Disease relevance of Nfkbib

• Inhibition of anchorage-independent growth and lung metastasis of A549 lung carcinoma cells by IkappaBbeta [1].
• To evaluate the role of the NF-kappaB signaling pathway in oncogenic transformation, we expressed IkappaBbeta, a specific inhibitor of NF-kappaB, in two human lung adenocarcinoma cell lines, A549 and H441 [1].
• Transfection with a plasmid containing cDNA encoding mouse IkappaBbeta, an inhibitor of NF-kappaB, resulted in increased toxicity by menadione [2].
• CONCLUSION: This represents the first example of an inhibitor of IkappaB kinase with anti-inflammatory activity in vivo and indicates that inhibitors of IkB kinase show the promise of being highly efficacious in inflammatory disorders such as inflammatory bowel disease [3].
• The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain [4].

High impact information on Nfkbib

• The knock-in mice do not express IkappaBalpha, but express a T7-tagged IkappaBbeta under the promoter and regulatory sequence of ikba [5].
• IkappaBalpha and IkappaBbeta possess injury context-specific functions that uniquely influence hepatic NF-kappaB induction and inflammation [6].
• Chemical cross-linking and coimmunoprecipitation show that NFkappaB/Rel factor-bound IkappaBbeta forms a ternary complex with Cn under in vitro and in vivo conditions that was sensitive to FK506 [7].
• Results show that phosphorylation at S313 and S315 from the COOH-terminal PEST domain of IkappaBbeta is critical for binding to Cn [7].
• Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta [7].

Biological context of Nfkbib

• Assignment of Nfkbib to murine chromosome bands 7A3-B3 by in situ hybridization [8].
• Finally, we show that in p65(-/-) fibroblasts, expression of a proteolysis-resistant form of IkappaBbeta, but not IkappaBalpha, causes a severe growth defect associated with apoptosis [9].
• Based on these findings, we propose that tight control of IkappaBbeta protein by p65 is necessary for the maintenance of cellular homeostasis [9].
• The mouse IkappaBbeta gene contains six exons and five introns that span 7435 nucleotides [10].
• We suggest that products of the enzymatic activity of phospholipases directly interfere with host cell signal transduction pathways, thus leading to persistent NF-kappaB activation via persistent IkappaBbeta degradation [11].

Anatomical context of Nfkbib

• 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 [12].
• Using p65(-/-) fibroblasts, we show that IkappaBbeta is profoundly reduced in these cells, but not in other NF-kappaB subunit knockouts [9].
• Immunolocalization of newly synthesized IkappaBbeta by confocal microscopy revealed its preferential accumulation in the cytosol [13].
• Rapid Up-regulation of IkappaBbeta and abrogation of NF-kappaB activity in peritoneal macrophages stimulated with lipopolysaccharide [13].
• Furthermore, treatment with MG-132 increased levels of multiubiquitinated IkappaBbeta protein in ts1-infected astrocytes [14].

Associations of Nfkbib with chemical compounds

• However Lys-9, the unique lysine residue in the NH2-terminal region of IkappaBbeta, is not absolutely required for its degradation [15].
• Detailed examination of the NF-kappaB cascade revealed that cardiac cells displayed a unique pattern of IkappaB degradation in response to LPS, with IkappaBbeta but not IkappaBalpha being degraded upon stimulation [16].
• Degradation of IkappaBbeta and the translocation of the NF-kappaB (p50/RelA) into the nucleus, which occurred at 1.5 hr after anti-CD3 activation, were inhibited by lactacystin [17].
• Pretreatment (for 1 h) of murine macrophages or rat aortic smooth muscle cells (activated with endotoxin) with calpain inhibitor I attenuated the binding of activated NF-kappaB to DNA and the degradation of IkappaBalpha, IkappaBbeta, and IkappaBvarepsilon [18].
• Analysis of IkappaBbeta by Western blot using high resolution polyacrylamide gel electrophoresis showed the presence of two bands in cytosolic extracts of LPS-treated macrophages at 3 h, but only one band with the same mobility as the control was detected at 6 h [13].

Physical interactions of Nfkbib

• IkappaBbeta complex crystals were formed by analogy to NF-kappaB [19].

Other interactions of Nfkbib

• Mutations at S313/S315 of IkappaBbeta abolished Cn binding, inhibited Cn-mediated increase of Rel proteins in the nucleus, and had a dominant-negative effect on the mitochondrial stress-induced expression of RyR1 and cathepsin L genes [7].
• Activation of this pathway requires the PKR-dependent degradation of the IkappaBbeta protein [20].
• When the effect of pro-inflammatory cytokines was investigated, tumor necrosis factor alpha, but not interleukin-1 or interferon-gamma, promoted an important degradation of IkappaBbeta followed by an increase in the mRNA at 1 h [13].
• Moreover, treatment of extracts of resynthesized IkappaBbeta with alkaline phosphatase resulted in the accumulation of the protein of slightly higher electrophoretic mobility, indicating the prevalence of a rapid phosphorylation of the newly synthesized IkappaBbeta [13].

Analytical, diagnostic and therapeutic context of Nfkbib

• Bronchoalveolar lavage IkappaBalpha/IkappaBbeta proteins were measured by immunoblot [21].

References