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)

Heat shock induces the accumulation of misfolded proteins and results in the preferential expression of heat shock proteins, which help the cell to recover from thermal damage. Heat shock is a well known transcriptional activator of the human immunodeficiency virus type 1 long terminal repeat (LTR). We report here that mutations or deletions of the LTR kappaB sites impaired the LTR transcriptional activation by heat shock. Further analysis revealed that, during heat shock recovery, the NF-kappaB p65 and p50 subunits migrated into the nucleus of HeLa cells, bound to DNA, and induced kappaB-dependent reporter gene expression. This NF-kappaB activation did not depend on new transcriptional and/or translational events and on the pro-oxidant state generated by heat shock. It was not concomitant with IkappaBalpha phosphorylation and was not abolished by the expression of IkappaB kinase or IkappaBalpha dominant-negative mutants. Moreover, NF-kappaB activation and migration into the nucleus were not concomitant with IkappaBalpha/beta or p105 degradation. However, during heat shock recovery, NF-kappaB was dissociated from its complexing partners, allowing its migration into the nucleus. Hence, we describe here a novel mechanism for activation of NF-kappaB based on the thermolability of the NF-kappaB.IkappaB complex.
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PMID:NFkappa B-dependent transcriptional activation during heat shock recovery. Thermolability of the NF-kappaB.Ikappa B complex. 1155 96

Toxoplasma gondii infection results in an infiltration of immune cells. The mechanisms responsible for triggering inflammatory cell infiltration in T. gondii infection are not fully understood. We report that T. gondii-infected HeLa cells induced nuclear factor-kappa B (NF-kappaB) activation and increased the expression of interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) mRNA. An inhibitor of NF-kappaB activation, calpain-1 inhibitor, blocked the chemokine secretion induced by live T. gondii. Activation of the IL-8 and NF-kappaB transcriptional reporters was suppressed in cells co-transfected with IkappaB kinase beta and the IkappaBalpha super-repressor plasmids. Moreover, the addition of IL-1alpha increased NF-kappaB activation and IL-8 mRNA expression in T. gondii-infected HeLa cells. These results suggest that NF-kappaB is a central regulator of the chemokine response in T. gondii-infected human epithelial cells and that chemokine IL-8 and MCP-1 secretion might be involved in the pathogenesis of T. gondii, via the recruitment of neutrophils, monocytes, and lymphocytes.
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PMID:Nuclear factor-kappa B plays a major role in the regulation of chemokine expression of HeLa cells in response to Toxoplasma gondii infection. 1157 May 62

Bacterial DNA and CpG-oligodeoxyribonucleotides (ODN) are powerful B cell activators, inducing apoptosis protection, cell cycle entry, proliferation, costimulatory molecule expression, immunoglobulin (Ig) and interleukin-6 (IL-6) secretion. However, proximal events in B cell activation by ODN are only partially characterized, including the translocation of NF-kappaB to the nucleus. In this paper, we provide evidence that CpG-ODN-induced cell cycle entry and apoptosis protection are blocked by SN50 or gliotoxin and thus require NF-kappaB activation. NF-kappaB activation occurred within 30 minutes of stimulation of murine B cells with a phosphorothioate (S) CpG-ODN and persisted for up to 40 hours, with p50, p65, and c-Rel as the major components. Similar to other NF-kappaB inducers, CpG-ODN caused an early IkappaBalpha and IkappaBbeta degradation plus cleavage of the p50 precursor and subsequent NF-kappaB nuclear translocation. A group of closely related S-ODN, which specifically blocked CpG-induced B cell activation at submicromolar concentrations, also prevented NF-kappaB DNA binding and transcriptional activation. These inhibitory S-ODN differed from stimulatory S-ODN by having 2-3 G substitutions in the central motif. As inhibitory S-ODN did not directly interfere with the NF-kappaB DNA binding but prevented CpG-induced NF-kappaB nuclear translocation of p50, p65, and c-Rel and blocked p105, IkappaBalpha, and IkappaBbeta degradation, we concluded that their putative target must lie upstream of inhibitory kinase (IKK) activation.
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PMID:CpG stimulation of primary mouse B cells is blocked by inhibitory oligodeoxyribonucleotides at a site proximal to NF-kappaB activation. 1157 1

Camptothecin (CPT) and derivatives are topoisomerase I poisons currently used as anticancer drugs. Their cytotoxicity is maximal for cells in S phase. Using asynchronous and S phase-synchronized HeLa cells, we showed that both the nuclear factor-kappaB (NF-kappaB) activation and its transcriptional activity, induced by CPT treatment, are enhanced in S phase cells. After CPT treatment, NF-kappaB activation reached a maximum within 2-3 hr and was still detectable after 24 hr. The nature of the complex evolved with time, forming mostly p50/p65 after 2 hr to almost exclusively p52 after 24 hr. In HeLa cells, the different steps of the induction were readily observable in S phase synchronized cells, whereas they were barely noticeable in a randomly growing cell population. The signal progressed through the activation of the IKK complex, the phosphorylation of IkappaBalpha, and the degradation of phosphorylated-IkappaBalpha and -IkappaBbeta. The stable expression of wild-type HA-tagged-IkappaBalpha or mutated HA-tagged-IkappaBalpha (S32,36A) allowed us to confirm the essential role of Ser32 and Ser36. NF-kappaB-activating kinase (NIK) could play a role upstream of the IKK complex, as the transient expression of a kinase inactive mutant NIK(K429,430A) abolished the activation of NF-kappaB by CPT. A kinase inactive mutant of mitogen-activated protein/ERK kinase kinase 1 (MEKK1), another kinase susceptible of acting upstream of the signalsome, did not. Cytotoxicity studies with clonal populations expressing different amounts of wild-type or mutated IkappaBalpha revealed that the overexpression of wild-type IkappaBa in large amount increases the sensitivity of HeLa cells to CPT more efficiently than a lower level of expression of non-phosphorylable IkappaBalpha.
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PMID:S phase dependence and involvement of NF-kappaB activating kinase to NF-kappaB activation by camptothecin. 1158 57

Activation of the transcription factor nuclear factor kappaB (NF-kappaB) has been implicated in the protection of cells from apoptosis. We have shown previously that the adenovirus type 5 E1A sensitizes cells to radiation-induced apoptosis by inhibiting NF-kappaB activity. However, the exact mechanism of inhibition is not known. In this study, we compared the activity of inhibitor of nuclear factor-kappaB (IkappaB) kinase (IKK) and the degradation of IkappaBalpha in E1A transfectants and parental human cancer cells after ionizing radiation treatment. We found that radiation-induced IKK activity and IkappaBalpha degradation were inhibited in the E1A transfectants. Recently, Akt has been implicated in NF-kappaB activation. To test whether Akt is regulated by E1A and is involved in radiation-induced NF-kappaB activity, we examined the phosphorylation status of Akt in the E1A transfectants and parental cells and in irradiated cells. The results indicated that radiation induced Akt phosphorylation and that E1A inhibited basal but not radiation-induced Akt phosphorylation. We additionally examined radiation-induced NF-kappaB activity in cells stably transfected with a dominant-negative, inactive Akt and in parental cancer cells treated with a phosphatidylinositol 3-kinase inhibitor, wortmannin. We found that dominant-negative Akt and wortmannin did not block radiation-induced NF-kappaB activity. Thus, our results suggest that inhibition of IKK activity and IkappaB degradation is the predominant mechanism for E1A-mediated inhibition of radiation-induced NF-kappaB activity and that radiation-induced Akt activation cannot be inhibited by E1A and is likely independent of radiation-induced NF-kappaB activity.
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PMID:E1A inhibition of radiation-induced NF-kappaB activity through suppression of IKK activity and IkappaB degradation, independent of Akt activation. 1160 72

Tumor necrosis factor (TNF)-alpha-induced phosphorylation of the IkappaB proteins by the IkappaB kinase (IKK) complex containing IKK-2 and subsequent degradation of the IkappaB proteins are prerequisites for NF-kappaB activation, resulting in the stimulation of a variety of pro-inflammatory target genes. The C-C chemokine eotaxin-1 is a potent chemoattractant for eosinophils and Th2 lymphocytes, may play an important role in the pathogenesis of atopic dermatitis, and acts via binding to its receptor CCR3. To investigate the role of NF-kappaB signaling in the regulation of these genes, we stably expressed a transdominant mutant of IkappaBalpha and a constitutively active mutant of IKK-2 in mouse NIH3T3 fibroblasts. The transdominant IkappaBalpha mutant completely inhibited TNF-alpha-mediated induction of both eotaxin-1 and CCR3, whereas expression of constitutively active IKK-2 was sufficient to drive almost full expression of these two genes in the absence of TNF-alpha. Moreover, we observed elevated expression levels of CCR3 and eotaxin-1 protein levels in the skin of IkappaBalpha-deficient mice characterized by a widespread dermatitis. Finally, using dermal fibroblasts derived from IkappaBalpha-deficient mice, we observed elevated basal expression, enhanced inducibility by TNF-alpha, and attenuated down-regulation upon TNF-alpha withdrawal of both CCR3 and eotaxin-1 mRNA levels. These results demonstrate that the IKK-2/IkappaBalpha/NF-kappaB pathway plays a critical role for CCR3 and eotaxin-1 expression in fibroblasts and suggests a critical link to the pathogenesis of atopic dermatitis.
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PMID:The IKK-2/Ikappa Balpha /NF-kappa B pathway plays a key role in the regulation of CCR3 and eotaxin-1 in fibroblasts. A critical link to dermatitis in Ikappa Balpha -deficient mice. 1169 38

Signal transduction pathways that lead to the modulation of genes related to survival and repair mechanisms are activated in neurons that survive injury. These protein kinase/phosphatase cascades converge on transcription factors, the DNA binding proteins that directly regulate gene expression. In this study we examined expression of the NF-kappaB p50 subunit in the rat hippocampus 7 days after injury caused by middle cerebral artery occlusion or trimethyltin treatment. We found increased levels of p50 in neurons throughout the hippocampus after both treatments, localized not only in cell bodies but also in processes. At the 7-day time point, Fluoro-Jade histochemistry revealed hippocampal neurodegeneration in trimethyltin-treated rats but not in those lesioned by middle cerebral artery occlusion. p50 was not expressed in Fluoro-Jade-positive degenerating cells, supporting the role of this transcriptional subunit in neurosurvival. Because phosphorylation of the inhibitor IkappaB protein by IkappaB kinase is the classic step in NF-kappaB activation, phospho-IkappaBalpha immunoreactivity was examined as an indication of IkappaB kinase activity. Levels of phospho-IkappaBalpha were increased in neurons throughout the hippocampus 7 days postinjury. Immunoblotting for phospho-IkappaBalpha demonstrated increased levels 1 day postinjury that remained elevated for at least 7 days. These data suggest that NF-kappaB signal transduction is involved in an adaptive response of neurons that survive injury.
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PMID:NF-kappaB p50 is increased in neurons surviving hippocampal injury. 1171 55

IkappaB kinase (IKK) is a key mediator of NF-kappaB activation induced by various immunological signals. In T cells and most other cell types, the primary target of IKK is a labile inhibitor of NF-kappaB, IkappaBalpha, which is responsible for the canonical NF-kappaB activation. Here, we show that in T cells infected with the human T-cell leukemia virus (HTLV), IKKalpha is targeted to a novel signaling pathway that mediates processing of the nfkappab2 precursor protein p100, resulting in active production of the NF-kappaB subunit, p52. This pathogenic action is mediated by the HTLV-encoded oncoprotein Tax, which appears to act by physically recruiting IKKalpha to p100, triggering phosphorylation-dependent ubiquitylation and processing of p100. These findings suggest a novel mechanism by which Tax modulates the NF-kappaB signaling pathway.
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PMID:Retroviral oncoprotein Tax induces processing of NF-kappaB2/p100 in T cells: evidence for the involvement of IKKalpha. 1172 16

Neutrophil-dependent inflammation dependent on monosodium urate (MSU) crystal-induced IL-8 expression occurs in gout. MSU crystals activate phagocyte Src family tyrosine kinases and the serine/threonine kinase p70s6k. Thus, using monocytic THP-1 cells, we assessed the potential for Src family kinases and p70s6k to mediate MSU-induced IL-8 expression. MSU crystals induced phosphorylation of p70s6k and the Src kinases c-Src, Lyn, Hck, and Fyn. IL-8 expression was attenuated more by the Src kinase inhibitor PP1 than by the p70s6k inhibitor rapamycin. PP1 inhibited crystal-induced phosphorylation of ERK1/2 and IkappaBalpha and suppressed IkappaB kinase (IKK) activation and NF-kappaB binding to the IL-8 promoter, signals that mediate MSU-induced IL-8 expression. Transfection of the native Src inhibitor, C-terminal Src kinase (Csk), also suppressed crystal-induced c-Src, ERK1/2, and IkappaBalpha phosphorylation and IL-8 expression. We conclude that Src family tyrosine kinase signaling plays a significant role in MSU crystal-induced IL-8 expression via stimulation of ERK1/2 pathway and NF-kappaB activation.
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PMID:Src family protein tyrosine kinase signaling mediates monosodium urate crystal-induced IL-8 expression by monocytic THP-1 cells. 1173 59

Gene expression profiling has revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two distinct diseases. Patients with one DLBCL subtype, termed activated B cell-like (ABC) DLBCL, have a distinctly inferior prognosis. An untapped potential of gene expression profiling is its ability to identify pathogenic signaling pathways in cancer that are amenable to therapeutic attack. The gene expression profiles of ABC DLBCLs were notable for the high expression of target genes of the nuclear factor (NF)-kappaB transcription factors, raising the possibility that constitutive activity of the NF-kappaB pathway may contribute to the poor prognosis of these patients. Two cell line models of ABC DLBCL had high nuclear NF-kappaB DNA binding activity, constitutive IkappaB kinase (IKK) activity, and rapid IkappaB(alpha) degradation that was not seen in cell lines representing the other DLBCL subtype, germinal center B-like (GCB) DLBCL. Retroviral transduction of a super-repressor form of IkappaBalpha or dominant negative forms of IKKbeta was toxic to ABC DLBCL cells but not GCB DLBCL cells. DNA content analysis showed that NF-kappaB inhibition caused both cell death and G1-phase growth arrest. These findings establish the NF-kappaB pathway as a new molecular target for drug development in the most clinically intractable subtype of DLBCL and demonstrate that the two DLBCL subtypes defined by gene expression profiling utilize distinct pathogenetic mechanisms.
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PMID:Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. 1174 86


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