NF-κB
NF-KB ( nuclear factor ' kappa -light -chain - enhancer " of activated B- cells) is a specific transcription factor, which is found in practically all cell types and tissues. It can influence the transcription dependent genes via binding to specific regulatory sections of DNA. NF -kB has numerous target genes and mediates diverse effects.
Importance
NF-KB is of great importance for the regulation of the immune response, cell proliferation and cell death. The activation of NF -kB is considered critical for the formation of inflammation. Finally, NF- kappa B performs important functions in the development of the immune system and the lymphatic organs. The role of NF -kB in other contexts (eg the nervous system ) is the subject of current research.
The versatile functions of NF -kB is also associated with numerous diseases. It is often unclear to what extent the activation of NF -kB engages actually causal in the disease process. In some types of cancer such a role is increasingly seen as likely so that components of the NF -kB signaling pathway have become important targets for the development of new drugs.
Structure
It acts with NF -kB is not a single protein, but five or seven different proteins whose common characteristic is a domain of approximately 300 amino acids, called the Rel homology domain. Two subunits may bind to each other in various combinations, and in this way form dimers. The five or seven currently known mammalian subunits of NF-KB are ( alternative name in parentheses):
From the genes for NF- κB1 and NF- κB2 two proteins can be produced, which differ in their length and are named according to their molecular mass. RelA, RelB, and c -Rel also be referred to as Rel- proteins and contain - in contrast to NF- κB1, and NF- κB2 - in addition to the Rel homology domain and at least one trans-activation domain. Although many different dimers are possible, one frequently observed, a combination of a non- Rel protein (NF- κB1, or NF- κB2 ) and a Rel protein; classic example is the p50/RelA-Heterodimer. Such heterodimers have an activating effect due to the transactivation domain of the Rel proteins, while described an inhibitory function for dimers without the involvement of Rel proteins ( esp. for p50/p50 ).
Operation
NF -kB can be connected to a specific DNA motif of about ten base pairs, the so-called kappa B motif bind. The kappa B motif has been demonstrated in a number of regulatory regions in the DNA and subject to a certain variability, which allows a fine regulation in terms of various NF-KB dimers. The binding of NF-KB to the DNA motif leads in most cases to an increased transcription of dependent genes; depending on the dimer composition also observed a rare repression of transcription. It is currently assumed that - are regulated in about 500 different genes of NF- kappa B - in order of magnitude. These include many cytokines and adhesion molecules, which play an important role in the regulation of the immune system.
Regulation and classification in cellular signaling pathways
In a few cell types, NF-KB is always present in the cell nucleus and thus constitutively (i.e., without the action of external stimuli) active. This concerns, for example, B lymphocytes and dendritic cells. In most of the other cell types, however, NF-KB is present in the cytoplasm inactive and therefore has no access to the DNA present in the cell nucleus. This retention in the cytoplasm is achieved by inhibitory kappa B proteins ( IκBα ), which bind to NF -kB and disable it that way.
To the stimuli which can cause activation of NF-KB, including growth factors, cytokines (such as TNF- α and IL- 1β ), as well as bacterial and viral antigens (e.g., lipopolysaccharides, or double stranded RNA ) and chemical and physical toxicants (eg: UV radiation, free radicals). Such stimulation results in a change of activity of cellular signaling pathways, which are frequently mediated by phosphorylation. Among the important for NF -kB signaling pathways and the MAP kinase pathway is important.
The final common pathway of activation of NF -kB is the activation of the IκBα kinase complex ( IKK ), which phosphorylates IκBα proteins and thus its ubiquitination and degradation by the proteasome initiates. NF -kB molecules are thus released from their inhibitors and can now enter the nucleus, where they exert their specific functions. IκBα is rapidly resynthesized to again take its inhibitory control of NF-KB.
Characteristic of NF -kB is the rapid activation, which uses only a few minutes after stimulation. This is due to the fact that no time-consuming synthesis of new proteins is necessary for the activation, is NF-KB in the cytoplasm but already operational and needs to be released only by its specific inhibitor. Another characteristic of NF-KB is its low specificity, because the genes under its control are exceedingly numerous. These characteristics predestine NF- kappa B for use in processes that make a rapid and comprehensive change of gene transcription required.
In addition to NF -kB transcription factors are more about their subcellular localization ( inactive in the cytoplasm, active in the nucleus ) regulated and therefore also referred to as latent cytoplasmic factors.
Examples of regulated by NF- kappa B genes
Cyclooxygenase- 2 (COX -2)
Probably the cyclooxygenase -2 by NF- kappa B is transcribed amplified. NF-KB would be an intracellular pathway leading through the TNF- α and IL- 1β increased formation of prostaglandin E2.
Similarly, interleukin -6 is transcribed amplified by NF -kB.
Examples of natural inhibitors of NF-KB
Natural inhibitors of NF-KB are: allicin, genistein, quercetin, curcumin, gingko, EGCG and tocotrienols. These substances are the active ingredients of garlic, soy, onions, turmeric ( curcuma ), ginko biloba, green tea, and red palm oil.