Disease relevance of NFKB1

• Furthermore, cotransfection of NFKB1 and RelA, although able to support activation from the human immunodeficiency virus type 1 long terminal repeat, failed to activate expression from the IL-8 promoter [1].
• Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis [2].
• Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer [3].
• Transient cotransfection experiments demonstrated that RelA and NFKB1 expression maximally stimulated HIV-1 LTR- and NF-kappa B-dependent reporter genes; differences in NF-kappa B-like binding activity were also reflected in higher constitutive levels of NF-kappa B-regulated gene expression in HIV-1-infected myeloid cells [4].
• The aim of the present study was to confirm the association of the -94ins/delATTG (W/D) NFKB1 promoter polymorphism with UC in a population of German origin and to test for a potential association with Crohn's disease (CD) [5].
• These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma [6].
• Constitutive NF-kappaB activation was observed in 40% of colorectal cancer tissues and 67% of cell lines [7].

Psychiatry related information on NFKB1

• Apart from its role in these events, evidence has begun to accumulate that NF-kappa B is involved in brain function, particularly following injury and in neurodegenerative conditions such as Alzheimer's disease [8].
• The presence of regulatory sequences for the binding of transcription factors such as NF-kappa B and AP-2, whose activation is associated with the immediate response of the cell to an injury, may be an indication of the important role which HO-1 may play in defense mechanisms against tissue injury [9].
• Thus this NF-kappa B-like factor may be involved in the mechanism causing AIDS dementia [10].
• RESULTS: Levels of RNA transcripts encoding the serotonin transporter protein and components of the NF-kappa B transcription factor complex are significantly increased in individuals with bipolar disorder compared with unaffected controls [11].

High impact information on NFKB1

• Recent data provide evidence that NF-kappa B is constitutively active in several cell types, potentially playing unexpected roles in regulation of gene expression [12].
• Function and activation of NF-kappa B in the immune system [13].
• Interference with the activation or activity of NF-kappa B may be beneficial in suppressing toxic/septic shock, graft-vs-host reactions, acute inflammatory reactions, acute phase response, and radiation damage [13].
• A signaling pathway involving guanosine 3',5'-cyclic monophosphate is activated by sAPP alpha and modulates the activities of potassium channels, N-methyl-D-aspartate receptors, and the transcription factor NF kappa B. Additional functions of beta-APP may include modulation of cell adhesion and regulation of proliferation of nonneuronal cells [14].
• The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene [15].

Chemical compound and disease context of NFKB1

• This study demonstrates that lipopolysaccharide (LPS) mediates induction of transcription factor NF kappa B and activation of the cytomegalovirus (CMV) promoter-enhancer in the SW480 cell line [16].
• Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum [17].
• Luciferase reporter gene assays and Western blot analysis in human fibrosarcoma HT1080 cells and HMC were performed to analyze the effect of simvastatin on the transcription factors nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1), which regulate tissue factor gene expression [18].
• The inhibitory effects of clarithromycin on NF-kappa B activation and IL-8 production in adenoidal fibroblasts might explain, in part, the mechanism of this drug in improving otitis media with effusion [19].
• OSCC with lymph node metastasis or advanced stage had significantly higher frequency of NFKB1 ins and HO-1 L allelotypes [20].

Biological context of NFKB1

• NFKB1 promoter/exon 1 luciferase reporter plasmid constructs containing the -94delATTG allele and transfected into either HeLa or HT-29 cell lines showed less promoter activity than comparable constructs containing the -94insATTG allele [2].
• Genome-wide screens in IBD families show evidence for linkage on chromosome 4q where NFKB1 maps [2].
• We sequenced the NFKB1 promoter, exon 1 and all coding exons in 10 IBD probands and two controls, and identified six nucleotide variants, including a common insertion/deletion promoter polymorphism (-94ins/delATTG) [2].
• We also studied a single nucleotide polymorphism in intron 11 of the NFKB1 gene (rs1020759), which probably lacks any functional role, and found no significant association with the disease [3].
• The U2 subgroup was associated with overexpression of genes involved in T-cell activation and apoptosis, including NFKB1 and BCL-2 [21].

Anatomical context of NFKB1

• Antisense oligonucleotides to RelA, but not NFKB1, inhibited phorbol myristate acetate-induced IL-8 production in Jurkat T lymphocytes [1].
• This response arises from exceedingly low basal expression of the p105/p50 NF-kappaB subunit encoded by the NFKB1 gene in these cell lines [22].
• 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 [23].
• Here, we show that NTHi strongly activates NF-kappa B in human epithelial cells via two distinct signaling pathways, NF-kappa B translocation-dependent and -independent pathways [24].
• Inflammatory stimulation of endothelial cells by tumor necrosis factor alpha (TNF-alpha) involves activation of nuclear factor kappa B (NF-kappa B) and p38 mitogen-activated protein (MAP) kinase signaling pathways [25].

Associations of NFKB1 with chemical compounds

• However, expression of the death domain of RIP Induces apoptosis, but potently inhibits NF-kappa B activation by TNF [26].
• Anti-beta(2)-GPI antibody binding has been shown to induce nuclear factor-kappa B (NF-kappa B) translocation leading to a proinflammatory EC phenotype similar to that elicited by interaction with microbial products (lipopolysaccharide [LPS]) and proinflammatory cytokines (interleukin 1 beta [IL-1 beta], tumor necrosis factor alpha [TNF-alpha]) [27].
• Thus, we have explored the effect of two inhibitors of the NF-kappa B activation, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), on the production of these cytokines by EC [28].
• Extracellular SMase does not have access to intracellular sphingomyelin, but treatment of ECs with membrane-permeant ceramide analogues still completely fails to activate NF-kappa B and only activates JNK at late times [29].
• These data reveal a second mechanism by which NF-kappa B activity may be regulated by DEX [30].
• Small interfering RNA-mediated knockdown of beclin 1 and atg7 expression, two autophagy-related genes, reduced TNFalpha- and reactive oxygen species-induced apoptosis in cells lacking NF-kappaB activation and in NF-kappaB-competent cells, respectively [31].
• Overall, our results demonstrate that gossypin inhibits the NF-kappaB activation pathway, which may explain its role in the suppression of inflammation, carcinogenesis, and angiogenesis [32].
• These effects were not observed in a form of Cezanne that was mutated at the catalytic cysteine residue (Cys209), indicating that the deubiquitinating activity of Cezanne is essential for NF-kappaB regulation [33].
• In addition LC8 inhibited NF-kappaB activation by other stimuli including interleukin-1beta and lipopolysaccharide, both of which generated reactive oxygen species [34].

Physical interactions of NFKB1

• Both the NF-IL6 and NF-kappa B binding sites in the IL-6 promoter were required for synergistic activation [35].
• We show here that NF-kappa B p100 is a component of the previously identified DNA-binding activity H2TF1 [36].
• In addition, ATFa, ATF2, and ATF3 interact directly with NF-kappa B in vitro, linking two unrelated families of transcription factors in a novel protein-protein interaction [37].
• We found that the IL-8 NF-kappa B-binding site specifically formed a complex with NF-kappa B-containing nuclear extracts from HTLV-I-infected T-cell lines and freshly isolated leukemic cells from adult T-cell leukemia patients [38].
• The exposure of MC to AIgA rapidly activated a NF-kappa B complex constituted of p50 and p65 subunits [39].
• UXT forms a dynamic complex with NF-kappaB and is recruited to the NF-kappaB enhanceosome upon stimulation [40].

Enzymatic interactions of NFKB1

• In promoter-reporter assay, the luciferase activities of the reporter constructs, including the putative NF-kappa B site deleted and mutated form were significantly reduced after HRG-beta 1 treatment as compared with the 1.5-kb VEGF-C promoter [41].
• Western blot analyses and electrophoretic mobility shift assays revealed that incubation with TNF alpha induced the expression of phosphorylated inhibitor kappa B (p-I kappa B) and activation of NF-kappa B in endometriotic stromal cells [42].
• We demonstrate that Ebp1 interacts with and is phosphorylated by the PKR protein kinase [43].
• A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B [44].

Regulatory relationships of NFKB1

• TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival [45].
• PKC blockade with H7 does not inhibit activation of these NF-kappa B-like proteins but does inhibit ELAM-1 gene transcription [46].
• We find that concentrations of TNF that strongly activate NF-kappa B and JNK within 15 minutes do not produce either a measurable decline in sphingomyelin or a measurable generation of ceramide in cultured human umbilical vein ECs at any time examined [29].
• CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling [47].
• Thus, the IL-1 beta gene may be considered as an important additional member of the family of cytokine genes regulated in part by the NF-kappa B/rel family of transcription factors [48].
• We find that HMGB1 activates the canonical nuclear factor kappaB (NF-kappaB) pathway via extracellular signal-regulated kinase phosphorylation [49].

Other interactions of NFKB1

• Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated [45].
• The death domain of tumor necrosis factor (TNF) receptor-1 (TNFR1) triggers distinct signaling pathways leading to apoptosis and NF-kappa B activation through its interaction with the death domain protein TRADD [26].
• We show that induction of a trimer of the NFAT and Oct sites is not sensitive to phorbol ester treatment, and that mutations in the NF-kappa B site have no effect on inducibility of the IL-2 promoter [50].
• Here we report that transient expression of TRAF6 stimulated both ERK and NF kappa B activity in the 293 cell line [51].
• NF-kappa B and p53 activation was assessed by electromobility shift assays [52].
• RPS3 knockdown impaired NF-kappaB-mediated transcription of selected p65 target genes but not nuclear shuttling or global protein translation [53].

Analytical, diagnostic and therapeutic context of NFKB1

• Site-directed mutagenesis of a cis-acting DNA element at -5.8 kb in the hiNOS promoter identifies a bifunctional NF-kappa B/Stat 1 motif [54].
• Sequence analysis of the 5' flanking region of the ELAM-1 gene reveals consensus DNA-binding sequences for two known transcription factors, NF-kappa B and AP-1 [46].
• Thus, nuclear factor-kappa B (NF-kappa B) was activated in bone marrow (BM) and cord blood (CB) progenitors, whereas signal transducer and activator of transcription 3 (STAT3) and STAT5 activation was restricted to peripheral granulocyte-colony-stimulating factor (G-CSF)-mobilized and BM progenitors, respectively [55].
• In addition, NF kappa B-binding proteins obtained from both lines showed, in electrophoretic mobility shift assays, the same migration pattern as T-cell-derived proteins but differed from monocyte- and B-cell-derived proteins [56].
• Cytosolic to nuclear translocation of NF-kappa B was confirmed by Western immunoblot and immunocytochemical analyses [57].

References