Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.10 (IKK)
4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas-associated death domain protein (FADD), caspase-8-related protein (Casper), and caspase-8 are components of the tumor necrosis factor receptor type 1 (TNF-R1) and Fas signaling complexes that are involved in TNF-R1- and Fas-induced apoptosis. Here we show that overexpression of FADD and Casper potently activates NF-kappaB. In the presence of caspase inhibitors, overexpression of caspase-8 also activates NF-kappaB. A caspase-inactive point mutant, caspase-8(C360S), activates NF-kappaB as potently as wild-type caspase-8, suggesting that caspase-8-induced apoptosis and NF-kappaB activation are uncoupled. NF-kappaB activation by FADD and Casper is inhibited by the caspase-specific inhibitors crmA and BD-fmk, suggesting that FADD- and Casper-induced NF-kappaB activation is mediated by caspase-8. FADD, Casper, and caspase-8-induced NF-kappaB activation are inhibited by dominant negative mutants of TRAF2, NIK, IkappaB kinase alpha, and IkappaB kinase beta. A dominant negative mutant of RIP inhibits FADD- and caspase-8-induced but not Casper-induced NF-kappaB activation. A mutant of Casper and the caspase-specific inhibitors crmA and BD-fmk partially inhibit TNF-R1-, TRADD, and TNF-induced NF-kappaB activation, suggesting that FADD, Casper, and caspase-8 function downstream of TRADD and contribute to TNF-R1-induced NF-kappaB activation. Moreover, activation of caspase-8 results in proteolytic processing of NIK, which is inhibited by crmA. When overexpressed, the processed fragments of NIK do not activate NF-kappaB, and the processed C-terminal fragment inhibits TNF-R1-induced NF-kappaB activation. These data indicate that FADD, Casper, and pro-caspase-8 are parts of the TNF-R1-induced NF-kappaB activation pathways, whereas activated caspase-8 can negatively regulate TNF-R1-induced NF-kappaB activation by proteolytically inactivating NIK.
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PMID:Activation of NF-kappaB by FADD, Casper, and caspase-8. 1075 78

Proteins possessing the caspase recruitment domain (CARD) motif have been implicated in pathways leading to activation of caspases or NF-kappaB in the context of apoptosis or inflammation, respectively. Here we report the identification of a novel protein, CARDINAL, that contains a CARD motif and also exhibits a high degree of homology to the C terminus of DEFCAP/NAC, a recently described member of the Apaf-1/Nod-1 family. In contrast with the majority of CARD proteins described to date, CARDINAL failed to promote apoptosis or NF-kappaB activation. Rather, CARDINAL potently suppressed NF-kappaB activation associated with overexpression of TRAIL-R1, TRAIL-R2, RIP, RICK, Bcl10, and TRADD, or through ligand-induced stimulation of the interleukin-1 or tumor necrosis factor receptors. Co-immunoprecipitation experiments revealed that CARDINAL interacts with the regulatory subunit of the IkappaB kinase (IKK) complex, IKKgamma (NEMO), providing a molecular basis for CARDINAL function. Thus, CARDINAL is a novel regulator of NF-kappaB activation in the context of pro-inflammatory signals.
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PMID:CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways. 1155 59

Tumor necrosis factor receptor 1 (TNFR1) can trigger distinct signaling pathways leading to either the activation of NF-kappaB transcription factors or apoptosis. NF-kappaB activation results in the expression of antiapoptotic genes that inhibit the apoptosis pathway that is activated in parallel. However, the molecular mechanism of this inhibition remains poorly characterized. We have isolated a Jurkat T-cell mutant that exhibits enhanced sensitivity to TNF-induced apoptosis as a result of a deficiency in I-kappaB kinase gamma (IKKgamma)/NEMO, an essential component of the IKK complex and NF-kappaB pathway. We show here that the zinc finger protein A20 is an NF-kappaB-inducible gene that can protect the IKKgamma-deficient cells from TNF-induced apoptosis by disrupting the recruitment of the death domain signaling molecules TRADD and RIP to the receptor signaling complex. Our study, together with reports on the role of other antiapoptotic proteins such as c-FLIP and c-IAP, suggests that, in order to ensure an effective shutdown of the apoptotic pathway, TNF induces multiple NF-kappaB-dependent genes that inhibit successive steps in the TNFR1 death signaling pathway.
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PMID:A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells. 1216 98

We describe the cloning and characterization of tumor necrosis factor receptor (TNF-R)-associated ubiquitous scaffolding and signaling protein (TRUSS), a novel TNF-R1-interacting protein of 90.7 kDa. TRUSS mRNA was ubiquitously expressed in mouse tissues but was enriched in heart, liver, and testis. Co-immunoprecipitation experiments showed that TRUSS was constitutively associated with unligated TNF-R1 and that the complex was relatively insensitive to stimulation with TNF-alpha. Deletion mutagenesis of TNF-R1 indicated that TRUSS interacts with both the membrane-proximal region and the death domain of TNF-R1. In addition, the N-terminal region of TRUSS (residues 1 to 440) contains sequences that permit association with the cytoplasmic domain of TNF-R1. Transient overexpression of TRUSS activated NF-kappaB and increased NF-kappaB activation in response to ligation of TNF-R1. In contrast, a COOH-terminal-deletion mutant of TRUSS (TRUSS(1-723)) was found to inhibit NF-kappaB activation by TNF-alpha. Co-precipitation and co-immunoprecipitation assays revealed that TRUSS can interact with TRADD, TRAF2, and components of the IKK complex. These findings suggest that TRUSS may serve as a scaffolding protein that interacts with TNF-R1 signaling proteins and may link TNF-R1 to the activation of IKK.
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PMID:TRUSS, a novel tumor necrosis factor receptor 1 scaffolding protein that mediates activation of the transcription factor NF-kappaB. 1458 90

Epstein-Barr virus latent membrane protein 1 (LMP1) activation of NF-kappaB is critical for Epstein-Barr virus-infected B lymphocyte survival. LMP1 activates the IkappaB kinase complex and NF-kappaB through two cytoplasmic signaling domains that engage tumor necrosis factor receptor-associated factor (TRAF)1/2/3/5 or TRADD and RIP. We now use cells lacking expression of TRAF2, TRAF5, TRAF6, IKKalpha, IKKbeta, IKKgamma, TAB2, IL-1 receptor-associated kinase (IRAK)1, or IRAK4 to assess their roles in LMP1-mediated NF-kappaB activation. LMP1-induced RelA nuclear translocation was similar in IKKalpha knockout (KO) and WT murine embryo fibroblasts (MEFs) but substantially deficient in IKKbeta KO MEFs. NF-kappaB-dependent promoter responses were also substantially deficient in IKKbeta KO MEFs but were hyperactive in IKKalpha KO MEFs. More surprisingly, NF-kappaB responses were near normal in TRAF2 and TRAF5 double-KO MEFs, IKKgamma KO MEFs, TAB2 KO MEFs, and IRAK4 KO MEFs but were highly deficient in TRAF6 KO MEFs and IRAK1 KO HEK293 cells. Consistent with the importance of TRAF6, LMP1-induced NF-kappaB activation in HEK293 cells was inhibited by expression of dominant-negative TAB2 and Ubc13 alleles. These data extend a role for IKKalpha in IKKbeta regulation, identify an unusual IKKbeta-dependent and IKKgamma-independent NF-kappaB activation, and indicate that IRAK1 and TRAF6 are essential for LMP1-induced NF-kappaB activation.
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PMID:Epstein-Barr virus latent membrane protein 1 activation of NF-kappaB through IRAK1 and TRAF6. 1467 2

Previously we have shown that ASK-interacting protein 1 (AIP1, also known as DAB2IP), a novel member of the Ras-GAP protein family, mediates TNF-induced activation of ASK1-JNK signaling pathway. However, the mechanism by which TNF signaling is coupled to AIP1 is not known. Here we show that AIP1 is localized on the plasma membrane in resting endothelial cells (EC) in a complex with TNFR1. TNF binding induces release of AIP1 from TNFR1, resulting in cytoplasmic translocation and concomitant formation of an intracellular signaling complex comprised of TRADD, RIP1, TRAF2, and AIPl. A proline-rich region (amino acids 796-807) is critical for maintaining AIP1 in a closed form, which associates with a region of TNFR1 distinct from the death domain, the site of TNFR1 association with TRADD. An AIP1 mutant with deletion of this proline-rich region constitutively binds to TRAF2 and ASK1. A PERIOD-like domain (amino acids 591-719) of AIP1 binds to the intact RING finger of TRAF2, and specifically enhances TRAF2-induced ASK1 activation. At the same time, the binding of AIP1 to TRAF2 inhibits TNF-induced IKK-NF-kappaB signaling. Taken together, our data suggest that AIP1 is a novel transducer in TNF-induced TRAF2-dependent activation of ASK1 that mediates a balance between JNK versus NF-kappaB signaling.
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PMID:AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-induced ASK1-JNK activation. 1531 Jul 55

Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes. Because activation of NF-kappaB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NF-kappaB activation. In the present study, we tested this hypothesis by investigating the effect of this steroid on the activation of NF-kappaB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NF-kappaB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1. NF-kappaB activation was not cell type-specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NF-kappaB activation expressed in most tumor cells. Through inhibition of IkappaB kinase activation, this steroid blocked IkappaBalpha phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65-mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti-apoptosis (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), proliferation (cyclin D1 and c-Myc), and metastasis (MMP-9, COX-2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Overall, our results indicate that guggulsterone suppresses NF-kappaB and NF-kappaB-regulated gene products, which may explain its anti-inflammatory activities.
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PMID:Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. 1532 87

Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB activation. However, the mechanism by which RIP mediates TNF-alpha-induced signal transduction is not fully understood. In this study, we reconstituted RIP-deficient Jurkat T cells with a fusion protein composed of full-length MEKK3 and the death domain of RIP (MEKK3-DD). In these cells, MEKK3-DD substitutes for RIP and directly associates with TRADD in TNF receptor complexes following TNF-alpha stimulation. We found that TNF-alpha-induced NF-kappaB activation was fully restored by MEKK3-DD in these cells. In contrast, expression of a fusion protein composed of NEMO, a component of the IkappaB kinase complex, and the death domain of RIP (NEMO-DD) cannot restore TNF-alpha-induced NF-kappaB activation in RIP-deficient cells. These results indicate that the role of RIP is to specifically recruit MEKK3 to the TNF-alpha receptor complex, whereas the forced recruitment of NEMO to the TNF-alpha receptor complex is insufficient for TNF-alpha-induced NF-kappaB activation. Although MEKK2 has a high degree of homology with MEKK3, MEKK2-DD, unlike MEKK3-DD, also fails to restore TNF-alpha-induced NF-kappaB activation in RIP-deficient cells, indicating that RIP-dependent recruitment of MEKK3 plays a specific role in TNF-alpha signaling.
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PMID:Restoration of NF-kappaB activation by tumor necrosis factor alpha receptor complex-targeted MEKK3 in receptor-interacting protein-deficient cells. 1557 79

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

Considering the potential role of interleukin-8 (IL-8) in inflammation, angiogenesis, tumorigenesis, and metastasis, we investigated the molecular mechanism involved in IL-8-mediated signaling. In this report we provide evidence that like TNF, an inducer of NF-kappaB and also a NF-kappaB-dependent gene product, IL-8 induces NF-kappaB in a unique pathway. IL-8 induces NF-kappaB activation in a dose-dependent manner in different cell types as detected by a DNA-protein binding assay. IL-8 induces NF-kappaB-dependent reporter gene expression as well as ICAM-1, VCAM-1, and Cox-2 expression. IL-8 also induces IkappaBalpha phosphorylation followed by degradation and p65 translocation. IL-8 induces c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase (MAPK) in a dose- and time-dependent manner. IL-8-induced NF-kappaB activation is for the most part unaltered when cells are transfected with dominant-negative TRADD, FADD, or TRAF2, but is inhibited with dominant-negative TRAF6-, NIK-, IKK-, or IkappaBalpha-transfected cells. The data suggest that IL-8-induced NF-kappaB activation proceeds through a TRAF2-independent but TRAF6-dependent pathway, followed by recruitment of IRAK and activation of IKK. IL-8-induced NF-kappaB activation is not observed in a cell-permeable peptide that has TRAF6 binding motif-treated cells or IRAK-deficient cells. IL-8-induced NF-kappaB activation proceeds mostly through interaction with TRAF6 and partially through the Rho-GTPase pathways. This is the first report that IL-8 induces NF-kappaB in a distinct pathway, and activation of NF-kappaB and its dependent genes may be one of the pathways of IL-8-induced inflammation and angiogenesis.
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PMID:Interleukin-8 induces nuclear transcription factor-kappaB through a TRAF6-dependent pathway. 1559 Oct 54


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