP1) or similar to NAP1 TBK1 adaptor (SINTBAD) assemble TBK1 and IKK-epsilon complexes. The different scaffold proteins undergo similar post-translational modifications, including phosphorylation and non-degradative polyubiquitylation. Moreover, increasing evidence indicates that distinct scaffold proteins assemble IKK, and potentially TBK1 and IKK-epsilon subcomplexes, in a stimulus-specific manner, which might be a mechanism to achieve specificity.
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PMID:Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated? 1835 49


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