nuclear factor kappa-B (NF-kappa B)
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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
Expression
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
More general terms
More specific terms
Additional terms
- IKB protein
- NF kappa-B signalling
- NF-kappa B p52 subunit; NF-kappa p100; DNA-binding factor KBF2; H2TF1; lymphocyte translocation chromosome 10; oncogene Lyt-10; Lyt10 (NFKB2, LYT10)
- rel protein family
References
- ↑ 893443960
- ↑ Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249-70. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1988147
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/2006423 - ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/2017258
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/7878466
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/11799112
- ↑ 7.0 7.1 Orlowski RZ, Baldwin AS Jr. NF-kappaB as a therapeutic target in cancer. Trends Mol Med. 2002 Aug;8(8):385-9. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/12127724
- ↑ Baldwin AS Jr. Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest. 2001 Jan;107(1):3-6. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/11160144