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[Nuclear factor kappa-B] NF-kappa-B is a transcription factor identified originally in nuclei of mature B-cells as a protein essential kappa immunoglobulin light chain gene expression. Expression of NF-kappa-B is not restricted to B-cells (Sen and Baltimore, 1986). NF-kappa-B is a pleiotropic transcription factor expressed in numerous different cell types after stimulation and/or cell activation by a wide variety of stimuli (cytokines, growth factors and mitogens, hormones, receptor ligation, crosslinking of surface molecules, viruses and viral proteins, oxidative stress, and chemical agents such as phorbol esters). Many different genes contain functional NF-kappa-B binding sites (GGGACTTTCC) in their promoters. The expression of such NF-kappa-B-responsive genes is upregulated by treatment of cells with a variety of physiological and pharmacological stimuli. NF-kappa-B-responsive genes include those encoding a number of cytokines and growth factors, cytokine receptors, receptor signaling proteins, cell adhesion molecules, and many other proteins involved in various processes, including immune responses, acute phase reaction and inflammation, cell growth and differentiation, growth control of certain tumors, and cell death by apoptosis. Some viral promoters also contain functional NF-kappa-B binding sites. Some of the processes regulated by NF-kappa-B are associated with the inappropriate activation of the transcription factor while others involve inhibition of NF-kappa-B activity.
Pathways involved in the regulation of NF-kappa-B are extremely complex.
NF-kappa-B constitutes an entire family of transcription factors that consists of homodimeric and heterodimeric complexes formed from combinations of members of the Rel family of proteins, which are related to the viral rel oncogene found in the Reticuloendotheliosis Virus Strain T, a replication-defective, acutely transforming type C retrovirus that induces leukemia in young turkeys and chickens (Baldwin). There are five mammalian members of the Rel family of proteins. These include c-Rel (Brownell et al, 1986), NF-kappa-B1 (NF-kappa-B subunit 1; p105/p50) (Meyer et al, 1991), NF-kappa-B2 (NF-kappa-B subunit 2; p100/p52; called also Lyt10 (Neri et al, 1991), RelA (p65; NF-kappa-B subunit 3) (Deloukas et al, 1993), and RelB (called I-Rel by Ruben et al, 1997). The most common form of NF-kappa-B found in virtually all cell types is composed of two subunits of 50 kDa (p50; derived from p105, a 105 kDa precursor) and 65 kDa (p65). The p50 and p52 subunits primarily serve as DNA binding subunits. RelA (p65), RelB, and c-Rel are responsible for gene activation in vivo (Fujita et al, 1992). Homodimers of p50 correlate cause transcriptional repression (Kang et al, 1992; Plaskin et al, 1993). Gene expression can be regulated specifically because NF-kappa-B heterodimeric forms differ in cell type specificity, DNA binding site preference, interaction with inhibitory proteins, activation requirements, and kinetics of activation (Miyamoto and Verma, 1995). For example, active NF-kappa-B complexes in pre-B-cells are primarily p50/p65 heterodimers. In mature B-cells a constitutively expressed form of NF-kappa-B is a c-Rel/p50 heterodimer (Miyamoto et al, 1994). Transport of p50/p65 heterodimers into the nucleus is rapid while p50/c-Rel dimers are expressed with a delayed response and accumulate in the nucleus more slowly (Pimentel-Muinos et al, 1995).
NF-kappa-B dimers are regulated at the level of synthesis as some of the subunit genes contain NF-kappa-B binding sites in their promoter regions. Activities of NF-kappa-B are regulated also by inhibitory proteins. Inactive NF-kappa-B preexists in the cytoplasm of cells where it is complexed by the inhibitor I-kappa-B (Inhibitor of NF-kappa-B). Mammalian I-kappa-B constitutes a protein family that includes I-kappa-B-alpha, I-kappa-B-beta, I-kappa-B-gamma, I-kappa-B-delta, I-kappa-B-epsilon and BCL3 (Verma et al, 1997, Miyamoto and Verma, 1995; Siebenlist et al, 1994; Beg and Baldwin, 1993; Kerr et al, 1992). Cytoplasmic sequestering of NF-kappa-B results from masking of the nuclear localization sequence of NF-kappa-B proteins (see also: signal sequence) (Beg et al, 1992). These inhibitory proteins display differential affinities for different NF-kappa-B dimers. NF-kappa-B dimers can induce their own inhibitors, which then bind to cytoplasmic dimers to restore the inhibited state and reestablish cytoplasmic pools of NF-kappa-B/I-kappa-B complexes. Various activating agents can mediate the dissociation of I-kappa-B from NF-kappa-B and thus translocation of the liberated transcription factor into the nucleus. This process involves the activities of other kinases such as IKK-1 (I-kappa-B kinase-1; also IKK-alpha), IKK-2 (I-kappa-B kinase-2; also IKK-beta), and NEMO (IKK-gamma), which themselves are subject to phosphorylation and concomitant activation by kinases such as the NF-kappa-B inducible kinase NIK (Verma et al, 1995). Signal dependent phosphorylation results in the ubiquitination of I-kappa-B proteins and targets the cytoplasmic inhibitors to the ubiquitin-proteasome pathway (Chen et al, 1995; Li et al, 1995; Alkalay et al, 1995). For an inhibitor that associates with the RelA subunit (RAI) see also: iASPP.
NF-kappa-B regulates the expression of several hundred genes, including many that encode cytokines, chemokines, or adhesion molecules (Burstein and Duckett, 2003). The physiologic importance of NF-kappa-B and its inhibitors is shown by experiments involving the generation of transgenic and knock-out animals. The important role of Rel subunit genes is underlined by the observation that loss of a particular Rel protein cannot be compensated by another Rel protein (Kontgen et al, 1995; Gerondakis et al, 1995; Burkly et al, 1995; Weih et al, 1995).
Transgenic knock-out mice lacking the p50 subunit of NF-kappa-B have multifocal defects in immune responses (Sha et al, 1995).
c-Rel knock-out mice have proliferative defects in T-cells and B-cells and produce lower amounts of IL3, IL15, GM-CSF, TNF-alpha and IFN-gamma (Kontgen et al, 1995). Knock-out mice lacking expression of RelA show massive degeneration of the liver due to cell death by apoptosis (Beg and Baldwin, 1993).
RelB knock-out mice do not develop thymic dendritic cells (Burkly et al, 1995; Weih et al, 1995).
Neurath et al (1996) have shown that local administration of antisense oligonucleotides directed against the p65 subunit of NF-kappa-B abrogates established experimental chronic intestinal inflammation in mice.
Schwarz et al (1997) have generated knock-out mice that lack the BCL3 gene. The spleens of these mice lack germinal centers These mice have normal immunoglobulin levels but fail to produce antigen-specific antibodies.
I-kappa-B-alpha knock-out mice show normal development but die approximately one week after birth due to wide spread dermatitis (Klement et al, 1996).
Knock-out mice lacking expression of IKK-1 die within a few hours after birth (Takeda et al, 1999; Hu et al, 1999, 2001). The animals show abnormal limb and craniofacial development despite normal skeletal development. Epidermal cells are highly proliferative with dysregulated epidermal differentiation with a failure of keratinocytes to undergo terminal differentiation. IKK-1 does not appear to be essential for cytokine induced activation of NF-kappa-B as embryonic fibroblasts or thymocytes show normal NF-kappa-B activation in response to TNF-alpha or IL1.
Knock-out mice lacking expression of the IKK-2 gene have been generated by Li et al (1995). Absence of IKK-2 causes embryonic lethality. These animals die from extensive liver cell apoptosis. The defect can be rescued by the inactivation of the TNF receptor type 1. Fibroblasts derived from these mice show markedly reduced activation of NF-kappa-B in response to TNF-alpha and IL1-alpha and enhanced apoptosis in response to TNF-alpha.
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ENTRY LAST MODIFIED: January 2005
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