Disease relevance of NFKBIA

• To assess the role of nuclear factor kappaB (NFKB) in cellular radiosensitivity, three different IkappaB-alpha (also known as NFKBIA) expression plasmids, i.e., S-IkappaB (mutations at (32, 36)Ser), Y-IkappaB (a mutation at (42)Tyr), and SY-IkappaB, were constructed and introduced into human brain tumor M054 cells [1].
• This study investigated common variants within the genes coding for NF-kappaB and IkappaB, NFKB1 and NFKBIA, for involvement in sporadic breast cancer [2].
• A polymorphism of the NFKBIA gene is associated with Crohn's disease patients lacking a predisposing allele of the CARD15 gene [3].
• Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells [4].
• These results suggest that JD and EqM can induce apoptosis in IkappaBalpha-deficient lymphoma cells through a mechanism involving direct inhibition of transcription factor REL [5].
• Experiments in cells exposed to cycles of H/R followed by hypoxia demonstrated differential patterns of SUMOylation and phosphorylation of IkappaBalpha, greatly impacting its proteosomal degradation by the 26 S proteasome [6].

Psychiatry related information on NFKBIA

• Further, LPS-induced IkappaBalpha degradation was not affected by acute alcohol consumption indicating an IkappaBalpha-independent mechanism, as observed earlier in the in vitro acute alcohol studies [7].

High impact information on NFKBIA

• The position of the sixth ankyrin repeat shows that full-length IkappaBalpha will occlude the NF-kappaB DNA-binding cleft [8].
• It shows a stack of six IkappaBalpha ankyrin repeats facing the C-terminal domains of the NF-kappaB Rel homology regions [8].
• Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity [9].
• The MAD-3 cDNA encodes an I kappa B-like protein that is likely to be involved in regulation of transcriptional responses to NF-kappa B, including adhesion-dependent pathways of monocyte activation [10].
• Surprisingly, GR was recruited to both of these elements, despite the fact that GR failed to repress the IkappaBalpha promoter [11].

Chemical compound and disease context of NFKBIA

• The molecular mechanism(s) by which hypoxia/reoxygenation (H/R) regulates p56lck-dependent activation of NFkappaB through tyrosine phosphorylation of IkappaBalpha and modulates the expression of downstream genes that are involved in cell migration in human breast cancer cells are not well defined [12].
• Tumor necrosis factor-alpha-induced apoptosis in prostate cancer cells through inhibition of nuclear factor-kappaB by an IkappaBalpha "super-repressor" [13].
• Using monocytic cells stably expressing different transdominant molecules of IkappaBalpha, we determined that persistent HIV infection of these cells targets the NH2 but not the COOH terminus of IkappaBalpha [14].
• Carbachol activated NF-kappaB in human 1321N1 astrocytoma cells, as evidenced by translocation of the p65 subunit of NF-kappaB to the nucleus, phosphorylation and degradation of IkappaBalpha in the cytosol, and increase NF-kappaB binding to DNA [15].
• Furthermore, resveratrol did not protect IkappaBalpha, a cytoplasmic NF-kappaB inhibitor, from degradation in HSV-1 infected cells [16].

Biological context of NFKBIA

• A protecting allele was found in the NFKBIA promotor for the patients with primary progressive MS (15.4% vs 28.4% in the control group, P < 0.01) [17].
• No association was noted with any of the SNP tested for the single locus associations in NFKB1, RelA, and NFKBIA or with multi-locus haplotypes [18].
• Unlike ubiquitin modification, which requires phosphorylation of S32 and S36, SUMO-1 modification of IkappaBalpha is inhibited by phosphorylation [19].
• Deletion of either site or overexpression of dominant negative IkappaBalpha led to reduced levels of TNF-alpha/IFN-gamma-stimulated reporter gene activity [20].
• Transfection experiments demonstrate that the MAD3 promoter can be activated by various combinations of members of the rel/NF-kappa B family, as well as by phorbol esters and tumor necrosis factor [21].

Anatomical context of NFKBIA

• Based on our data we present a new model of NF-kappaB regulation in human neutrophils by nuclear IkappaBalpha [22].
• Here we characterized the apparent inability of newly synthesized IkappaBalpha to terminate activation of NFkappaB in glial cells [23].
• Here, we report that melanocytes expressing a conditionally oncogenic form of BRAF(V600E) exhibit enhanced beta-Trcp expression, increased IKK activity and a concomitant increase in the rate of IkappaBalpha degradation [24].
• VZV infection also inhibited the characteristic degradation of IkappaBalpha that is induced by exposure of fibroblasts to tumor necrosis factor alpha [25].
• PI-3K/Akt and NF-kappaB/IkappaBalpha pathways are activated in Jurkat T cells in response to TRAIL treatment [26].

Associations of NFKBIA with chemical compounds

• The nuclear export inhibitor leptomycin B (LMB) sequestered NF-kappaB/IkappaBalpha complexes in the nucleus [27].
• Results further demonstrate that the pathway can be blocked by treatment with pharmacologic doses of a specific protease inhibitor, pepstatin-A, even in the presence of a mutated NF-kappa B inhibitor, I-kappa B alpha [28].
• We found that H2O2 induced the tyrosine phosphorylation of IkappaBalpha, which is needed for NF-kappaB activation [29].
• Although H2O2 activated IkappaBalpha kinase, it did not induce the serine phosphorylation of IkappaBalpha [29].
• Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) suppresses NF-kappaB activation and NF-kappaB-regulated gene products through modulation of p65 and IkappaBalpha kinase activation, leading to potentiation of apoptosis induced by cytokine and chemotherapeutic agents [30].

Physical interactions of NFKBIA

• Both beta-arrestin 1 and 2 interact with IkappaBalpha in transfected cells as assessed by immunoprecipitation experiments [31].
• The synthetic epoxyquinoids jesterone dimer and epoxyquinone A monomer induce apoptosis and inhibit REL (human c-Rel) DNA binding in an IkappaBalpha-deficient diffuse large B-cell lymphoma cell line [5].
• Unexpectedly, our in vivo studies also demonstrate that I kappa B/MAD-3 binds directly to NF-kappa B p50 [32].
• Addition of the structurally unrelated NO donors S-nitrosoglutathione (300 microM) or sodium nitroprusside (1 mM) before low shear stress significantly increased cytoplasmic IkappaBalpha and concomitantly reduced NF-kappaB binding activity and kappaB-dependent VCAM-1 promoter activity [33].
• The phosphorylation of IkappaBalpha on Ser(32) and Ser(36) is initiated by an IkappaB kinase (IKK) complex that includes a catalytic heterodimer composed of IkappaB kinase 1 (IKK-1) and IkappaB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator [34].

Enzymatic interactions of NFKBIA

• PMA activates PKC (protein kinase C) enzymes which phosphorylate IkappaBalpha, leading to its degradation, therefore we used GF109203X to inhibit PKC activity [35].
• Therefore, these results indicate that beta-TrCP plays a critical role in the activation of NF-kappaB by assembling the ubiquitin ligase complex for both phosphorylated IkappaBalpha and IkappaBbeta [36].
• Transfection of a dominant negative mutant IkappaBalpha protein that cannot be serine phosphorylated led to suppression of IL-8 promoter activity [37].
• TBK-1 and IKK-i phosphorylate Ser(36) of IkappaBalpha [34].
• Using an in vitro dephosphorylation reaction, we found that FAP-1 dephosphorylates IkappaBalpha [38].

Regulatory relationships of NFKBIA

• beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha [31].
• We also show that a S32/36 IkappaBalpha mutant blocks EGFR-induced NF-kappaB activation [39].
• In addition, overexpression of the dominant inhibitory mutant (S32A/S36A) of IkappaBalpha inhibited PMA-stimulated and RSK1-enhanced megakaryocytic differentiation, indicating that NF-kappaB mediates a signal for megakaryocytic differentiation downstream of RSK1 [40].
• In addition, treatment with SFN and PEITC potently inhibited phosphorylation of both IKKbeta and IKKalpha and significantly inhibited the in vitro phosphorylation of IkappaBalpha mediated by IKKbeta [4].
• Analogous to treatments with SFN and PEITC, SR-IkappaBalpha also strongly inhibited NF-kappaB transcriptional activity as well as VEGF, cylcin D1, and Bcl-X(L) expression [4].

Other interactions of NFKBIA

• Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation [19].
• By using a yeast two-hybrid screen, we identified the inhibitor of NF-kappaB, IkappaBalpha, as a binding partner of beta-arrestin 1 [31].
• This transcription factor is regulated by a family of structurally related inhibitors including IkappaBalpha, IkappaBbeta, and IkappaBepsilon, which trap NF-kappaB in the cytoplasm [41].
• In the resting cell, RhoA suppresses Cdc42 activation, IkappaBalpha degradation, nuclear factor-kappaB (NF-kappaB) activation, and induction of TNFalpha and NF-kappaB-dependent chemokines [42].
• Suppression of NF-kappaB activity in PC-3 cells by a mutant IkappaBalpha super-repressor adenoviral vector decreased the CXCR4 mRNA expression and inhibited adhesion and TEM [43].

Analytical, diagnostic and therapeutic context of NFKBIA

• Using deletion and site-directed mutagenesis, we identified a previously uncharacterized nuclear export sequence in residues 45-54 of IkappaBalpha that was required for cytoplasmic localization of inactive complexes [27].
• Immunofluorescence experiments demonstrated further that IkappaBalpha acts by partially redirecting HDAC3 to the cytoplasm [44].
• The level of IkappaBalpha in Mo was detected by Western blot analysis [45].
• Additionally, inhibition of these transcription factors using adenovirus vectors encoding either the IkappaBalpha repressor gene or a dominant negative JunD mutant leads to a strong down-regulation of IL-6 gene expression at the mRNA and protein level as measured by real-time PCR and ELISA, respectively [46].
• 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 [47].

References