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 transcription factor NF-kappaB is a key regulator of cellular activation, proliferation and apoptosis. Defects in the NF-kappaB pathway contribute to a broad array of malignant, neurodegenerative and chronic inflammatory diseases. IKK-dependent IkappaB alpha degradation by the 26S proteasome is a critical NF-kappaB regulatory control point, which is emerging as an important target for drug development. To directly monitor regulation of IKK activation in intact organisms, we engineered an IkappaB alpha-firefly luciferase (IkappaB alpha-FLuc) fusion reporter. In cultured cells and living animals, the reporter provided a continuous, noninvasive readout of the kinetics of ligand-induced IKK activation and the pharmacodynamics of selective inhibitors of both IKK and the 26S proteasome. This IkappaB alpha-FLuc reporter now permits continuous readout of IKK activation in vivo, facilitates development and validation of target-specific therapeutics, and complements conventional NF-kappaB transcriptional reporters for more complete temporal and regional investigations of the NF-kappaB signaling pathway in health and disease.
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PMID:Real-time imaging of ligand-induced IKK activation in intact cells and in living mice. 1609 86

Activation of NF-kappaB by the intracellular pathogen Toxoplasma gondii is associated with the localization of phosphorylated IkappaB alpha to the parasitophorous vacuole membrane (PVM). This is mediated by a parasite-derived IkappaB kinase (TgIKK) activity and is independent of host IKK function. In the present study, we examined the roles of host IKK and parasite-derived TgIKK on the temporal modulation of NF-kappaB activation. Despite the presence of TgIKK activity at the PVM, nuclear translocation of NF-kappaB and subsequent gene expression exhibited a requirement for the host IKK complex. A detailed kinetic analysis of NF-kappaB activation revealed a biphasic, hierarchical and temporally regulated response. We propose a novel paradigm for the modulation of NF-kappaB-dependent gene expression by T. gondii that involves both the host IKK complex and TgIKK activity at different phases of infection. Thus, T. gondii effectively alters gene expression in a temporal dimension by exploiting the NF-kappaB signaling machinery and subsequently rewiring the activation circuits of the infected host cell.
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PMID:Host and parasite-derived IKK activities direct distinct temporal phases of NF-kappaB activation and target gene expression following Toxoplasma gondii infection. 1633 66

(R)-4-(3,4-Dihydro-8,8-dimethyl)-2H,8H-benzo[1,2-b:3,4-b'] dipyran-3yl)-1,3-benzenediol (glabridin) is known to have anti-inflammatory, antimicrobial, and cardiovascular protective activities. In the present study, we report the inhibitory effect of glabridin on intercellular adhesion molecule-1 (ICAM-1) expression in tumor necrosis factor-alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells (HUVECs). Glabridin inhibited THP-1 cell adhesion to HUVECs stimulated by TNF-alpha and cell surface expression of ICAM-1 in TNF-alpha-stimulated HUVECs. The mRNA expression of adhesion molecules, including ICAM-1, vascular cell adhesion molecule-1, and E-selectin, was also suppressed by glabridin. Further study demonstrated the inhibitory effect of glabridin on nuclear factor (NF)-kappaB/Rel DNA binding, inhibitory factor-kappaB alpha (IkappaB alpha), and IkappaB beta degradation, IkappaB kinase activation, and p65 nuclear translocation in TNF-alpha-stimulated HUVECs. Treatment of a variety of cell lines with glabridin revealed that inhibitory effect of glabridin on NF-kappaB/Rel activation is not cell type-specific, and both inducible and constitutive NF-kappaB/Rel activation was suppressed by glabridin treatment. Moreover, TNF-alpha-induced phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was blocked by glabridin treatment in HUVECs. Glabridin also suppressed sphingosine-1-phosphate (S1P)-induced cell surface expression and mRNA expression of ICAM-1. Further study demonstrated that TNF-alpha-induced sphingosine kinase activity was inhibited by glabridin, and the inhibitory effect of glabridin on TNF-alpha-induced ICAM-1 expression was reversed by addition of exogenous S1P. Together, our results indicate that the inhibitory effect of glabridin on ICAM-1 expression might be mediated, at least in part, by inhibiting sphingosine kinase pathway and subsequent inhibition of signaling pathways, including Akt, ERK, and NF-kappaB/Rel signaling pathway.
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PMID:Glabridin suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells by blocking sphingosine kinase pathway: implications of Akt, extracellular signal-regulated kinase, and nuclear factor-kappaB/Rel signaling pathways. 1635 64

CCL20 is expected to play a crucial role in the initiation of immune responses and tumour growth. However, expression of CCL20 in Epstein-Barr virus (EBV)-associated diseases has not been studied. We examined the contribution of EBV infection and EBV-encoded latent membrane protein (LMP)-1 to CCL20 expression. EBV infection and LMP-1 induced CCL20 mRNA expression in the EBV-negative Burkitt lymphoma (BL) cell lines and the embryonic kidney cell line. Histone deacetylase inhibitor-stimulated endogenous LMP-1 also induced CCL20 expression in an EBV-positive BL cell line. Analysis of the CCL20 promoter showed that it was activated by LMP-1 C-terminal activation region (CTAR)-1 and CTAR-2. Co-expression of IkappaB alpha, IkappaB beta, IkappaB kinase (IKK)alpha, IKKbeta, IKKgamma, nuclear factor (NF)-kappaB-inducing kinase and tumour necrosis factor receptor-associated factor 2 dominant-negative constructs with LMP-1 inhibited the activation of the CCL20 promoter by LMP-1, suggesting that LMP-1 induces CCL20 via NF-kappaB signalling. The requirement for the NF-kappaB-binding site in the CCL20 promoter in LMP-1 responsiveness was established. Our results indicate that activation of the NF-kappaB pathway by LMP-1 is required for the activation of CCL20 expression.
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PMID:Transactivation of CCL20 gene by Epstein-Barr virus latent membrane protein 1. 2162 63

Epstein-Barr virus latent infection integral membrane protein 1 (LMP1) mimics a constitutively active TNF receptor (TNFR). LMP1 has two C-terminal cytosolic domains, transformation effector sites (TES)1 and -2, that engage TNFR-associated factors (TRAFs) and the TNFR-associated death domain protein, respectively, and activate NF-kappaB. NF-kappaB activation is critical for Epstein-Barr virus-infected lymphoblast survival. TES1- and TES2-mediated NF-kappaB activations are IL-1 receptor-associated kinase 1 (IRAK1)-dependent. Because IRAK1 is upstream of TRAF6 in IL-1 activation of NF-kappaB, the potential role of IRAK1 in LMP1-mediated NF-kappaB activation through TRAF6 and inhibitor of kappaB (IkappaB) kinase (IKK) was initially investigated. Surprisingly, LMP1 expression activated TRAF6 ubiquitination, IKKbeta induction of IkappaB alpha phosphorylation, and p65 nuclear translocation in both WT and IRAK1-deficient I1A 293 cells. LMP1 also induced IKK alpha-mediated p100 processing and p52 nuclear localization in WT and IRAK1-deficient I1A 293 cells. Further, LMP1 TES1 and TES2 induced p65, p50, and p52 NF-kappaB DNA binding in WT and IRAK1-deficient I1A 293 cells. However, LMP1 induced p65/RelA S536 phosphorylation only in WT 293 cells or in IRAK1 kinase point mutant reconstituted I1A 293 cells but not in IRAK1-deficient I1A 293 cells. IRAK1 was also required for LMP1 activation of p38, one of the kinases that can mediate p65/RelA S536 phosphorylation and activate NF-kappaB-dependent transcription. Thus, the critical IRAK1 role in LMP1-induced NF-kappaB activation is in mediating p65/RelA S536 phosphorylation through an effect on p38 or other p65 S536 kinases.
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PMID:IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-kappaB activation. 1647 6

Phosphorylation of histone H3 protein at serine 10 is an important step in chromatin remodeling during transcriptional transactivation. IkappaB kinase-alpha (IKK-alpha) and Mitogen- and Stress-activated protein Kinases 1 and 2 (MSK1/2) have been shown to play key roles in the transcriptional regulation of immediate early genes such as c-fos. Interestingly, IKK-alpha and MSK1/2 have also been implicated as histone H3-Ser10 kinases. In this work, we have shown that MSK1/2 are required for epidermal growth factor (EGF)-induced, but not tumor necrosis factor-induced, histone H3-Ser10 phosphorylation, both globally and at specific promoters. Consistent with this, MSK1/2 are required for optimal immediate early c-fos transcription in response to EGF potentially through control of both H3-Ser10 and promoter-associated cAMP-response element-binding protein phosphorylation. Furthermore, MSK1/2 control EGF-induced IkappaB alpha promoter H3-Ser10 phosphorylation in the absence of elevated transcription. These studies demonstrate the existence of pathway-specific mechanisms to control histone H3-Ser10 phosphorylation and gene expression.
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PMID:The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation. 1651

Furonaphthoquinone compounds have been reported to exhibit anticancer, antibacterial and antiviral properties. The molecular basis for these diverse properties is not known. 2-Methyl-2-(2-methylpropenyl)-2,3-dihydronaphthoquinone [2,3-b]furan-4,9-dione (NFD-37) is a synthetic furonaphthoquinone compound. In the present study, NFD-37 was found to inhibit interleukin (IL)-6 production in lipopolysaccharide (LPS)-stimulated murine macrophages RAW 264.7. Further, NFD-37 attenuated LPS-induced synthesis of IL-6 transcript but also inhibited LPS-induced IL-6 promoter activity. Since nuclear factor (NF)-kappaB activation has been shown to play a key role in LPS-induced IL-6 expression, the effect of NFD-37 on LPS-induced NF-kappaB activation was further analyzed. NFD-37 exhibited a dose-dependent inhibitory effect on LPS-induced phosphorylation of inhibitory kappaB alpha protein (IkappaB alpha), and subsequently inhibited LPS-induced IkappaB alpha degradation as well as NF-kappaB transcriptional activity. In another experiment, NFD-37 inhibited both IL-6 promoter activity and NF-kappaB transcriptional activity elicited by an expression vector encoding IkappaB kinase beta. Taken together, NFD-37 down-regulated LPS-induced IL-6 expression through NF-kappaB activation, which could provide a pharmacological basis for the anti-inflammatory properties of furonaphthoquinone analogs.
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PMID:Suppression of interleukin-6 production in macrophages by furonaphthoquinone NFD-37. 1664 77

Nuclear factor (NF)-kappaB is a key regulator of synovial inflammation. We investigated the effect of local NF-kappaB inhibition in rat adjuvant arthritis (AA), using the specific IkappaB kinase (IKK)-beta blocking NF-kappaB essential modulator-binding domain (NBD) peptide. The effects of the NBD peptide on human fibroblast-like synoviocytes (FLS) and macrophages, as well as rheumatoid arthritis (RA) whole-tissue biopsies, were also evaluated. First, we investigated the effects of the NBD peptide on RA FLS in vitro. Subsequently, NBD peptides were administered intra-articularly into the right ankle joint of rats at the onset of disease. The severity of arthritis was monitored over time, rats were sacrificed on day 20, and tissue specimens were collected for routine histology and x-rays of the ankle joints. Human macrophages or RA synovial tissues were cultured ex vivo in the presence or absence of NBD peptides, and cytokine production was measured in the supernatant by enzyme-linked immunosorbent assay. The NBD peptide blocked interleukin (IL)-1-beta-induced IkappaB alpha phosphorylation and IL-6 production in RA FLS. Intra-articular injection of the NBD peptide led to significantly reduced severity of arthritis (p < 0.0001) and reduced radiological damage (p = 0.04). This was associated with decreased synovial cellularity and reduced expression of tumor necrosis factor (TNF)-alpha and IL-1-beta in the synovium. Incubation of human macrophages with NBD peptides resulted in 50% inhibition of IL-1-beta-induced TNF-alpha production in the supernatant (p < 0.01). In addition, the NBD peptide decreased TNF-alpha-induced IL-6 production by human RA synovial tissue biopsies by approximately 42% (p < 0.01). Specific NF-kappaB blockade using a small peptide inhibitor of IKK-beta has anti-inflammatory effects in AA and human RA synovial tissue as well as in two important cell types in the pathogenesis of RA: macrophages and FLS. These results indicate that IKK-beta-targeted NF-kappaB blockade using the NBD peptide could offer a new approach for the local treatment of arthritis.
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PMID:Local treatment with the selective IkappaB kinase beta inhibitor NEMO-binding domain peptide ameliorates synovial inflammation. 1668 67

Proteasome inhibitors are currently used as chemotherapeutic drugs because of their ability to block NF-kappaB, a transcription factor constitutively activated in many different types of human cancer. In the present study, we demonstrate that proteasome inhibitors induce cell death in endometrial carcinoma cell lines and primary explants but, instead of blocking NF-kappaB, they increase its transcriptional activity. Proteasome inhibitors induce phosphorylation of IKK alpha/beta, phosphorylation and degradation of IkappaB alpha, and phosphorylation of the p65 NF-kappaB subunit on serine 536. Proteasome inhibitor-induced NF-kappaB activity can be blocked by a non-degradable form of IkappaB alpha or dominant negative forms of either IKK alpha or IKK beta. Lentiviral delivery of shRNAs to either IKK alpha or IKK beta cause blockade of NF-kappaB transcriptional activity and inhibit phosphorylation of p65 on serine 536, but has no effect on IkappaB alpha degradation. These results suggest a role for p65 phosphorylation in proteasome inhibitor-induced NF-kappaB activation. Accordingly, siRNA knockdown of p65 inhibits proteasome inhibitor-induced NF-kappaB transcriptional activity. Our results demonstrate that proteasome inhibitors, including bortezomib, induce cell death on endometrial carcinoma cells and primary explants. However, they activate NF-kappaB instead of blocking its transcriptional potential. Therefore, the concept that proteasome inhibitors are blockers of NF-kappaB activation should be carefully examined in particular cell types.
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PMID:Proteasome inhibitors induce death but activate NF-kappaB on endometrial carcinoma cell lines and primary culture explants. 1673 6

The role of NFkappaB and it's upstream kinases in regulating adhesion molecule expression in the smooth muscle of the vasculature remains controversial. We therefore examined the effect of blocking the NFkappaB pathway on TNFalpha-stimulated ICAM-1 and VCAM-1 expression in primary cultures of human aortic smooth muscle cells using an adenoviral wild-type IkappaB alpha construct (Ad.IkappaB alpha) and dominant-negative IKKalpha (Ad.IKKalpha+/-) and IKKbeta (Ad.IKKbeta+/-) constructs. Ad.IkappaB alpha treatment was found to block NFkappaB DNA-binding, and thereby completely prevent TNFalpha-stimulated ICAM-1 and VCAM-1 expression without influencing IKK activity. Ad.IKKbeta+/- treatment completely inhibited TNFalpha-stimulated IKK kinase activity, IkappaB alpha degradation and NFkappaB DNA-binding in addition to completely blocking TNFalpha-stimulated ICAM-1 and VCAM-1 expression. Ad.IKKalpha+/- treatment however had no detectable effect on NFkappaB DNA-binding or ICAM-1 and VCAM-1 expression. Our results demonstrate that TNFalpha-stimulated ICAM-1 and VCAM-1 expression in human aortic smooth muscle cells is NFkappaB-dependent, that IKKbeta is a suitable target for drug therapy and Ad.IKKbeta+/- an effective inhibitor of TNFalpha-stimulated ICAM-1 and VCAM-1 expression.
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PMID:IKKalpha and IKKbeta function in TNFalpha-stimulated adhesion molecule expression in human aortic smooth muscle cells. 1687 5


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