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nuclear factor kappa-B (NF-kappa B)

Function: - pleiotropic transcription factor present in almost all cell types - role in many biological processed including inflammation, immunity, differentiation, cell growth, tumorigenesis & apoptosis - NF-kappa-B dimers bind at kappa-B sites in the DNA of their target genes - the individual NF-kappa-B dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity & specificity - different dimer combinations act as transcriptional activators or transcriptional repressors - NF-kappa-B is controlled by various mechanisms of post-translational modification & subcellular compartmentalization as well as by interactions with other cofactors or corepressors - NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family - in a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus - NF-kappa B p65 binds to IKB, inhibiting transcriptional activity of NF-kappa B by retaining it in the cytoplasm - activation of NF-kappa B with translocation to the nucleus appears to require phophorylation-dependent proteolysis of IKB - ransactivation domains of NFkB are regulated by the catalytic domain of protein kinase A, casein kinase 2 & IKK itself - the classic form, heterodimer RELA/p65-c-Rel, is a transcriptional activator - regulates numerous genes including cytokine receptors, cytokines, cell adhesion receptors; genes involved in immune & inflammatory responses, oncogenesis, control of apoptosis (both pro- & anti-apoptotic), cell cycle, cell differentiation & migration - binds to 2 adjacent sites in LTR of HIV-1 as well as genomic EkB site. - activated by inflammatory cytokines such as TNF-alpha, interleukin 1, T-cell activation signals, growth factors & stress inducers - also activated in endothelial cells by oxidized LDLs & fluid shear stress - most viruses encode proteins capable of activating NFkB (ie. LMP-1 of Epstein-Barr virus & HTLV-I Tax) Inhibition: - molecules that inhibit NF-kappa B include sulindac, cyclopentenone prostaglandins, arsenic trioxide, thalidomide, parthenolide, resveratrol, PS-1145 (drug that inhibits I-kappa-B kinase) [7], aspirin, flavonoids, curcumin Structure: - homodimers & heterodimers of Rel/NF kappa B family proteins classic form is p65/RelA + p50 subunit - homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL & NFKB2/p52 Compartment: - nucleus, cytoplasm Expression: ubiquitous Pathology: - NF kappa B is dysregulated in many forms of cancer & may promote metastasis in some cases. - NFkB is also activated in rheumatoid arthritis, & may have a role in asthma, inflammatory bowel disease, cachexia & euthyroid sick syndrome

Interactions

molecular events

General

molecular complex redox-modulated transcription factor

Properties

COMPARTMENT: cytoplasm SUBUNITS: NF-kappa B p50 subunit (2) MOTIF: RHD {42-367} MOTIF: Ser phosphorylation site {S337} nuclear translocation signal {360-365} GRR {372-394} glycine-rich region {375-433} Cleavage {433-434} CFLAR interaction {435-968} MOTIF: ankyrin repeat NAME: ankyrin repeat SITE: 542-571 ankyrin repeat NAME: ankyrin repeat SITE: 581-610 ankyrin repeat NAME: ankyrin repeat SITE: 614-643 ankyrin repeat NAME: ankyrin repeat SITE: 650-679 ankyrin repeat NAME: ankyrin repeat SITE: 684-714 ankyrin repeat NAME: ankyrin repeat SITE: 718-747 ankyrin repeat NAME: ankyrin repeat SITE: 771-801 death domain NAME: death domain SITE: 805-892 Ser phosphorylation site {S903} Ser phosphorylation site {S907} Ser phosphorylation site {S927} Ser phosphorylation site {S932} NF-kappa B p65 (2) MOTIF: RHD {19-306} MOTIF: Thr phosphorylation site {T254} Ser phosphorylation site {S276} Ser phosphorylation site {S281} nuclear translocation signal {301-304} Ser phosphorylation site {S311} Activation {415-459} MOTIF: Thr phosphorylation site {T435} Ser phosphorylation site {S468} Thr phosphorylation site {T505} Ser phosphorylation site {S529} Ser phosphorylation site {S536}

Database Correlations

Kegg hsa/hsa04210

References

  1. 893443960
  2. Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249-70. Review. PMID: 1988147
  3. Ruben SM, Dillon PJ, Schreck R, Henkel T, Chen CH, Maher M, Baeuerle PA, Rosen CA. Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B. Science. 1991 Oct 4;254(5028):11. PMID: 1925549 - Ruben SM, Dillon PJ, Schreck R, Henkel T, Chen CH, Maher M, Baeuerle PA, Rosen CA. Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B. Science. 1991 Mar 22;251(5000):1490-3. Erratum in: Science. 1991 Oct 4;254(5028):11. PMID: 2006423
  4. Riviere Y, Blank V, Kourilsky P, Isra'l A. Processing of the precursor of NF-kappa B by the HIV-1 protease during acute infection. Nature. 1991 Apr 18;350(6319):625-6. PMID: 2017258
  5. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science. 1995 Mar 10;267(5203):1485-8. PMID: 7878466
  6. Mayo MW, Madrid LV, Westerheide SD, Jones DR, Yuan XJ, Baldwin AS Jr, Whang YE. PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit. J Biol Chem. 2002 Mar 29;277(13):11116-25. Epub 2002 Jan 17. PMID: 11799112
  7. Orlowski RZ, Baldwin AS Jr. NF-kappaB as a therapeutic target in cancer. Trends Mol Med. 2002 Aug;8(8):385-9. Review. PMID: 12127724
  8. Baldwin AS Jr. Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest. 2001 Jan;107(1):3-6. Review. PMID: 11134170 - Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. 2001 Feb;107(3):241-6. Review. PMID: 11160144

Component-of

molecular complex

Components

NF-kappa B p50 subunit; NF-kappa B p105 subunit; NF-kappa C; DNA-binding factor KBF1; EBP-1 (NFKB1) NF-kappa B p65; nuclear factor NF-kappa-B p65 subunit (RELA, NFKB3)