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NFkB
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.
Send comments, questions and suggestions to edhaas@davidson.edu
Many thanks to Dr. A. Malcolm Campbell for his guidance in this endeavor as well as others. 1048266630-023226-915