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)

When expressed in heterologous cells, the viral FLIP protein (vFLIP) of Kaposi's-sarcoma-associated herpesvirus (KSHV) has been reported both to block Fas-mediated apoptosis and to activate the NF-kappaB activation pathway by interaction with IkappaB kinase (IKK). In a yeast-two-hybrid screen, we identified IKKgamma as an interacting partner of vFLIP. We expressed fragments of IKKgamma in mammalian cells and bacteria, and identified the central CCR3/4 (amino acids 150-272) as the vFLIP binding region. To investigate the proteins interacting with vFLIP in a KSHV-infected primary effusion lymphoma (PEL) cell line, we immunoprecipitated vFLIP and identified four associated proteins by mass spectrometry: IKK components IKKalpha, beta and gamma, and the chaperone, Hsp90. Using gel filtration chromatography, we demonstrated that a single population of vFLIP in the cytoplasm of PEL cells co-eluted and co-precipitated with an activated IKK complex. An inhibitor of Hsp90, geldanamycin, inhibited IKK's kinase activity induced by vFLIP and killed PEL cells, suggesting that vFLIP activation of IKK contributes to PEL cell survival.
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PMID:KSHV vFLIP binds to IKK-gamma to activate IKK. 1289 Jul 56

Fas-associated factor-1 (FAF1) is a Fas-binding pro-apoptotic protein that is a component of the death-inducing signaling complex in Fas-mediated apoptosis. Here, we show that FAF1 is involved in negative regulation of NF-kappaB activation. Overexpression of FAF1 decreased the basal level of NF-kappaB activity in 293 cells. NF-kappaB activation induced by tumor necrosis factor (TNF)-alpha, interleukin-1beta, and lipopolysaccharide was also inhibited by FAF1 overexpression. Moreover, FAF1 suppressed NF-kappaB activation induced by transducers of diverse NF-kappaB-activating signals such as TNF receptor-associated factor-2 and -6, MEKK1, and IkappaB kinase-beta as well as NF-kappaB p65, one of the end point molecules in the NF-kappaB activation pathway, suggesting that NF-kappaB p65 might be a target molecule upon which FAF1 acts. Subsequent study disclosed that FAF1 physically interacts with NF-kappaB p65 and that the binding domain of FAF1 is the death effector domain (DED)-interacting domain (amino acids 181-381), where DEDs of the Fas-associated death domain protein and caspase-8 interact. The NF-kappaB activity-modulating potential of FAF1 was also mapped to the DED-interacting domain. Finally, overexpression of FAF1 prevented translocation of NF-kappaB p65 into the nucleus and decreased its DNA-binding activity upon TNFalpha treatment. This study presents a novel function of FAF1, in addition to the previously known function as a component of the Fas death-inducing signaling complex, i.e. NF-kappaB activity suppressor by cytoplasmic retention of NF-kappaB p65 via physical interaction.
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PMID:Fas-associated factor-1 inhibits nuclear factor-kappaB (NF-kappaB) activity by interfering with nuclear translocation of the RelA (p65) subunit of NF-kappaB. 1460 Jan 57

We recently demonstrated that heme oxygenase (HO)-1 is constitutively expressed in human CD4+CD25+ regulatory T cells and induced by anti-CD28 or anti-CD28/anti-CD3 stimulation, even in CD4+CD25- responder T cells. To study the effects of HO-1 expression on lymphocyte survival, we transfected the HO-1 gene or induced the gene to express HO-1 protein with cobalt protoporphyrin (CoPP) in Jurkat T cells. Consistently, anti-Fas antibody triggered apoptotic cell death in wild-type Jurkat T cells. Surprisingly, however, HO-1-overexpressing Jurkat T cells showed strong resistance to Fas-mediated apoptosis. In contrast, abrogation of HO-1 expression by antisense oligomer against HO-1 gene from CoPP-treated cells or depletion of iron by desferrioxamine from HO-1-transfected cells abolished the resistance. In addition, exogenously added iron rendered wild-type Jurkat T cells resistant. The resistance involved IkappaB kinase (IKK) activation via iron-induced reactive oxygen species formation, NF-kappaB activation by activated IKK, and c-FLIP expression by activated NF-kappaB. Primary CD4+ T cells induced by CoPP to express HO-1 also showed more resistance to Fas-mediated apoptosis than untreated cells. Our findings suggest that HO-1 plays a critical and nonredundant role in Fas-mediated activation-induced cell death of T lymphocytes.
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PMID:Overexpression of heme oxygenase (HO)-1 renders Jurkat T cells resistant to fas-mediated apoptosis: involvement of iron released by HO-1. 1501 71

The tumor necrosis factor (TNF) ligand-receptor system plays an essential role in apoptosis that contributes to secondary damage after traumatic brain injury (TBI). TNF also stimulates inflammation by activation of gene transcription through the IkappaB kinase (IKK)/NF-kappaB and JNK (c-Jun N-terminal protein kinase)/AP-1 signaling cascades. The mechanism by which TNF signals between cell death and survival and the role of receptor localization in the activation of downstream signaling events are not fully understood. Here, TNF receptor 1 (TNFR1) signaling complexes in lipid rafts were investigated in the cerebral cortex of adult male Sprague Dawley rats subjected to moderate (1.8-2.2 atmospheres) fluid-percussion TBI and naive controls. In the normal rat cortex, a portion of TNFR1 was present in lipid raft microdomains, where it associated with the adaptor proteins TRADD (TNF receptor-associated death domain), TNF receptor-associated factor-2 (TRAF-2), the Ser/Thr kinase RIP (receptor-interacting protein), TRAF1, and cIAP-1 (cellular inhibitor of apoptosis protein-1), forming a survival signaling complex. Moderate TBI resulted in rapid recruitment of TNFR1, but not TNFR2 or Fas, to lipid rafts and induced alterations in the composition of signaling intermediates. TNFR1 and TRAF1 were polyubiquitinated in lipid rafts after TBI. Subsequently, the signaling complex contained activated caspase-8, thus initiating apoptosis. In addition, TBI caused a transient activation of NF-kappaB, but receptor signaling interacting proteins IKKalpha and IKKbeta were not detected in raft-containing fractions. Thus, redistribution of TNFR1 in lipid rafts and nonraft regions of the plasma membrane may regulate the diversity of signaling responses initiated by these receptors in the normal brain and after TBI.
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PMID:Tumor necrosis factor receptor 1 and its signaling intermediates are recruited to lipid rafts in the traumatized brain. 1559 Sep 16

Fas-associated death-domain protein (FADD) is an adaptor molecule that links death receptors to caspase-8 in many cell types including cardiomyocytes (CMs). Although FADD has previously been reported to play an important role in CM apoptosis, the effect of FADD on CM NF-kappaB signaling, which is a proinflammatory pathway, has not been delineated. To investigate the role of FADD in CM NF-kappaB activation, we utilized adenoviral gene transfer of wild-type FADD and a truncation mutant that lacks the death-effector domain (FADD-DED) in rat CMs in vitro TNF-alpha activated NF-kappaB in CMs as demonstrated by phosphorylation and degradation of inhibitory-kappaB (IkappaB)-alpha-enhanced nuclear p65 and NF-kappaB DNA-binding activity as well as increased mRNA for the NF-kappaB-dependent adhesion molecule VCAM-1 (19 +/- 4.1-fold) as measured by quantitative RT-PCR. Gene transfer of FADD inhibited TNF-alpha-induced IkappaB-alpha phosphorylation, decreased p65 nuclear translocation and NF-kappaB DNA-binding activity, and reduced VCAM-1 transcript levels by 53-65%. Interestingly, FADD-DED exhibited a similar but weaker inhibitory effect on NF-kappaB activation. The effects of FADD on NF-kappaB were cell-type specific. FADD expression also inhibited TNF-alpha-mediated NF-kappaB activation in human endothelial cells but not in rat pulmonary artery smooth muscle cells. In contrast, FADD expression actually activated NF-kappaB in human embryonic kidney (HEK)-293 cells. In CMs, FADD inhibited NF-kappaB activation as well as phosphorylation of IkappaB-alpha and IkappaB kinase (IKK)-beta in response to cytokine stimulation or expression of the upstream kinases NF-kappaB-inducing kinase and IKK-beta. These data demonstrate that FADD inhibits NF-kappaB activation in CMs, and this inhibition likely occurs at the level of phosphorylation and activation of IKK-beta.
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PMID:Fas-associated death-domain protein inhibits TNF-alpha mediated NF-kappaB activation in cardiomyocytes. 1598 38

Restimulation of the T-cell receptor (TCR) in activated T cells induces CD95 (Fas/Apo-1)-mediated activation-induced cell death (AICD). The TCR-proximal mechanisms leading to AICD are elusive. Here we characterize hematopoietic progenitor kinase 1 (HPK1) as a differentially regulated TCR-proximal signaling protein involved in AICD of primary T cells. We show that HPK1 is a functional component of the endogenous IkappaB kinase (IKK) complex and is crucial for TCR-mediated NFkappaB activation. While full-length HPK1 enhances IKKbeta phosphorylation, siRNA-mediated knockdown of HPK1 blunts TCR-mediated NFkappaB activation and increases cell death. We also demonstrate proteolytic processing of HPK1 into HPK1-C, specifically in AICD-sensitive primary T cells. The cleavage product HPK1-C sequesters the inactive IKK complex and suppresses NFkappaB upon TCR restimulation by binding to IKKalpha and IKKbeta. T cells of HPK1-C transgenic mice are sensitized towards TCR-mediated AICD. Consequently, preventing HPK1-C generation in primary T cells by siRNA-mediated knockdown results in decreased AICD. Thus, these results show a novel mechanism of sensitization of T lymphocytes towards AICD by suppression of NFkappaB, and propose that HPK1 is a life/death switch in T lymphocytes.
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PMID:Activation or suppression of NFkappaB by HPK1 determines sensitivity to activation-induced cell death. 1634 Oct 93

Members of the IFN regulatory factor (IRF) family regulate gene expression critical to immune response, hemopoiesis, and proliferation. Although related by homology at their N-terminal DNA-binding domain, they display individual functional properties. The distinct properties result from differences in regulated expression, response to activating signals, and interaction with DNA regulatory elements. IRF-3 is expressed ubiquitously and is activated by serine phosphorylation in response to viral infection or TLR signaling. Evidence indicates that the kinases TANK-binding kinase 1 and inhibitor of NF-kappaB kinase-epsilon specifically phosphorylate and thereby activate IRF-3. We evaluated the contribution of another member of the IRF family, IRF-5, during viral infection since prior studies provided varied results. Analysis of phosphorylation, nuclear translocation, dimerization, binding to CREB-binding protein, recognition of DNA, and induction of gene expression were used comparatively with IRF-3 as a measure of IRF-5 activation. IRF-5 was not activated by viral infection; however, expression of TANK-binding kinase 1 or inhibitor of NF-kappaB kinase-epsilon did provide clear activation of IRF-5. IRF-5 is therefore distinct in its activation profile from IRF-3. However, similar to the biological effects of IRF-3 activation, a constitutively active mutation of IRF-5 promoted apoptosis. The apoptosis was inhibited by expression of Bcl-x(L) but not a dominant-negative mutation of the Fas-associated death domain. These studies support the distinct activation profiles of IRF-3 in comparison to IRF-5, but reveal a potential shared biological effect.
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PMID:Differential activation of IFN regulatory factor (IRF)-3 and IRF-5 transcription factors during viral infection. 1675 92

The CD95 (Apo1/Fas)/CD95 ligand system plays pivotal roles in various aspects of immune regulation and function by triggering apoptosis. Besides the apoptosis signaling pathway, CD95 ligation also induces the activation of NF-kappaB. Previous studies suggest that IkappaB kinase (IKK) may be a key player in cell survival by mediating NF-kappaB activation. However, the roles of IKK in CD95 ligation-mediated apoptosis and NF-kappaB activation are still not clear. In this report, we show that expression of the caspase-resistant uncleavable IKKbeta (UCIKKbeta) mutant suppressed CD95 ligation-mediated cell death in HeLa cells. Furthermore, CD95 ligation induced much more cell death in IKKbeta-/- murine embryonic fibroblasts (MEFs) than in wild type MEFs, despite that IKK was only marginally activated upon CD95 ligation. Pretreatment of HeLa cells with a specific IKK inhibitor NEMO-binding domain (NBD) peptide blocked CD95 ligation-induced NF-kappaB transcriptional activity. And UCIKKbeta enhanced the basal NF-kappaB activity, and consequently led to higher NF-kappaB activity upon CD95 ligation in HeLa cells. Therefore, IKK antagonizes CD95 ligation-mediated apoptosis by regulating NF-kappaB activity.
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PMID:IKK antagonizes CD95 ligation-mediated apoptosis by regulating NF-kappaB activity. 1711 53

This study presents a molecular inhibitory mechanism by Fas-associated factor 1 (FAF1) on IkappaB kinase (IKK) activation, where divergent NF-kappaB-activating stimuli converge. FAF1 interacts with IKKbeta in response to proinflammatory stimuli (such as tumor necrosis factor-alpha, interleukin-1beta, and lipopolysaccharide) and suppresses IKK activation. Interaction of the leucine-zipper domain of IKKbeta with FAF1 affected the IKK heterocomplex (IKKalpha/beta) and homocomplex (IKKalpha/alpha, IKKbeta/beta) formations and attenuated IKKgamma recruitment to IKKbeta. Overexpression of FAF1 reduced the level of IKKbeta activity, whereas FAF1 depletion increased the activity. These results indicate that FAF1 inhibits IKK activation and its downstream signaling by interrupting the IKK complex assembly through physical interaction with IKKbeta. Taken together, FAF1 robustly suppresses NF-kappaB activation through the inhibition of IKK activation in combination with previously reported cytoplasmic retention of NF-kappaB p65 (Park, M. Y., Jang, H. D., Lee, S. Y., Lee, K. J., and Kim, E. (2004) J. Biol. Chem. 279, 2544-2549). Such redundant suppression would prevent inadvertent activation of the NF-kappaB pathway.
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PMID:FAF1 suppresses IkappaB kinase (IKK) activation by disrupting the IKK complex assembly. 1768 21

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


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