Disease relevance of Nfkbia

• IkappaBalpha deficiency results in a sustained NF-kappaB response and severe widespread dermatitis in mice [1].
• These results provide evidence that NF-KB and IkappaBalpha play an important role in survival, constitutive and inducible expression of proinflammatory cytokines, and growth of squamous cell carcinoma [2].
• RESULTS: The IkappaBalpha super-repressor adenovirus infection caused a moderate reduction of NF-kappaB activity in liver [3].
• Neuronal activity and transcription of proinflammatory cytokines, IkappaBalpha, and iNOS in the mouse brain during acute endotoxemia and chronic infection with Trypanosoma brucei brucei [4].
• Additionally, we found evidence that PIR IkappaBalpha degradation controls constitutive NF-kappaB activation in certain multiple myeloma cells [5].

High impact information on Nfkbia

• In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR) [6].
• Growth arrest triggered by oncogenic Ras can be bypassed by IkappaBalpha-mediated blockade of NF-kappaB, generating malignant human epidermal tissue resembling squamous cell carcinoma [7].
• Here, we directed a degradation-resistant IkappaBalpha transgene to mouse hepatocytes in an inducible manner and showed substantial tissue specificity using various means, including a new method for live-animal imaging [8].
• The subsequent molecular events that regulate the termination of nuclear NF-kappaB action remain poorly defined, although the activation of de novo IkappaBalpha gene expression by NF-kappaB likely plays a key role [9].
• This deacetylation reaction promotes effective binding to IkappaBalpha and leads in turn to IkappaBalpha-dependent nuclear export of the complex through a chromosomal region maintenance-1 (CRM-1)-dependent pathway [9].

Chemical compound and disease context of Nfkbia

• Here we describe that adenoviral expression of the NF-kappaB inhibitory protein ABIN-1, but not an IkappaBalpha superrepressor (IkappaBalpha(s)), completely prevents lethality in the TNF/D-(+)-galactosamine-induced model of liver failure [10].
• As examined by electrophoretic mobility gel shift assay, paclitaxel activated NF-kappaB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of IkappaBalpha kinase activation and IkappaBalpha phosphorylation and degradation [11].
• To evaluate the contribution of NF-kappaB activation to excitotoxic insult, we analysed the effect of IkappaBalpha (IkappaBalpha) phosphorylation blockade on glutamate-induced toxicity in adult mouse hippocampal slices [12].
• To improve the effectiveness of herpes simplex virus (HSV) thymidine kinase/ganciclovir (HSV-tk/GCV) suicide gene therapy, the replication-defective HSV vector TOIkappaB expressing both HSV-TK and a mutant form of the NF-kappaB inhibitor IkappaBalpha (IkappaBalphaM) was developed [13].
• RESULTS: In unmanipulated mice, degradation of IkappaBalpha, as occurs after serine phosphorylation, was evident in liver by the end of ischemia and during early reperfusion [14].

Biological context of Nfkbia

• The sensitivity and kinetics of TNF-alpha-induced apoptosis are shown to be enhanced in a number of cell types expressing a dominant-negative IkappaBalpha (IkappaBalphaM) [15].
• Activation of nuclear factor-kappaB by core and NS3 was associated with increased IkappaBalpha phosphorylation [16].
• Recruitment of IKKs to the nucleus in response to TNF-alpha may induce chromatin-associated IkappaBalpha release and gene activation [17].
• Acetylation at lysines 218, 221, and 310 differentially regulates RelA's DNA binding activity, assembly with IkappaBalpha, and transcriptional activity [18].
• We found a distinct consensus sequence within this domain of IkappaBalpha for PIR degradation [19].

Anatomical context of Nfkbia

• In most cell types other than mature B lymphocytes and macrophages, the transcription factor NF-kappaB remains in an inactive form in the cytosol by being bound to the inhibitory proteins IkappaBalpha and IkappaBbeta [20].
• Thus, our findings suggest that nonconventional PIR degradation of IkappaBalpha may play a physiological role in the development of B cells in vivo [19].
• After transfection with IKBalphaM, only a few UM-SCC-9 clones were obtained that stably expressed the mutant IkappaB, suggesting that expression of a mutant IkappaBalpha may affect survival of the transfected UM-SCC cell lines [2].
• Primary murine splenic B cells but not T cells were found to contain high levels of IkappaBepsilon protein, equivalent to levels of the abundant IkappaBalpha [21].
• Surprisingly, immunodepletion of cellular extracts suggests IKKalpha is predominantly responsible for IkappaBalpha phosphorylation in intestinal epithelial cells [22].

Associations of Nfkbia with chemical compounds

• Serine 927 resides in a conserved motif (Asp-Ser(927)-Gly-Val-Glu-Thr-Ser(932)) homologous to the IKK target sequence in IkappaBalpha [23].
• We show that this degradation induced by a chemotherapeutic agent, doxorubicin (DoxR), does not require the classical serine 32 and 36 phosphorylation or the PEST domain of IkappaBalpha [24].
• Degradation of IkappaBalpha is partially blocked by phosphatidylinositol 3-kinase inhibitor LY294002 and is mediated by the proteasome [24].
• Glutamate produced a delayed and transient activation of NF-kappaB/Rel, which was associated with a brief loss of IkappaBalpha [25].
• The decrease in cytoplasmic levels of IkappaBalpha produced by exposure of neutrophils to LPS was prevented by N-acetylcysteine or alpha-tocopherol [26].

Enzymatic interactions of Nfkbia

• Unlike canonical signaling pathways that promote IkappaBalpha phosphorylation and degradation, eIF2alpha phosphorylation did not increase phosphorylated IkappaBalpha levels or affect the stability of the protein [27].
• Recombinant mPLK produced in bacteria is a protein kinase capable of autophosphorylating and phosphorylating IkappaBalpha [28].
• In addition, haloperidol induces the DNA binding activity of the redox-sensitive nuclear factor-kappa B (NF-kappaB) and concomitantly upregulates the levels of the phosphorylated form of IkappaBalpha protein in vivo [29].
• The aim of this work was to investigate whether in vivo and in vitro pentoxifylline (PTX) sensitizes hematological tumor cells to adriamycin (ADM)-induced apoptosis, and to investigate the involvement of caspase cascades and phosphorylated forms of IkappaBalpha [30].

Regulatory relationships of Nfkbia

• We hypothesize that IKK1 plays a checkpoint role in the proper control of IkappaBalpha kinase activity in innate and adaptive immunity [31].
• The delayed restoration of IkappaBalpha in pathogen-activated IKK1-/- ELDM was a direct consequence of uncontrolled IKK2 kinase activity [31].
• The effect on nuclear factor-kappaB (NF-kappaB) activation correlated with RANKL-induced IkappaBalpha kinase activation [32].
• The sequential engagement of two distinct pathways, coupled with the negative feedback inhibition of RelA complexes by NF-kappaB-induced resynthesis of IkappaBalpha, resulted in a pronounced temporal change in the nature of the NF-kappaB activity during the course of stimulation [33].
• Furthermore, the production of super-repressor IkappaBalpha suppressed the increase in blood glucose level after pyruvate injection [3].

Other interactions of Nfkbia

• Increased NFkappaB activity in IKK1 mutant ELDM was the result of prolonged degradation of IkappaBalpha in response to infectious pathogens [31].
• Upon stimulation, rapid degradation of IkappaBalpha allows nuclear translocation of NF-kappaB [1].
• Expression of certain NF-kappaB-regulated genes, such as IkappaBalpha and macrophage inflammatory protein 2, is minimally affected by the absence of GSK-3beta [34].
• 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 [35].
• Both vanadate-induced degradation of IkappaBalpha and activation of JNK were potently inhibited by pretreatment of cells with N-acetylcysteine or dimercaprol [36].

Analytical, diagnostic and therapeutic context of Nfkbia

• To study the importance of IkappaBalpha in signal transduction, IkappaBalpha-deficient mice were derived by gene targeting [1].
• Phosphorylation of ERK, p38MAPK and IkappaBalpha was detected by Western blotting [37].
• METHODS: TNF-alpha was administered to BALB/c mice after treatment with an adenovirus expressing a mutant form IkappaBalpha (Ad5IkappaB), the PI3K inhibitor wortmannin, or both [38].
• In WT astrocytes, phospho-IkappaBalpha was highly expressed after oxygen-glucose deprivation (OGD) and 2 h of reperfusion, concomitant with the decrease in IkappaBalpha [39].
• IkappaBalpha overexpressing mice were given a third-degree scald burn over 40% of the total body surface area or wild-type littermates were given either a scald or sham burn to provide appropriate controls [40].

References