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)

Optimal T cell activation and interleukin-2 production requires a second signal in addition to antigen-mediated T cell receptor (TCR) signaling. The CD28 molecule has been demonstrated to act as an effective costimulatory molecule upon binding by B7.1 or B7.2 present on antigen-presenting cells. The CD28 signal acts in concert with the TCR signal to significantly augment activation of the NF-kappaB family of transcription factors. The interleukin-2 gene is regulated by NF-kappaB among other transcription factors, in part, via a CD28 responsive element (CD28RE) present in the IL-2 promoter. Enhanced activation of NF-kappaB by CD28 is mediated by rapid phosphorylation and proteasome-mediated degradation of the NF-kappaB inhibitory proteins IkappaB alpha and IkappaB beta, which allows for accelerated nuclear expression of the liberated NF-kappaB. Herein, we provide evidence that the catalytic activities of two recently identified IkappaB kinases, IKKalpha and IKKbeta, are significantly elevated when T cells are stimulated through CD28 in addition to mitogen treatment. Catalytically inactive forms of IKKs are able to block the in vivo phosphorylation of IkappaB alpha induced by mitogen and CD28. Furthermore, CD28-mediated reporter gene transactivation of the CD28RE/AP-1 composite element is consistently attenuated by the IKK mutants. These findings suggest that cellular signaling pathways initiated at the TCR and CD28 converge at or upstream of IKK, resulting in more robust kinase activity and enhanced and prolonged NF-kappaB activation.
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PMID:IkappaB kinases serve as a target of CD28 signaling. 973 79

Interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) stimulate transcription factors AP-1 and NF-kappaB through activation of the MAP kinases JNK and p38 and the IkappaB kinase (IKK), respectively. The TNF-alpha and IL-1 signals are transduced through TRAF2 and TRAF6, respectively. Overexpressed TRAF2 or TRAF6 activate JNK, p38, or IKK in the absence of extracellular stimulation. By replacing the carboxy-terminal TRAF domain of TRAF2 and TRAF6 with repeats of the immunophilin FKBP12, we demonstrate that their effector domains are composed of their amino-terminal Zn and RING fingers. Oligomerization of the TRAF2 effector domain results in specific binding to MEKK1, a protein kinase capable of JNK, p38, and IKK activation, and induction of TNF-alpha and IL-1 responsive genes. TNF-alpha also enhances the binding of native TRAF2 to MEKK1 and stimulates the kinase activity of the latter. Thus, TNF-alpha and IL-1 signaling is based on oligomerization of TRAF2 and TRAF6 leading to activation of effector kinases.
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PMID:Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. 1034 18

Influenza A viruses are capable of inducing the expression of a variety of cytokine and proapoptotic genes in infected cells. The promoter regions of most of these genes harbor binding sites for the transcription factor NF-kappaB which is an important mediator of immune and inflammatory responses. Our present study is based on an observation that influenza A virus infection of cells stimulates transcriptional activation of the HIV-1 long terminal repeat (LTR) which harbors two regulatory NF-kappaB elements, and is aimed at identifying the molecular mechanisms involved in this process. We found that the expression of influenza virus hemagglutinin (HA), matrix protein (M), and nucleoprotein (NP), as single factors is sufficient to transcriptionally activate the HIV-1 LTR. This process is mediated by oxidative radicals because treatment of cells with pyrrolidine dithiocarbamate, a scavenger of such radicals, abolished the transactivating ability. Expression of different influenza proteins induces activation of NF-kappaB-dependent gene expression but not transcriptional activation of an AP-1/Ets-dependent promoter, indicating a selectivity for NF-kappaB transactivation. Furthermore, influenza protein expression induces activation of IkappaB kinase (IKK). Accordingly coexpression of a catalytically inactive mutant of IKK abolishes influenza protein induced activation of NF-kappaB as well as HIV-1 LTR-dependent reporter gene expression, suggesting that IKK is an important intermediate within this signaling process. Taken together, our results show that various influenza virus proteins act as viral transactivators to modulate transcriptional activity of kappaB-element harboring promoters such as the HIV-LTR.
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PMID:Influenza virus-induced NF-kappaB-dependent gene expression is mediated by overexpression of viral proteins and involves oxidative radicals and activation of IkappaB kinase. 1072 60

Matrix metalloproteinases (MMPs) are thought to play crucial roles in tumor invasion and metastasis. Because we have shown that EBV latent membrane protein 1 (LMP1) enhances MMP-9 expression by activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 (T. Yoshizaki, et al., Proc. Natl. Acad. Sci. USA, 95: 3621-3626, 1998), we therefore tested whether up-regulation of MMP-9 by LMP1 could be correlated with enhanced invasiveness of tumor cells in vitro. Whether aspirin and sodium salicylate could reduce invasiveness and whether LMP1 could enhance MMP-9 expression in tumors grown in nude mice were also tested. C33A cells stably expressing LMP1 had increased expression of MMP-9 and showed greater invasion through reconstituted basement membrane compared with vector-transfected C33A cells (P < 0.02). Treatment with aspirin or sodium salicylate inhibited invasiveness of the LMP1-expressing C33A cells (P < 0.03) and suppressed both the LMP1-induced MMP-9 expression in zymographic analyses and LMP1-induced MMP-9 promoter activity in CAT reporter assays (P < 0.01). Endogenous MMP-2 levels were unaffected by either drug. Both drugs repressed the CAT activity of the truncated MMP-9 promoter construct, which only contained a binding site for AP-1, to the basal level (P < 0.05). Moreover, EMSA indicated that the effects of the salicylates were through the inhibition of not only NF-kappaB but also AP-1 binding activity. Inhibitory effect of salicylates could be reversed by p50/p65 subunits of NF-kappaB or c-Jun overexpression. The inhibitory effect of aspirin on NF-kappaB activity was attributable to the inhibition of IkappaB kinase activity. Finally, tumors derived from C33A cells stably expressing LMP1 grown in nude mice showed enhanced MMP-9 levels compared with tumors derived from vector-transfected C33A cells. This enhancement was inhibited by treatment of the mice with aspirin. These results suggest that aspirin may be able to suppress invasion and metastasis of EBV-associated tumors that express LMP1 by suppression of MMP-9.
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PMID:Aspirin inhibits tumor cell invasiveness induced by Epstein-Barr virus latent membrane protein 1 through suppression of matrix metalloproteinase-9 expression. 1081 Nov 39

Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-kappa B in these responses, we hypothesized that vesnarinone must modulate NF-kappa B activation. We investigated the effect of vesnarinone on NF-kappa B activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-kappa B in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of I kappa B alpha, an inhibitor of NF-kappa B. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-kappa B activation in a variety of cells. NF-kappa B-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-kappa B activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-kappa B-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-kappa B-inducing kinase sites by vesnarinone, thus suppressing NF-kappa B reporter gene expression. Vesnarinone also blocked NF-kappa B activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-kappa B and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone's ability to suppress inflammation, immunomodulation, and growth regulation.
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PMID:Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis. 1082 Feb 60

Stimulation of T cells by antigens or mitogens triggers multiple signaling pathways leading to activation of genes encoding interleukin-2 and other growth-regulatory cytokines. The same stimuli also activate the gene encoding an apoptosis-inducing molecule, Fas ligand (FasL), which contributes to activation-induced cell death. It has been proposed that the signaling pathways involved in cytokine gene induction also contribute to activation-induced FasL expression; however, genetic evidence for this proposal is lacking. In the present study, the role of the NF-kappaB signaling pathway in FasL gene expression was examined using a mutant T cell line deficient in an essential NF-kappaB signaling component, IkappaB kinase gamma. These mutant cells have a blockade in signal-induced activation of NF-kappaB but remained normal in the activation of NF-AT and AP-1 transcription factors. Interestingly, the NF-kappaB signaling defect has no effect on mitogen-stimulated FasL gene expression, although it completely blocks the interleukin-2 gene induction. We further demonstrate that NF-kappaB activation is required for protecting T cells from apoptosis induction by mitogens and an agonistic anti-Fas antibody. These genetic results suggest that the NF-kappaB signaling pathway is not required for activation-induced FasL expression but rather mediates cell growth and protection from activation-induced cell death.
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PMID:The NF-kappa B signaling pathway is not required for Fas ligand gene induction but mediates protection from activation-induced cell death. 1083 65

Use of an NF-kappaB-dependent selectable marker facilitated the isolation of a cell line containing a cDNA encoding Act1, an NF-kappaB activator. Act1 associates with and activates IkappaB kinase (IKK), leading to the liberation of NF-kappaB from its complex with IkappaB. Many signaling pathways that liberate NF-kappaB also activate activating transcription factor (ATF) and activator protein 1 (AP-1) through Jun kinase (JNK). Act1 also activates JNK, suggesting that it might be part of a multifunctional complex involved in the activation of both NF-kappaB and JNK. Act1 fails to activate NF-kappaB in an IL-1-unresponsive mutant cell line in which all known signaling components are present, suggesting that it interacts with an unknown component in IL-1 signaling.
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PMID:Act1, an NF-kappa B-activating protein. 1096 24

Epidemiological studies demonstrate that environmental and occupational exposure of chromium(VI) [Cr(VI)] or Cr(VI)-containing particles can cause a number of human diseases, including inflammation and cancer. The biological mechanisms responsible for the initiation and progression of diseases resulting from exposure to Cr(VI) are not fully understood. The present studies evaluated the ability of Cr(IV) to induce activation of NF-kappaB and AP-1, two important transcription factors governing the expression of many early response genes involved in inflammation and carcinogenesis. The activation of NF-kappaB and AP-1 by Cr(IV) was dose dependent. Aspirin, a well-established antioxidant, substantially inhibited Cr(VI)-induced activation of both NF-kappaB and AP-1. SB202190, a specific inhibitor for p38, attenuated AP-1 activation induced by Cr(IV), whereas PD98059, a specific inhibitor for Erk, exhibited no effect on Cr(IV)-induced AP-1 activation. Blockage of NF-kappaB signaling pathway by a transient transfection of a dominant negative expressing vector for IkappaB kinase beta resulted in inhibition of Cr(IV)-induced NF-kappaB, but not AP-1 activation. These data suggest that the activation of AP-1 or NF-kappaB by Cr(IV) is through the involvement of MAP kinase or IKK pathway, respectively.
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PMID:Participation of MAP kinase p38 and IkappaB kinase in chromium (VI)-induced NF-kappaB and AP-1 activation. 1098 89

Optimal activation of Rel/NF-kappaB transcription factors in T lymphocytes requires a CD28-delivered co-stimulatory signal in addition to TCR engagement. Although, Rel/NF-kappaB transcription factors are critical regulators of many T cell functions, the mechanisms and molecules, which link the surface receptors to their activation, are poorly characterized. Using Jurkat T cells stimulated with superantigen presented on B7-positive APC, we showed that CD28- and TCR-stimulated NF-kappaB-dependent transcription is associated to the activation of IkappaB kinase beta (IKKbeta) and, to a lesser extent, of IkappaB kinase alpha (IKKalpha). A dominant negative mutant of the MAP3 kinase MEKK1, a kinase known to regulate the JNK pathway and to activate NF-kappaB-dependent transcription in many cell types, strongly inhibits CD28- and TCR-induced IKK activity, whereas the dominant negative mutants of the NF-kappaB-inducing kinase (NIK) did not exert any significant effects. In addition, TCR/CD28 stimulation results in the recruitment and autophosphorylation of endogenous MEKK1, whereas endogenous NIK was not detectably activated. Our data identify MEKK1 as a critical step in coupling signals initiated by TCR and CD28 to the downstream pathways which lead to both AP-1 and NF-kappaB activation in T lymphocytes.
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PMID:Mitogen-activated kinase kinase kinase 1 regulates T cell receptor- and CD28-mediated signaling events which lead to NF-kappaB activation. 1100 75

The hepatitis C virus (HCV) core protein is a multifunctional viral nucleocapsid protein. Previously, it has been demonstrated that the HCV core protein interacts with the cytoplasmic domain of tumor necrosis factor receptor 1 (TNFR1). Since the TNFR1 is engaged in stimulation of transcriptional factor NF-kappaB and AP-1 through activation of IkappaB kinase and c-Jun N-terminal kinase (JNK, or stress-activated protein kinase), respectively, we have examined whether the interaction between core protein and TNFR1 can modulate JNK. In this study, we demonstrate that the HCV core protein synergistically activates TNFalpha-induced JNK at a core concentration dependent manner in human embryonic kidney (HEK) 293 cells. HCV core-mediated synergism of JNK activation was also detected in stable cells expressing HCV core protein. Furthermore, we demonstrate that HCV core protein does not compete with TNF receptor-associated death domain (TRADD) for its interaction with the death domain of TNFR1. Our in vivo data show that HCV core and TRADD form a ternary complex with TNFR1. These findings suggest that the HCV core protein modulates TNFR1 signaling and may, thus, play a role in chronic infection of HCV patients.
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PMID:Hepatitis C virus core protein potentiates c-Jun N-terminal kinase activation through a signaling complex involving TRADD and TRAF2. 1122 77


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