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

---

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

Cytokine mediated activation of alveolar macrophages (AMs) is an important event in the pathogenesis of fibrosing alveolitis (FA). Through membrane-associated antigens, cytokines (e.g., tumor necrosis-factor-alpha and interleukin-1) are believed to activate a common kinase cascade that initiates the cytoplasmic degradation of IkappaB and nuclear translocation of "nuclear factor-kappaB" (NF-kappaB). In the nucleus, NF-kappaB promotes the transcription of genes encoding chemokines and cytokines involved in chronic inflammation. Preventing cytokine-mediated NF-kappaB activation is a potential strategy for attenuating the lung injury that occurs in FA. Previously, we have demonstrated that, unlike AMs from healthy volunteers, AMs from patients with inflammatory lung diseases express the coxsackie/adenovirus receptor and the alphav integrins required for adenovirus (Adv) infection. This property allows Adv-mediated transgene delivery to diseased, but not normal, AMs and analysis of molecular pathways involved in gene transcription. In this study, AMs were infected with Adv constructs expressing a defective beta subunit of IkappaB kinase (AdvIKKbetakd) and a defective NF-kappaB inducing kinase (AdvNIKkd) to investigate the contribution of these molecules to NF-kappaB activation. We observed that IKKbeta, but not NIK, was required for NF-kappaB activation. The results of this study identify IKKbeta, but not NIK, as a potential therapeutic target in diseases that involve NF-kappaB-dependent gene transcription.
...
PMID:Nuclear factor-kappaB activation in alveolar macrophages requires IkappaB kinase-beta, but not nuclear factor-kappaB inducing kinase. 1193 28

In this study, we examined the role of the nuclear factor-kappaB (NF-kappaB)-inducing kinase (NIK) in distinct signaling pathways leading to NF-kappaB activation. We show that a dominant-negative form of NIK (dnNIK) delivered by adenoviral (Ad5dnNIK) vector inhibits Fas-induced IkappaBalpha phosphorylation and NF-kappaB-dependent gene expression in HT-29 and HeLa cells. Interleukin (IL)-1beta- and tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activation and kappaB-dependent gene expression are inhibited in HeLa cells but not in Ad5dnNIK-infected HT-29 cells. Moreover, Ad5dnNIK failed to sensitize HT-29 cells to TNF-alpha-induced apoptosis at an early time point. However, cytokine- and Fas-induced signals to NF-kappaB are finally integrated by the IkappaB kinase (IKK) complex, since IkappaBalpha phosphorylation, NF-kappaB DNA binding activity, and IL-8 gene expression were strongly inhibited in HT-29 and HeLa cells overexpressing dominant-negative IKKbeta (Ad5dnIKKbeta). Our findings support the concept that cytokine signaling to NF-kappaB is redundant at the level of NIK. In addition, this study demonstrates for the first time the critical role of NIK and IKKbeta in Fas-induced NF-kappaB signaling cascade.
...
PMID:Differential requirement for NF-kappaB-inducing kinase in the induction of NF-kappaB by IL-1beta, TNF-alpha, and Fas. 1205 4

The signaling pathway responsible for the activation of nuclear factor-kappaB (NF-kappaB) by oncogenic forms of Ras remains unclear. Both, the transactivation and DNA binding activities of NF-kappaB, were increased in 267B1 human prostate epithelial cells transformed by viral Kirsten-ras (267B1/Ki-ras cells) compared with those in the parental cells. This increased NF-kappaB activity was attributed to a heterodimeric complex of p50 and p65 subunits. Although the abundance of the inhibitor protein IkappaBbeta was higher in 267B1/Ki-ras cells than in 267B1 cells, an electrophoretic mobility-shift assay suggested that IkappaBalpha is responsible for the activation of NF-kappaB in the former cells. Consistent with this notion, the phosphorylation of IkappaBalpha appeared increased in 267B1/Ki-ras cells, and the proteasome inhibitor I abolished the constitutive activation of NF-kappaB in these cells. The expression of dominant negative mutants of either NIK (NF-kappaB-inducing kinase) or IKKbeta (IkappaB kinase beta) inhibited the activity of NF-kappaB in 267B1/Ki-ras cells. Furthermore, chemical inhibitors specific for Ras activation, sulindac sulfide and farnesytranferase inhibitor I, markedly reduced IkappaBalpha phosphorylation and NF-kappaB activation in the Ki-ras-transformed cells while transfection of these cells with NIK or IKKbeta counteracted the inhibitory effect on NF-kappaB activation. These results suggest that oncogenic Ki-Ras induces transactivation of NF-kappaB through the NIK-IKKbeta-IkappaBalpha pathway.
...
PMID:Constitutive activation of NF-kappaB in Ki-ras-transformed prostate epithelial cells. 1208 27

The human lymphotoxin beta receptor (LTbetaR), a member of the tumor necrosis factor (TNF) receptor superfamily, is essential for not only the development and organization of secondary lymphoid tissues, but also for chemokine release. Even though LTbetaR was shown to recruit TNF-receptor-associated factor (TRAF) 2, 3, and 5, and to induce cell apoptosis or NF-kappaB activation, however, the downstream signaling leading to chemokine expression is not illustrated yet. In this study, we find that overexpression of LTbetaR in HEK293 cells increases IL-8 promoter activity and leads to IL-8 release. LTbetaR-induced IL-8 gene expression requires NF-kappaB (-80 to -71) and AP-1 (-126 to -12) binding sites located in IL-8 promoter, and NF-kappaB is more crucial than AP-1 for IL-8 gene expression. Reporter assay with dominant-negative mutants of TRAFs reveals that TRAF2, 3, and 5, as well as the downstream signal molecules NIK, IKKalpha, and IKKbeta, are involved in IL-8 gene expression. LTbetaR-mediated IL-8 response was inhibited by the dominant-negative mutants of ASK1, MKK4, MKK7, and JNK, but not by those of MEKK1, TAK1, MEK, ERK, and p38 MAPK. This suggests that IL-8 induction by LTbetaR is via TRAFs-elicited signaling pathways, including NIK/IKK-dependent NF-kappaB activation and ASK/MKK/JNK-dependent AP-1 activation.
...
PMID:Lymphotoxin beta receptor induces interleukin 8 gene expression via NF-kappaB and AP-1 activation. 1216 72

Cigarette smoke (CS) contains several carcinogens known to initiate and promote tumorigenesis and metastasis. Because various genes that mediate carcinogenesis and tumorigenesis are regulated by nuclear factor-kappaB (NF-kappaB), we postulated that the effects of CS must be mediated through activation of this transcription factor. Therefore, in the present report we investigated whether cigarette smoke condensate (CSC) activates NF-kappaB, and whether the pathway employed for activation is similar to that of TNF, one of the potent activators of NF-kappaB. Our results show that the treatment of human histiocytic lymphoma U-937 cells with CSC activated NF-kappaB in a dose- and time-dependent manner. The kinetics of NF-kappaB activation by CSC was comparable with that of TNF. CSC-induced NF-kappaB activation was not cell type-specific, as it also activated NF-kappaB in T cells (Jurkat), lung cells (H1299), and head and neck squamous cell lines (1483 and 14B). Activation of NF-kappaB by CSC correlated with time-dependent degradation of IkappaB(alpha), an inhibitor of NF-kappaB. Further studies revealed that CSC induced phosphorylation of the serine residue at position 32 in IkappaB(alpha). In vitro immunocomplex kinase assays showed that CSC activated IkappaB(alpha) kinase (IKK). The suppression of CSC-activated NF-kappaB-dependent reporter gene expression by dominant negative form of IkappaB(alpha), TRAF2, NIK and IKK suggests a similarity to the TNF-induced pathway for NF-kappaB. CSC also induced the expression of cyclooxygenase-2, an NF-kappaB regulated gene product. Overall, our results indicate that through phosphorylation and degradation of IkappaB(alpha), CSC can activate NF-kappaB in a wide a variety of cells, and this may play a role in CS-induced carcinogenesis.
...
PMID:Cigarette smoke condensate activates nuclear transcription factor-kappaB through phosphorylation and degradation of IkappaB(alpha): correlation with induction of cyclooxygenase-2. 1218 95

We have previously shown that bisperoxovanadium (bpV) phosphotyrosyl phosphatase inhibitors can potently activate NF-kappaB. We have already determined that p56(lck), ZAP-70, SLP-76, capacitative entry of calcium, and calcium-regulated effectors are important in bpV-induced NF-kappaB activation. In this study, we evaluated whether other signal transducers previously reported in NF-kappaB induction by T cell activating stimuli are also activated by bpV compounds. Nuclear translocation of NF-kappaB was evaluated in cell lines deficient for either CD45 or p36(LAT) to assess the role of these signal transducers in bpV-mediated NF-kappaB activation. A deficiency of either protein greatly reduced the extent of NF-kappaB nuclear translocation following bpV treatment. Isoform-specific PKC inhibitors were then used to show that bpV compounds activate NF-kappaB through both calcium-sensitive and -insensitive PKC isoforms. The implication of the IkappaB-kinase complex was then investigated through the use of an IkappaBalpha-specific kinase assay and plasmids expressing catalytically inactive forms of IKKalpha and IKKbeta. Upstream kinases involved in IKK complex activation such as TPL-2/COT, NIK, and IKKepsilon were also shown to play an important role in bpV-mediated NF-kappaB activation. Finally, reporter gene transcriptional assays and gel shift assays were performed to compare the kinetics of activation of NF-kappaB by bpV with those of antigenic and TNFalpha stimulation. We demonstrate, both in Jurkat cells and in primary T cells, that bpV-mediated NF-kappaB activation kinetics are comparable to those of an antigenic stimulation but occur much slower than the kinetics seen upon TNFalpha treatment.
...
PMID:NF-kappaB induction by bisperoxovanadium compounds requires CD45, p36(LAT), PKC, and IKK activity and exhibits kinetics of activation comparable to those of TCR/CD28 coengagement. 1284 75

Molecular and biochemical analysis indicates that nuclear transcription factor kappaB (NF-kappaB)-inducing kinase (NIK) mediates IKK activation and NF-kappaB transcriptional activity. However, gene deletion studies suggest that NIK triggers gene expression without affecting IkappaBalpha degradation and NF-kappaB DNA binding activity. In order to investigate the role of NIK in NF-kappaB transcriptional activity, we used mouse embryonic fibroblasts (MEF) derived from wild-type (wt) and IkappaB kinase gamma (IKKgamma) gene deficient (IKKgamma(-/-)) mice. We report that although TNF-induced NF-kappaB transcriptional activity is abolished in IKKgamma(-/-) cells, adenoviral gene delivery of NIK (Ad5NIK) still enhanced transcriptional activity and IL-6 mRNA accumulation. Moreover, NIK targets the transactivation function of NF-kappaB through stimulation of the transactivation domain (TAD) of RelA (S536) in IKKgamma(-/-) cells. Interestingly, Ad5NIK, but not TNF, induces RelA S536 and p38 mitogen-activated protein kinase (MAPK) phosphorylation in IKKgamma(-/-) cells. Functional analysis demonstrated that Ad5NIK-induced NF-kappaB transcriptional activity, IL-6 mRNA expression and RelA phosphorylation are inhibited by the p38 inhibitor SB203580, suggesting a role for this MAPK in NIK signaling to NF-kappaB. These data demonstrate for the first time the presence of an IKKgamma-independent NIK/p38 MAPK-dependent signaling pathway that activates NF-kappaB and induces pro-inflammatory gene expression through RelA phosphorylation.
...
PMID:NF-kappaB inducing kinase activates NF-kappaB transcriptional activity independently of IkappaB kinase gamma through a p38 MAPK-dependent RelA phosphorylation pathway. 1521 63

The IkappaB kinase (IKK) complex is one major step in the regulation of the NF-kappaB/Rel system that is involved in inflammatory and immune responses as well as in proliferation and apoptosis. At present it is not clear whether besides the "classical" IKKalpha-IKKbeta-IKKgamma configuration additional complexes exist in vivo that solely contain IKKbeta and IKKgamma (without IKKalpha). In the current study we were able to demonstrate in monocytic cells that endogenous complexes, which only include IKKbeta as the kinase-active molecule do indeed exist in vivo and that these complexes contain IKKgamma as an additional component. Furthermore, we showed that these IKKbeta-IKKgamma complexes are involved in mainstream NF-kappaB activation cascades because they can be activated by tumor necrosis factor. In contrast, these subcomplexes appear not to participate in NIK-dependent pathways. As a next step we showed that exogenous IKKbeta-IKKgamma complexes can be formed in an intact cell by overexpression and that these artificial complexes fulfill the requirement for participation in regular signaling. Finally, in the absence of IKKalpha we found a retarded proteolysis of IkappaBalpha, but not of IkappaB in, which is associated with a reduced IKK activity. Differential pathways represented by various IKK subcomplexes may open attractive possibilities in treatment of inflammation or cancer allowing specific therapeutic intervention.
...
PMID:Detection of IKKbeta-IKKgamma subcomplexes in monocytic cells and characterization of associated signaling. 1522

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.
...
PMID:Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. 1532 87

Curcumin (diferuloylmethane) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animal models. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase; and an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF(Epidermal growth factor)-receptor tyrosine kinase and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF(nucleor factor)kappaB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, while the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the major metabolites of curcumin in mice, rats and humans.
...
PMID:Suppression of protein kinase C and nuclear oncogene expression as possible action mechanisms of cancer chemoprevention by Curcumin. 1535 94


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

---