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Gene Review

Nfkb1  -  nuclear factor of kappa light polypeptide...

Mus musculus

Synonyms: DNA-binding factor KBF1, EBP-1, NF kappaB1, NF-KB1, NF-kappa-B1 p84/NF-kappa-B1 p98, ...
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Disease relevance of Nfkb1


Psychiatry related information on Nfkb1


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 [14].
  • Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling [15].
  • IkappaB kinase beta (IKKbeta), required for NF-kappaB activation, links chronic inflammation with carcinogenesis [16].
  • Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response [17].
  • 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 [17].

Chemical compound and disease context of Nfkb1


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 [22].
  • Thus both the Nfkb1 and the Bcl3 genes are necessary for unloading-induced atrophy and the associated phenotype transition [22].
  • 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 [23].
  • 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 [24].
  • 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 [23].

Anatomical context of Nfkb1

  • Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy [22].
  • 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 [25].
  • 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 [24].
  • 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) [26].
  • Moreover, the patients' blood and fibroblastic cells responded to other NF-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide [27].
  • 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 [28].
  • NF-kappa B prevents cell death caused by tumor necrosis factor (TNF) and other genotoxic insults by directly inducing antiapoptotic target genes [29].
  • In this study, TNF-alpha-induced p105 proteolysis was revealed to additionally require the phosphorylation of serine 932 [30].
  • Of note, pretreatment with antioxidant trolox protects against the inhibitory effect of profound GSH depletion on IKK activation and NF-kappaB nuclear translocation but fails to restore expression of NF-kappaB target genes, revealing both IKK-dependent and -independent inhibition [31].
  • A high rate of NF-kappaB/p65 degradation in LNK cells correlates with Pro1 activity, since treatment with the proteasome inhibitor MG132 increased levels of NF-kappaB/p65 protein and decreased Pro1 activity [32].
  • COG112 inhibited the C. rodentium-stimulated induction of iNOS and the CXC chemokines KC and MIP-2 to the same degree as the NF-kappaB inhibitors MG132 or BAY 11-7082, and there was no additive effect when COG112 and these inhibitors were combined [33].

Physical interactions of Nfkb1

  • Heterogeneity of IKK complexes in vivo may provide a mechanism for differential regulation of NF-kappaB activation [34].
  • However, NF-kappaB DNA binding activity is reduced in GSK-3beta null cells and in cells treated with a pharmacological inhibitor of GSK-3 [35].
  • 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 [36].
  • 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 [37].
  • 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 [38].
  • NF-kappaB regulation of YY1 occurred at the transcriptional level, mediated by direct binding of the p50/p65 heterodimer complex to the YY1 promoter [39].
  • Chromatin immunoprecipitation assays confirmed that Bcl-3 bound to the promoter of the NF-kappaB-regulated inducible NO synthase gene in cells from estrogen-treated mice [40].

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 [41].
  • 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 [42].

Regulatory relationships of Nfkb1


Other interactions of Nfkb1


Analytical, diagnostic and therapeutic context of Nfkb1


  1. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Cai, D., Yuan, M., Frantz, D.F., Melendez, P.A., Hansen, L., Lee, J., Shoelson, S.E. Nat. Med. (2005) [Pubmed]
  2. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Iotsova, V., Caamaño, J., Loy, J., Yang, Y., Lewin, A., Bravo, R. Nat. Med. (1997) [Pubmed]
  3. Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. van Loo, G., De Lorenzi, R., Schmidt, H., Huth, M., Mildner, A., Schmidt-Supprian, M., Lassmann, H., Prinz, M.R., Pasparakis, M. Nat. Immunol. (2006) [Pubmed]
  4. p50-NF-kappaB complexes partially compensate for the absence of RelB: severely increased pathology in p50(-/-)relB(-/-) double-knockout mice. Weih, F., Durham, S.K., Barton, D.S., Sha, W.C., Baltimore, D., Bravo, R. J. Exp. Med. (1997) [Pubmed]
  5. Inhibition of Helicobacter hepaticus-induced colitis by IL-10 requires the p50/p105 subunit of NF-kappa B. Tomczak, M.F., Erdman, S.E., Davidson, A., Wang, Y.Y., Nambiar, P.R., Rogers, A.B., Rickman, B., Luchetti, D., Fox, J.G., Horwitz, B.H. J. Immunol. (2006) [Pubmed]
  6. NF-kappa B prevents beta cell death and autoimmune diabetes in NOD mice. Kim, S., Millet, I., Kim, H.S., Kim, J.Y., Han, M.S., Lee, M.K., Kim, K.W., Sherwin, R.S., Karin, M., Lee, M.S. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  7. Tissue-specific effects of the nuclear factor kappaB subunit p50 on myocardial ischemia-reperfusion injury. Frantz, S., Tillmanns, J., Kuhlencordt, P.J., Schmidt, I., Adamek, A., Dienesch, C., Thum, T., Gerondakis, S., Ertl, G., Bauersachs, J. Am. J. Pathol. (2007) [Pubmed]
  8. The NF-kappaB p50:p50:HDAC-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes. Elsharkawy, A.M., Oakley, F., Lin, F., Packham, G., Mann, D.A., Mann, J. J. Hepatol. (2010) [Pubmed]
  9. Dehydration activates an NF-kappaB-driven, COX2-dependent survival mechanism in renal medullary interstitial cells. Hao, C.M., Yull, F., Blackwell, T., Kömhoff, M., Davis, L.S., Breyer, M.D. J. Clin. Invest. (2000) [Pubmed]
  10. Nuclear factor kappaB/p49 is a negative regulatory factor in nerve growth factor-induced choline acetyltransferase promoter activity in PC12 cells. Toliver-Kinsky, T., Wood, T., Perez-Polo, J.R. J. Neurochem. (2000) [Pubmed]
  11. NF-kappaB-mediated self defense of macrophages faced with bacteria. Kitamura, M. Eur. J. Immunol. (1999) [Pubmed]
  12. Chronic alcohol consumption accelerates liver injury in T cell-mediated hepatitis: alcohol disregulation of NF-kappaB and STAT3 signaling pathways. Jaruga, B., Hong, F., Kim, W.H., Sun, R., Fan, S., Gao, B. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  13. Neuroprotective role for the p50 subunit of NF-kappaB in an experimental model of Huntington's disease. Yu, Z., Zhou, D., Cheng, G., Mattson, M.P. J. Mol. Neurosci. (2000) [Pubmed]
  14. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Ghosh, S., May, M.J., Kopp, E.B. Annu. Rev. Immunol. (1998) [Pubmed]
  15. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A., Fässler, R. Cell (2006) [Pubmed]
  16. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Maeda, S., Kamata, H., Luo, J.L., Leffert, H., Karin, M. Cell (2005) [Pubmed]
  17. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., Karin, M. Cell (2005) [Pubmed]
  18. Estrogen withdrawal-induced NF-kappaB activity and bcl-3 expression in breast cancer cells: roles in growth and hormone independence. Pratt, M.A., Bishop, T.E., White, D., Yasvinski, G., Ménard, M., Niu, M.Y., Clarke, R. Mol. Cell. Biol. (2003) [Pubmed]
  19. Influence of 3' half-site sequence of NF-kappa B motifs on the binding of lipopolysaccharide-activatable macrophage NF-kappa B proteins. Muroi, M., Muroi, Y., Yamamoto, K., Suzuki, T. J. Biol. Chem. (1993) [Pubmed]
  20. Transforming growth factor-beta 1 inhibits non-pathogenic Gram negative bacteria-induced NF-kappa B recruitment to the interleukin-6 gene promoter in intestinal epithelial cells through modulation of histone acetylation. Haller, D., Holt, L., Kim, S.C., Schwabe, R.F., Sartor, R.B., Jobin, C. J. Biol. Chem. (2003) [Pubmed]
  21. 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. Ukil, A., Biswas, A., Das, T., Das, P.K. J. Immunol. (2005) [Pubmed]
  22. Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy. Hunter, R.B., Kandarian, S.C. J. Clin. Invest. (2004) [Pubmed]
  23. Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. De Smaele, E., Zazzeroni, F., Papa, S., Nguyen, D.U., Jin, R., Jones, J., Cong, R., Franzoso, G. Nature (2001) [Pubmed]
  24. Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Yamamoto, Y., Verma, U.N., Prajapati, S., Kwak, Y.T., Gaynor, R.B. Nature (2003) [Pubmed]
  25. Genetic analyses of NFKB1 and OCA-B function: defects in B cells, serum IgM level, and antibody responses in Nfkb1-/-Oca-b-/- mice. Kim, U., Gunther, C.S., Roeder, R.G. J. Immunol. (2000) [Pubmed]
  26. Crystal structure of p50/p65 heterodimer of transcription factor NF-kappaB bound to DNA. Chen, F.E., Huang, D.B., Chen, Y.Q., Ghosh, G. Nature (1998) [Pubmed]
  27. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. Filipe-Santos, O., Bustamante, J., Haverkamp, M.H., Vinolo, E., Ku, C.L., Puel, A., Frucht, D.M., Christel, K., von Bernuth, H., Jouanguy, E., Feinberg, J., Durandy, A., Senechal, B., Chapgier, A., Vogt, G., de Beaucoudrey, L., Fieschi, C., Picard, C., Garfa, M., Chemli, J., Bejaoui, M., Tsolia, M.N., Kutukculer, N., Plebani, A., Notarangelo, L., Bodemer, C., Geissmann, F., Israël, A., Véron, M., Knackstedt, M., Barbouche, R., Abel, L., Magdorf, K., Gendrel, D., Agou, F., Holland, S.M., Casanova, J.L. J. Exp. Med. (2006) [Pubmed]
  28. Proteasome regulation of activation-induced T cell death. Cui, H., Matsui, K., Omura, S., Schauer, S.L., Matulka, R.A., Sonenshein, G.E., Ju, S.T. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  29. Suppression of PTEN expression by NF-kappa B prevents apoptosis. Vasudevan, K.M., Gurumurthy, S., Rangnekar, V.M. Mol. Cell. Biol. (2004) [Pubmed]
  30. betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932. Lang, V., Janzen, J., Fischer, G.Z., Soneji, Y., Beinke, S., Salmeron, A., Allen, H., Hay, R.T., Ben-Neriah, Y., Ley, S.C. Mol. Cell. Biol. (2003) [Pubmed]
  31. Glutathione depletion down-regulates tumor necrosis factor alpha-induced NF-kappaB activity via IkappaB kinase-dependent and -independent mechanisms. Lou, H., Kaplowitz, N. J. Biol. Chem. (2007) [Pubmed]
  32. NF-kappa B p50/p65 affects the frequency of Ly49 gene expression by NK cells. Pascal, V., Nathan, N.R., Claudio, E., Siebenlist, U., Anderson, S.K. J. Immunol. (2007) [Pubmed]
  33. The apolipoprotein E-mimetic peptide COG112 inhibits the inflammatory response to Citrobacter rodentium in colonic epithelial cells by preventing NF-kappaB activation. Singh, K., Chaturvedi, R., Asim, M., Barry, D.P., Lewis, N.D., Vitek, M.P., Wilson, K.T. J. Biol. Chem. (2008) [Pubmed]
  34. IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex. Mercurio, F., Murray, B.W., Shevchenko, A., Bennett, B.L., Young, D.B., Li, J.W., Pascual, G., Motiwala, A., Zhu, H., Mann, M., Manning, A.M. Mol. Cell. Biol. (1999) [Pubmed]
  35. Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription. Steinbrecher, K.A., Wilson, W., Cogswell, P.C., Baldwin, A.S. Mol. Cell. Biol. (2005) [Pubmed]
  36. BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages. Wessells, J., Baer, M., Young, H.A., Claudio, E., Brown, K., Siebenlist, U., Johnson, P.F. J. Biol. Chem. (2004) [Pubmed]
  37. Distinct pathways for NF-kappa B regulation are associated with aberrant macrophage IL-12 production in lupus- and diabetes-prone mouse strains. Liu, J., Beller, D.I. J. Immunol. (2003) [Pubmed]
  38. Caspase-11 gene expression in response to lipopolysaccharide and interferon-gamma requires nuclear factor-kappa B and signal transducer and activator of transcription (STAT) 1. Schauvliege, R., Vanrobaeys, J., Schotte, P., Beyaert, R. J. Biol. Chem. (2002) [Pubmed]
  39. NF-kappaB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes. Wang, H., Hertlein, E., Bakkar, N., Sun, H., Acharyya, S., Wang, J., Carathers, M., Davuluri, R., Guttridge, D.C. Mol. Cell. Biol. (2007) [Pubmed]
  40. Despite inhibition of nuclear localization of NF-kappa B p65, c-Rel, and RelB, 17-beta estradiol up-regulates NF-kappa B signaling in mouse splenocytes: the potential role of Bcl-3. Dai, R., Phillips, R.A., Ahmed, S.A. J. Immunol. (2007) [Pubmed]
  41. A role for Akt in the rapid regulation of inflammatory and apoptotic pathways in mouse bladder. Tamarkin, F.J., Kang, W.S., Cohen, J.J., Wheeler, M.A., Weiss, R.M. Naunyn Schmiedebergs Arch. Pharmacol. (2006) [Pubmed]
  42. Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity. Post, A., Rücker, M., Ohl, F., Uhr, M., Holsboer, F., Almeida, O.F., Michaelidis, T.M. Neuropsychopharmacology (2002) [Pubmed]
  43. TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha. Arsura, M., Wu, M., Sonenshein, G.E. Immunity (1996) [Pubmed]
  44. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Dejardin, E., Droin, N.M., Delhase, M., Haas, E., Cao, Y., Makris, C., Li, Z.W., Karin, M., Ware, C.F., Green, D.R. Immunity (2002) [Pubmed]
  45. Induction of the gene encoding mucosal vascular addressin cell adhesion molecule 1 by tumor necrosis factor alpha is mediated by NF-kappa B proteins. Takeuchi, M., Baichwal, V.R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  46. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Sakurai, T., Maeda, S., Chang, L., Karin, M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  47. Alternate RNA splicing of murine nfkb1 generates a nuclear isoform of the p50 precursor NF-kappa B1 that can function as a transactivator of NF-kappa B-regulated transcription. Grumont, R.J., Fecondo, J., Gerondakis, S. Mol. Cell. Biol. (1994) [Pubmed]
  48. TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105. Belich, M.P., Salmerón, A., Johnston, L.H., Ley, S.C. Nature (1999) [Pubmed]
  49. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Senftleben, U., Cao, Y., Xiao, G., Greten, F.R., Krähn, G., Bonizzi, G., Chen, Y., Hu, Y., Fong, A., Sun, S.C., Karin, M. Science (2001) [Pubmed]
  50. Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. Rudolph, D., Yeh, W.C., Wakeham, A., Rudolph, B., Nallainathan, D., Potter, J., Elia, A.J., Mak, T.W. Genes Dev. (2000) [Pubmed]
  51. Activation of NF-kappaB/Rel by CD40 engagement induces the mouse germ line immunoglobulin Cgamma1 promoter. Lin, S.C., Stavnezer, J. Mol. Cell. Biol. (1996) [Pubmed]
  52. IkappaB kinase-independent IkappaBalpha degradation pathway: functional NF-kappaB activity and implications for cancer therapy. Tergaonkar, V., Bottero, V., Ikawa, M., Li, Q., Verma, I.M. Mol. Cell. Biol. (2003) [Pubmed]
  53. Normal liver regeneration in p50/nuclear factor kappaB1 knockout mice. DeAngelis, R.A., Kovalovich, K., Cressman, D.E., Taub, R. Hepatology (2001) [Pubmed]
  54. Hepatic ischemic preconditioning in mice is associated with activation of NF-kappaB, p38 kinase, and cell cycle entry. Teoh, N., Dela Pena, A., Farrell, G. Hepatology (2002) [Pubmed]
  55. Interleukin-1 alpha activates an NF-kappaB-like factor in osteoclast-like cells. Jimi, E., Ikebe, T., Takahashi, N., Hirata, M., Suda, T., Koga, T. J. Biol. Chem. (1996) [Pubmed]
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