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)

Reoviruses induce apoptosis both in cultured cells and in vivo. Apoptosis plays a major role in the pathogenesis of reovirus encephalitis and myocarditis in infected mice. Reovirus-induced apoptosis is dependent on the activation of transcription factor NF-kappaB and downstream cellular genes. To better understand the mechanism of NF-kappaB activation by reovirus, NF-kappaB signaling intermediates under reovirus control were investigated at the level of Rel, IkappaB, and IkappaB kinase (IKK) proteins. We found that reovirus infection leads initially to nuclear translocation of p50 and RelA, followed by delayed mobilization of c-Rel and p52. This biphasic pattern of Rel protein activation is associated with the degradation of the NF-kappaB inhibitor IkappaBalpha but not the structurally related inhibitors IkappaBbeta or IkappaBepsilon. Using IKK subunit-specific small interfering RNAs and cells deficient in individual IKK subunits, we demonstrate that IKKalpha but not IKKbeta is required for reovirus-induced NF-kappaB activation and apoptosis. Despite the preferential usage of IKKalpha, both NF-kappaB activation and apoptosis were attenuated in cells lacking IKKgamma/Nemo, an essential regulatory subunit of IKKbeta. Moreover, deletion of the gene encoding NF-kappaB-inducing kinase, which is known to modulate IKKalpha function, had no inhibitory effect on either response in reovirus-infected cells. Collectively, these findings indicate a novel pathway of NF-kappaB/Rel activation involving IKKalpha and IKKgamma/Nemo, which together mediate the expression of downstream proapoptotic genes in reovirus-infected cells.
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PMID:IkappaB kinase subunits alpha and gamma are required for activation of NF-kappaB and induction of apoptosis by mammalian reovirus. 1712 8

Lipopolysaccharides (LPS) are potent polyclonal B-lymphocyte activators. Recently, we have shown that LPS inhibits both spontaneous and drug-induced apoptosis in mature B lymphocytes, through cytosolic retention of Bax, a proapoptotic protein of the Bcl-2 family, by preventing its translocation to mitochondria. Research within the last few years has revealed that members of the NF-kappaB transcription factor regulate cell viability by activating genes involved in mitochondrion-dependent apoptosis. In this report, we examined the effect of sustained LPS stimulation on cytosolic and nuclear proteins of the IkappaB/NF-kappaB family to determine which NF-kappaB pathway, canonical (classical) or noncanonical (alternative), is activated by this agent in mature B cells. Immunoblotting analyses showed that LPS induced a time-dependent degradation of the NF-kappaB inhibitors IkappaBbeta and IkappaBepsilon (preferentially to isoform IkappaBalpha), via IkappaB kinase beta. In addition, we observed that LPS triggered the processing of NF-kappaB p105 to p50 and that of NF-kappaB p100 to p52 in parallel with nuclear translocation of active p50 and p52, as NF-kappaBp50/RelA and NF-kappaBp52/RelB heterodimers, respectively. These results suggest that sustained stimulation with LPS can activate NF-kappaB through both classical and alternative pathways.
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PMID:Lipopolysaccharide from Salmonella enterica activates NF-kappaB through both classical and alternative pathways in primary B Lymphocytes. 1769 69

Studies with diverse teratogens implicated the transcription factor NF-kappaB in mechanisms determining teratological susceptibility of embryos. Here, a teratogen such as cyclophosphamide (CP) was used to test whether teratogenic insult alters the classical NF-kappaB activation pathway, and how these alterations correlate with the ability of mouse embryos to resist the teratogen-induced process of maldevelopment. We observed that embryos tested 24 h after the exposure of females to 40 mg/kg CP exhibited a dramatic decrease in the level of NF-kappaB (p65 subunit)-DNA binding, IkappaB kinase beta (IKKbeta) activity, expression of p65 and IKKbeta proteins, as well as NF-kappaB inhibitory proteins (IkappaBs) such as IkappaBalpha, IkappaBbeta, and IkappaBepsilon, and died within the next 24 h. Embryos of females exposed to 15 mg/kg CP exhibited only a decrease in NF-kappaB-DNA binding and IKKbeta activity at 24 h. However, at 48 h, a more prominent decrease in NF-kappaB activity was observed, accompanied by a decreased expression of p65 and IKKbeta proteins. These embryos died within the next 24 h. After treatment with 10 mg/kg CP, embryos survived until the end of the antenatal period of development, demonstrating a transient decrease in NF-kappaB-DNA binding activity and no alterations in NF-kappaB signaling. These results suggest that the classical NF-kappaB activation pathway may be among targets that teratogens engage to initiate abnormal development. Besides, the observation that embryos destined to be dead exhibited a dramatically decreased rate of cell proliferation suggests a pathway, whereby teratogen-induced alterations in NF-kappaB signaling may culminate in such a final effect as embryonic death.
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PMID:Teratogen-induced distortions in the classical NF-kappaB activation pathway: correlation with the ability of embryos to survive teratogenic stress. 1839 65

Anthrax lethal toxin (LT) was previously shown to enhance transcriptional activity of NF-kappaB in tumor necrosis factor-alpha-activated primary human endothelial cells. Here we show that this LT-mediated increase in NF-kappaB activation is associated with the enhanced degradation of the inhibitory proteins IkappaBalpha and IkappaBbeta but not IkappaBepsilon. Moreover, this was accompanied by enhanced activation of the IkappaB kinase complex (IKK), which is responsible for targeting IkappaB proteins for degradation. Importantly, LT enhancement of IkappaBalpha degradation was completely blocked by a selective IKKbeta inhibitor, whereas IkappaBbeta degradation was attenuated, suggesting a mechanistic link. Consistent with the above data, LT-cotreated cells show elevated phosphorylation of two IKK substrates, IkappaBalpha and p65, both of which were blocked by incubation with the IKKbeta inhibitor. Consistent with NF-kappaB activation, LT increased transcription of the NF-kappaB regulated gene CD40. Conversely, LT inhibited transcription of another NF-kappaB-regulated gene, CCL2. This inhibition was linked to the LT-mediated suppression of another CCL2-regulating transcription factor, AP-1 (activator protein-1). These data suggest that LT-mediated enhancement of NF-kappaB is IKK-dependent, but importantly, the net effect of LT on the transcription of proinflammatory genes is driven by the cumulative effect of LT on the particular set of transcription factors that regulate a given promoter. Together, these findings provide new mechanistic insight on how LT may disrupt the host response to anthrax.
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PMID:Anthrax lethal toxin enhances IkappaB kinase activation and differentially regulates pro-inflammatory genes in human endothelium. 1962 Jul 8


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