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)

The prostaglandin H synthases (PGHS) catalyze the conversion of arachidonic acid to prostaglandin H(2), the committed step in prostanoid synthesis. Two forms of PGHS exist, PGHS-1 (COX-1) and PGHS-2 (COX-2). The gene encoding the latter form is known to be inducible by a number of stimuli including several inflammatory mediators. Recent evidence indicates that the inducible cyclooxygenase may have both pro- and anti-inflammatory properties through the generation of different prostaglandins. Previous reports indicate that the transcription factor NF-kappaB can function upstream of COX-2 to control transcription of this gene and that the cyclopentenone prostaglandins can inhibit NF-kappaB activation via the inhibition of the IkappaB kinase. Thus, it is suggested that cyclopentenones feed back to inhibit continued nuclear accumulation of NF-kappaB. In this report we demonstrate COX-2 expression inhibits nuclear translocation of NF-kappaB, and we confirm that the cyclopentenone prostaglandins inhibit NF-kappaB. In addition, we show that prostaglandin E(2) and its analogs promote the inherent transcriptional activity of the p65/RelA subunit of NF-kappaB in a manner independent of induced nuclear accumulation. Consistent with this evidence, prostaglandin E(2) strongly synergizes with the inflammatory cytokine tumor necrosis factor-alpha to promote NF-kappaB-dependent transcription and gene expression. The data provide a molecular rationale to explain both the pro- and anti-inflammatory nature of COX-2.
 ...
PMID:Positive and negative regulation of NF-kappaB by COX-2: roles of different prostaglandins. 1150 75

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.
 ...
PMID:CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways. 1155 59

The Tax oncoprotein encoded by human T-cell leukemia virus induces both T-cell activation and apoptosis. The mechanism by which Tax induces apoptosis has remained unclear. Using genetically manipulated T-cell lines, we demonstrate that Tax-induced T-cell death is dependent on NF-kappaB signaling. Tax fails to induce apoptosis in T cells lacking IkappaB kinase gamma (IKKgamma), an essential component of the NF-kappaB signaling pathway. This defect was rescued when the mutant cells were reconstituted with exogenous IKKgamma. We further demonstrate that the Tax-induced T-cell death is mediated by TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL), because this event can be effectively inhibited by a TRAIL-blocking antibody. Consistent with this functional aspect, Tax stimulates the expression of TRAIL mRNA. Finally, we provide genetic evidence demonstrating that the NF-kappaB signaling pathway is essential for TRAIL gene induction by both Tax and T-cell activation signals. These studies reveal a novel function of the NF-kappaB signaling pathway and suggest a key mechanism by which Tax induces T-cell death.
 ...
PMID:NF-kappaB signaling pathway governs TRAIL gene expression and human T-cell leukemia virus-I Tax-induced T-cell death. 1155 9

Alcohol consumption and viral hepatitis infection synergistically accelerate liver injury, but the underlying mechanism is not fully understood. Here we have examined the effects of ethanol on hepatitis B protein X (HBX)- or hepatitis C core protein (HCV core protein)-mediated activation of NF-kappaB, a critical signal in hepatic injury, regeneration, and tumor transformation. Acute ethanol or acetaldehyde exposure potentiates HBX or HCV core protein activation of NF-kappaB in primary mouse hepatocytes. Such potentiation can be abolished by blocking ethanol metabolism or overexpression of dominant negative NF-kappaB-inducing kinase (NIK), IkappaB kinase (IKK), or IkappaB. Moreover, pertussis toxin attenuates NF-kappaB activation induced by acetaldehyde but not by HBX or HCV core protein, whereas HBX or HCV core protein-mediated activation of NF-kappaB is abolished completely in tumor necrosis factor a receptor 1 (TNFR1) (-/-) hepatocytes. Finally, chronic ethanol consumption induces hepatic CYP2E1 protein expression and potentiates HBX or HCV core protein activation of NF-kappaB in the liver. These findings suggest that ethanol activates hepatic NF-kappaB via its metabolism and that HBX or HCV core protein activates hepatic NF-kappaB via TNFR1. With the essential role of TNFR1 in alcoholic liver injury, targeting TNFR1 by hepatitis viral proteins could contribute to cooperative effects of alcohol consumption and viral hepatitis on liver disease.
 ...
PMID:Additive activation of hepatic NF-kappaB by ethanol and hepatitis B protein X (HBX) or HCV core protein: involvement of TNF-alpha receptor 1-independent and -dependent mechanisms. 1164 Dec 61

To assess directly the role of protein kinase C (PKC)epsilon in the immune system, we generated mice that carried a homozygous disruption of the PKCepsilon locus. PKCepsilon(-/-) animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCepsilon(-/-) animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)gamma, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. Further analysis revealed that LPS-stimulated macrophages from PKCepsilon(-/-) mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IkappaB kinase, a reduction in IkappaB degradation, and a decrease in nuclear factor (NF)kappaB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCepsilon(-/-) mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCepsilon is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCepsilon, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality.
 ...
PMID:Protein kinase Cepsilon is required for macrophage activation and defense against bacterial infection. 1169 89

Because the transcription factor, nuclear factor (NF)-kappaB, plays a key role in cellular inflammatory and immune responses, components of the NF-kappaB-activating signaling pathways are frequently used as targets for anti-inflammatory agents. This study shows that 2-(3',4'-dihydroxyphenyl)-5-hydroxybenzo[b]furan (GF-015) and 2,3-di(3',4'-dihydroxy-transstyryl) pyridine (GF-90), two conjugated polyhydroxybenzene derivatives, inhibited a common step in NF-kappaB activation in human NCI-H292 epithelial cells by preventing tumor necrosis factor (TNF)-alpha- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IkappaB kinase (IKK) complex activation. Both agents inhibited the TNF-alpha- or TPA-induced expression of cyclooxygenase (COX)-2 mRNA and protein, COX-2 promoter activity, and prostaglandin E2 (PGE2) production. Overexpression of wild-type NF-kappaB-inducing kinase, IKKalpha, and IKKbeta led, respectively, to 3.5-, 2.6-, and 2.6-fold increases in COX-2 promoter activity, and these effects were inhibited by both compounds. GF-015 and GF-90 also prevented the TNF-alpha- and TPA-induced activation of IKK and NF-kappaB-specific DNA-protein binding activity. These results suggest that the inhibitory effect of GF-015 and GF-90 on TNF-alpha-induced COX-2 protein expression was caused by suppression of IKK activity and NF-kappaB activation in the COX-2 promoter, resulting in attenuation of COX-2 gene expression and PGE2 production.
 ...
PMID:Conjugated polyhydroxybenzene derivatives block tumor necrosis factor-alpha-mediated nuclear factor-kappaB activation and cyclooxygenase-2 gene transcription by targeting IkappaB kinase activity. 1172 53

Phosphatidylinositol 3'-kinase (PI3K) and the serine/threonine kinase AKT have critical roles in phosphorylating and transactivating the p65 subunit of nuclear factor kappaB (NF-kappaB) in response to the pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF). Mouse embryo fibroblasts (MEFs) lacking either the alpha or beta subunit of IkappaB kinase (IKK) were deficient in NF-kappaB-dependent transcription following treatment with IL-1 or TNF. However, in contrast to IKKbeta-null MEFs, IKKalpha-null MEFs were not substantially defective in the cytokine-stimulated degradation of Ikappabetaalpha or in the nuclear translocation of NF-kappaB. The IKK complexes from IKKalpha- or IKKbeta-null MEFs were both deficient in PI3K-mediated phosphorylation of the transactivation domain of the p65 subunit of NF-kappaB in response to IL-1 and TNF, and constitutively activated forms of PI3K or AKT did not potentiate cytokine-stimulated activation of NF-kappaB in either IKKalpha- or IKKbeta-null MEFs. Collectively, these data indicate that, in contrast to IKKbeta, which is required for both NF-kappaB liberation and p65 phosphorylation, IKKalpha is required solely for the cytokine-induced phosphorylation and activation of the p65 subunit of NF-kappaB that are mediated by the PI3K/AKT pathway.
 ...
PMID:Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. 1173 37

The transcription factor NF-kappaB is essential for survival of many cell types. However, cells can undergo apoptosis despite the concurrent NF-kappaB activation. It is unknown how the protection conveyed by NF-kappaB is overridden during apoptosis. We report here that IkappaB kinase (IKK) beta was specifically proteolyzed by Caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (TNF)-alpha-induced apoptosis. Proteolysis of IKKbeta eliminated its enzymatic activity, interfered with IKK activation, and promoted TNF-alpha killing. Point mutations that abrogate IKKbeta proteolysis generated a caspase-resistant IKKbeta mutant, which suppressed TNF-alpha-induced apoptosis. Thus, our study demonstrates that TNF-alpha-induced apoptosis requires caspase-mediated proteolysis of IKKbeta.
 ...
PMID:Blocking caspase-3-mediated proteolysis of IKKbeta suppresses TNF-alpha-induced apoptosis. 1174 36

The capillary networks of solid tumors are more permeable and less well organized than those of normal tissue. This review explores the hypothesis that these differences might be exploited as a selective antitumor strategy. Both high and low molecular weight compounds have been found to induce cytokines such as tumor necrosis factor (TNF) and to inhibit tumor blood flow in experimental tumors, with consequent induction of necrosis. Flavone acetic acid (FAA) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) are of particular interest. Accumulating evidence implicates the enzyme IkappaB kinase, which leads to the activation of the transcription factor, NFkappaB, as a target for these drugs. The downstream effects of FAA and DMXAA on the tumor microcirculation are complex, involving both direct and indirect effects on vascular endothelial cells. Induced changes in the shape and organization of vascular endothelial cells may lead to the activation of blood platelets and the release of 5-HT. Cytokines, 5-HT and nitric oxide (NO) released in response to FAA and DMXAA may induce a sustained increase in the permeability of tumor vascular cells, leading to cessation of blood flow and induction of tumor necrosis. Exploitation of this principle to clinical anticancer therapy represents an important challenge for the future.
 ...
PMID:Small-molecule cytokine inducers causing tumor necrosis. 1175

PTEN is a lipid phosphatase responsible for down-regulating the phosphoinositide 3-kinase product phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate is involved in the activation of the anti-apoptotic effector target, Akt. Although the Akt pathway has been implicated in regulating NF-kappaB activity, it is controversial as to whether Akt activates NF-kappaB predominantly through mechanisms that regulate nuclear translocation or transactivation potential. In this report, we utilized PTEN as a natural biological inhibitor of Akt activity to study the effects on tumor necrosis factor (TNF)-induced activation of NF-kappaB. We found that the reintroduction of PTEN into prostate cells inhibited TNF-stimulated NF-kappaB transcriptional activity. PTEN failed to block TNF-induced IKK activation, IkappaBalpha degradation, p105 processing, p65 (RelA) nuclear translocation, and DNA binding of NF-kappaB. However, PTEN inhibited NF-kappaB-dependent transcription by blocking the ability of TNF to stimulate the transactivation domain of the p65 subunit. PTEN also inhibited the transactivation potential of the cyclic AMP-response element-binding protein, but this was not observed for c-Jun. The transactivation potential of p65 following TNF stimulation could be rescued from PTEN-dependent repression by re-introducing expression constructs encoding activated forms of phosphoinositide 3-kinase, Akt, or Akt and IKK. The ability of PTEN to inhibit the TNF-induced transactivation function of p65 is important, because expression of PTEN blocked TNF-stimulated NF-kappaB-dependent gene expression, thus sensitizing cells to TNF-induced apoptosis. Maintenance of the PTEN tumor suppressor protein is therefore required to modulate Akt activity and to concomitantly control the transcriptional activity of the anti-apoptotic transcription factor NF-kappaB.
 ...
PMID:PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit. 1179 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>