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NFk

 

NFkB is the primary transcription factor activated in what may be the most ancient host defense mechanism known. Homologues exist in all known plants and animals, suggesting the gene evolved in their common ancestor more than a billion years ago. In all animals, NFkB is activated by the Toll receptor pathway. In humans, the soluble protein LBP binds bacterial lipopolysacchride(LPS). This LPS/LBP complex binds to Toll-like receptor 4(TLR-4). This binding activates TLR-4, whose cytosolic TIR domain binds MyD88. The death domain of MyD88, named for its role in apoptosis, binds that of the serine/threonine kinase IRAK, activating it. IRAK activates TRAF-6, which phosphorylates IkK, which phosphorylates IkB. IkB is an inhibitory protein bound to NFkB. Upon phosphorylation, IkB releases NFkB, and is subsequently degraded. NFkB enters the nucleus. In antigen presenting cells, NFkB induces costimulatory molecules, cytokines, and IkB, its own inhibitor. The method of activation has not been demonstrated in plants, however it is suspected to be the same as in animals, given that homologues for many of the human genes are known to exist.1 For an excellent diagram of the activation signal, click here.

NFkB consists of both homo and heterodimers of a number of highly similar subunits.2 Some of the more common of these are p50(NFkB1), p65(RelA), c-Rel, RelB, and p52(NFkB2).3 The two most common forms are p50/p65 heterodimers, and p50 homodimers, which recognize the sequence 5-GGGACTTTCC-3.2 Not surprisingly, it has been suggested that differing forms of NFkB may have slightly different activities.3 To see the DNA sequence of human NFkB1(listed oddly as p105, not p50), click here. For a chime image of NFkB click here.

The immunological function of NFkB is not its only function. NFkB is also known to have a large role in the inflammatory response due to injury, in part by inducing Cyclooxygenase(COX), the primary protein targeted by non-steroidal anti-inflammatory drugs(NSAIDs).(Nakao et al., 2002) NFkB has also recently been shown to be activated in the neonatal forebrain, suggesting a possible role in neuronal development.(Ward, et al., 2000) NFkB has long been known to be a survival signal for lymphocytes, but it has recently been shown to also have a function as an apoptosis inducer.(Kuhnel, et al., 2000)(Hauser, et al., 2002) It has also recently been shown to respond to cellular stress as an inducer of heat shock proteins.(Yi, et al., 2002)

NFkB has been studied in great detail for some time, however it has received even more attention since 1994 when it was discovered that HIV uses activated NFkB to upregulate transcription of its genome. The researchers reported that activation of infected cells induced NFkB to bind NFkB binding sequences in the long terminal repeats(LTRs) of the HIV genome, inducing transcription.(Swingler, et al., 1994) Inactivation of NFkB is not a viable therapeutic option however, as it would result in a more severe immunodeficiency than the disease.

 

 

Works Cited

1 Janeway CA, Travers P, Walport M, Shlomchik M. Immunobiology: The Immune System in Health and Disease. 5th Edition. New York: Garland Publishing.

 

2 http://www.activemotif.com/products/cell/transam/nfkb.html

 

3 http://www.researchd.com/miscabs/nfkbab.htm

 

Hauser P, Oberbauer R. 2002. Tubular apoptosis in the pathophysiology of renal disease. Wein Klin Wochenschr. 114(15-16): 671-7.

 

Kuhnel F, Zender L, Paul Y, Tietze MK, Trautwein C, Manns M, Kubicka S. 2000. NFkB mediates apoptosis through transcriptional activation of Fas(CD95) in adenoviral hepatitis. J Biol Chem. 275(9): 6421-7.

 

Nakao S, Ogtata Y, Shimizu E, Yamazaki M, Furuyama S, Sugiya H. 2000. Tumor necrosis factor alpha (TNF-alpha)-induced prostaglandin E2 release is mediated by the activation of cyclooxygenase-2 (COX-2) transcription via NfkappaB in human gingival fibroblasts. Mol Cell Biochem. 238(1-2): 11-8.

 

Swingler S, Morris A, Easton A. 1994. Tumor necrosis factor alpha and interleukin-1 beta induce specific subunits of NFKB to bind HIV-1 enhancer: characterization of transcription factors controlling human immunodeficiency virus type 1 gene expression in neural cells. Biochem Biophys Res Commun. 203(1): 623-30.

 

Ward NL, Hagg T. 2000. SEK1/MKK4, c-Jun and NFKappaB are differentially activated in forebrain neurons during postnatal development and injury in both control and p75NGFR-deficient mice. Eur J Neurosci. 12(6): 1867-81.

 

Yi MJ, Park SH, Cho HN, Yong Chun H, Kim JI, Cho CK, Lee SJ, Lee YS. 2002. Heat-shock protein 25(Hspb1) regulates manganese superoxide dismutase through activation of Nfkb (NF-kappaB). Radiat Res. 158(5): 641-9.

 


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