Disease relevance of Nfkb1

• We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD) [1].
• Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2 [2].
• Activation of transcription factor NF-kappaB in the central nervous system (CNS) has been linked to autoimmune demyelinating disease; however, it remains unclear whether its function is protective or pathogenic [3].
• Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice [3].
• In the absence of the p50, however, relB(-/+) mice (p50(-/-)relB(-/+)) had a mild inflammatory phenotype and moderate myeloid hyperplasia [4].
• The defect in response to IL-10-Ig appeared to be primarily the result of the absence of the p50/p105 subunit, because the ability of IL-10-Ig to inhibit colitis was also compromised in p50(-/-); RAG-2(-/-) (p50/RAG) mice [5].

Psychiatry related information on Nfkb1

• These results demonstrate that water deprivation and hypertonicity activate NF-kappaB [6].
• Decreased ChAT expression and increased NF-kappaB activity in the brain are associated with aging and Alzheimer's disease [7].
• NF-kappaB is a ubiquitous transcription factor that is extensively exploited by immune cells involved in host defense mechanisms [8].
• Chronic alcohol consumption accelerates liver injury in T cell-mediated hepatitis: alcohol disregulation of NF-kappaB and STAT3 signaling pathways [9].
• Neuroprotective role for the p50 subunit of NF-kappaB in an experimental model of Huntington's disease [10].

High impact information on Nfkb1

• Another exciting development has been the demonstration that in certain situations NF-kappa B acts as an anti-apoptotic protein; therefore, elucidation of the mechanism by which NF-kappa B protects against cell death is an important goal [11].
• Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling [12].
• IkappaB kinase beta (IKKbeta), required for NF-kappaB activation, links chronic inflammation with carcinogenesis [13].
• Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response [14].
• Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear [14].

Chemical compound and disease context of Nfkb1

• Estrogen withdrawal-induced NF-kappaB activity and bcl-3 expression in breast cancer cells: roles in growth and hormone independence [15].
• We propose that E2 withdrawal may initiate selection for hormone independence in breast cancer cells by activation of NF-kappaB and Bcl-3, which could then supplant E2 by providing both survival and growth signals [15].
• Lipopolysaccharide treatment of mouse macrophage-like J774 cells was found to result in the activation of three different nuclear proteins which specifically bind to oligonucleotide containing the NF-kappa B motif of the human immunodeficiency virus (HIV) gene [16].
• We concluded that the TGF-beta1/Smad signaling pathway helps maintain normal intestinal homeostasis to commensal luminal enteric bacteria by regulating NF-kappaB signaling in IEC through altered histone acetylation [17].
• 18 Beta-glycyrrhetinic acid triggers curative Th1 response and nitric oxide up-regulation in experimental visceral leishmaniasis associated with the activation of NF-kappa B [18].

Biological context of Nfkb1

• Furthermore, the marked unloading-induced activation of the NF-kappaB reporter gene in soleus muscles from WT mice was completely abolished in soleus muscles from Nfkb1 knockout mice [19].
• Thus both the Nfkb1 and the Bcl3 genes are necessary for unloading-induced atrophy and the associated phenotype transition [19].
• Activation of NF-kappaB antagonizes apoptosis or programmed cell death by numerous triggers, including the ligand engagement of 'death receptors' such as tumour-necrosis factor (TNF) receptor [20].
• These results define a new nuclear role of IKK-alpha in modifying histone function that is critical for the activation of NF-kappaB-directed gene expression [21].
• Normally, NF-kappaB dimers are sequestered in the cytoplasm by binding to inhibitory IkappaB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of IkappaBs [20].

Anatomical context of Nfkb1

• Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy [19].
• In addition, relative to Nfkb1(-/-) or Oca-b(-/-) mice, the Nfkb1(-/-)Oca-b(-/-) mice show a decrease in conventional B cell frequencies in the spleen and augmented reductions in T-independent and T-dependent Ab responses [22].
• The surprising result was that the animals developed osteopetrosis because of a defect in osteoclast differentiation, suggesting redundant functions of NF-kappaB1 and NF-kappaB2 proteins in the development of this cell lineage [2].
• Nevertheless, mouse embryo fibroblasts deficient in IKK-alpha are defective in the induction of NF-kappaB-dependent transcription [21].
• We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes [1].

Associations of Nfkb1 with chemical compounds

• NF-kappaB specifically recognizes kappaB DNA elements with a consensus sequence of 5'-GGGRNYYYCC-3' (R is an unspecified purine; Y is an unspecified pyrimidine; and N is any nucleotide) [23].
• Moreover, the patients' blood and fibroblastic cells responded to other NF-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide [24].
• 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 [25].
• NF-kappa B prevents cell death caused by tumor necrosis factor (TNF) and other genotoxic insults by directly inducing antiapoptotic target genes [26].
• In this study, TNF-alpha-induced p105 proteolysis was revealed to additionally require the phosphorylation of serine 932 [27].

Physical interactions of Nfkb1

• Heterogeneity of IKK complexes in vivo may provide a mechanism for differential regulation of NF-kappaB activation [28].
• However, NF-kappaB DNA binding activity is reduced in GSK-3beta null cells and in cells treated with a pharmacological inhibitor of GSK-3 [29].
• Following its induction, TNFalpha gene transcription is rapidly attenuated, in part due to the accumulation of NF-kappaB p50 homodimers that bind to three kappaB sites in the TNFalpha promoter [30].
• Mechanistically, the abnormal regulation of IL-12 in these strains was found to be strictly associated with novel patterns of Rel binding in vitro to the unique NF-kappaB site in the IL-12 p40 promoter [31].
• Transient transfections with caspase-11 promoter-luciferase reporter constructs and deletion/mutation analysis revealed an essential role for NF-kappaB binding in the up-regulation of caspase-11 in response to LPS [32].

Enzymatic interactions of Nfkb1

• Upon phosphorylation by PI3K, Akt can phosphorylate nuclear factor kappa B (NF-kappaB) and members of the forkhead family of transcription factors, which includes AFX [33].
• 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 [34].

Regulatory relationships of Nfkb1

• TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha [35].
• The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways [36].
• These findings establish that, as with other endothelial cell adhesion molecules, transcriptional induction of MAdCAM-1 by TNF-alpha requires activated NF-kappa B proteins [37].
• Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation [38].
• Transient transfection analysis revealed that p98NF-kappa B1, but not p105NF-kappa B1 or p84NF-kappa B1, acts as a transactivator of NF-kappa B-regulated gene expression and that this is dependent on sequences in the Rel homology domain required for DNA binding and on the novel 35 C-terminal aa of this isoform [39].

Other interactions of Nfkb1

• Following cell stimulation by agonists, p105 is proteolysed more rapidly and released Rel subunits translocate into the nucleus [40].
• Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway [41].
• Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice [42].
• The inhibition of NF-kappa B/Rel activity represents a novel TGF beta signaling mechanism [35].
• The lymphotoxin-beta receptor (LTbetaR) plays critical roles in inflammation and lymphoid organogenesis through activation of NF-kappaB [36].

Analytical, diagnostic and therapeutic context of Nfkb1

• These data demonstrate that NF-kappaB Rel proteins activated by CD40 ligation play an important role in induction of the germ line Cgamma1 promoter [43].
• Antiapoptotic activity of NF-kappaB in tumors contributes to acquisition of resistance to chemotherapy [44].
• Nuclear factor kappaB (NF-kappaB) is rapidly activated during liver regeneration following partial hepatectomy or carbon tetrachloride (CCl(4))-mediated liver injury and is felt to be important in the antiapoptotic and regenerative responses [45].
• In conclusion, the hepatoprotective effects of ischemic preconditioning are associated with activation of NF-kappaB and SAPKs that are associated with entry of hepatocytes into the cell cycle, a critical biological effect that favors survival of the liver against ischemic and IR injury [46].
• However, the NF-kappaB-like factor induced by IL-1-stimulated osteoclast-like cells is of smaller molecular size than the factor in osteoblasts, as shown by an electrophoretic mobility shift assay [47].

References