الفهرس 
What is NF- kB?Only 14 pages are availabe for public view
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Abstract
Nuclear factor-kappa B (NF-kB) comprises a family of structurally-related transcription factors that play a crucial role in gene regulation during a variety of normal cellular processes, such as immune and inflammatory responses, developmental processes, cellular growth, proliferation, and apoptosis. In addition, NF-kB is persistently active in a number of disease states, including cancer, chronic inflammation, asthma, neurodegenerative diseases, and heart disease.
The NF-kB complexes are homodimers or heterodimers of various combinations of the NF-kB family of cellular proteins which revealed a surprising homology to the oncogene avian reticuloendotheliosis viral oncogene homolog (v-re1): p65 which is also known as v-Rel homolog A (RelA), v-Rel homolog B (RelB), c-rel proto-oncogene protein (c-Rel), p50 (NF-κB1), and p52 (NF-κB2). In human skin, the NF-kB subunits, p50, p65, RelB, and c-Rel, were detected in both basal and suprabasal keratinocytes and in normal epidermis at mRNA and protein levels.
The activity of NF-kB is primarily regulated by interaction with inhibitory-kappa B (IkB) proteins which have different affinities for individual NF-kB complexes. A wide variety of agonists have been shown to activate NF-kB, such as interleukin (IL)-1, tumour necrosis factor–alpha (TNF-α), and gamma irradiation. When a cell receives any of a multitude of extracellular signals, IkB proteins are phosphorylated by the IkB kinase (IKK) complex, and targeted for degradation by the 26s proteosome allowing translocation of the NF-kB dimer to the nucleus where it can activate certain genes which mediate cell proliferation as well as inflammatory and immune responses.
NF-kB plays an important role in cell physiology. Normal activation of NF-kB is required for cell survival and immunity. NF-kB is a master transcriptional regulator critical for ectodermal development, differentiation, keratinocytes regulation, proliferation, and immune function. In addition to an apparent cell-cycle arrest effect, NF-kB in the epidermis also protects against apoptosis.
Also, NF-kB plays an important role in diseases. Dysregulation of NF-kB leads to development of many pathological states including proliferative and inflammatory disorders, such as psoriasis, eczema, Incontinentia pigmenti (IP), sunburn, Lyme disease, autoimmune diseases such as lupus erythematosus, as well as in skin carcinogenesis and several inherited diseases. The activation of NF-kB may be responsible for long-lasting inflammatory processes mediated by T cells such as lichen planus. Also, NF-kB plays an important role in the pathological processes induced by many viruses such as herpes simplex virus type 1 (HSV-1), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV). This suggests the potential of using NF-kB as a therapeutic target in modern medicine for treatment of these diseases.
NF-kB controls the expression of a series of cytokines including TNF-α, IL-1, IL-6, and IL-8 which can activate NF-kB in a positive regulatory loop that is involved in the pathogenesis of several inflammatory diseases, such as psoriasis, and lichen planus. Dysregulation of the NF-kB system and hyperactivated expression of inflammatory mediators are often found in association with some autoimmune diseases, such as lupus erythematosus.
Polymorphisms of the NF-kB genes is related to the development of several distinct genetic diseases that exhibit a large spectrum of dysfunction, such as skin inflammation, disturbed skin appendage development and immunodeficiencies. Incontinentia pigmenti (IP) is an X-linked dominantly inherited genodermatosis that was the first genetic disorder to be associated with NF-κB dysfunction.
NF-kB has been shown to play an important role in tumour pathogenesis and serves as a potential target in cancer therapy. Many human tumour cell lines display increased NF-kB levels and/or increased NF-kB transcriptional activity, such as squamous cell carcinoma, skin papillomas, Kaposi’s sarcoma, dysplastic nevi, primary melanoma, and metastatic melanoma. Studies have shown that the expression of NF-kB is significantly increased in dysplastic nevi, primary melanoma, and metastatic melanoma compared with normal nevi. NF-kB has diagnostic and prognostic significance in melanoma and can be used as a therapeutic option.
The extensive involvement of NF-kB transcription factors in human inflammation and disease establishes them as targets for therapeutics. Indeed, many common synthetic (e.g., aspirin), and traditional (e.g., green tea and curcumin) remedies target, at least in part, the NF-kB signaling pathway. There are over 800 compounds that have been shown to inhibit NF-kB signaling and the knowledge of the molecular details of this pathway is enabling the development of specific inhibitors of NF-kB signaling at various stages, such as antioxidants e.g.: gutathione and -lipoic acid, IkB phosphorylation inhibitors e.g.: thalidomide and sulfasalazine, and proteasome inhibitors e.g.: bortezomib; lactacystin and epoxomicin.