Classically, NF-kappa B is described as a transcription factor that reprograms gene expression of the immune system in response to injury, infection, and stress. The NF-kappa B transcription factor exists as a dimer composed of pairs of monomeric subunits that are part of the Rel Family of proteins. The Rel family of proteins and their related sequences were first identified in an oncogene derived from the avian reticuloendotheliosis retrovirus. The members of this family include NF-kappa B1/p50, NF-kappa B2/p52, RelA/p65, c-Rel, and RelB.
The combinatorial nature of the NF-kappa B transcription factor provides a level of regulation that allows it to mediate an array of pleiotropic responses to a diverse set of stimuli. Another level of NF-kappa B regulation is seen in the form of associated inhibitor proteins that interact with NF-kappa B to inhibit its DNA binding activity. These inhibitor proteins are members of the I kappa B family of proteins and include I kappa B-beta, I kappa B-delta/NF-kappa B2/p100, I kappa B-gamma/NF-kappa B/p105, I kappa B-epsilon, I kappa B-zeta, and Bcl3. Association with the inhibitory I kappa B proteins sequesters NF-kappa B in the cytoplasm to regulate its activity. The phosphorylation of I kappa B by the I kappa B kinase complex (IKK) results in the ubiquitination and degradation of I kappa B and the release and translocation of NF-kappa B to the nucleus where it can activate a vast number of genes. The regulatory kinase, IKK, is composed of two catalytic subunits, IKK-alpha and IKK-beta, and a regulatory subunit IKK-gamma/NEMO. Non-canonical regulatory mechanisms that do not involve the regulation NF-kappa B by the I kappa B proteins also exist. Such mechanisms include posttranslational modification, such as phosphorylation, of the NF-kappa B members.Due to its combinatorial nature, its ubiquitous expression, and its ability to mediate pleiotropic responses, NF-kappa B has become one of the most studied transcription factors. Recently, the dysregulation of NF-kappa B has been associated with a multitude of diseases and is being considered as a potential target of pharmacological intervention. These points illustrate that our understanding of NF-kappa B is far from complete and that it will to continue as a subject of intense study.
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