NF-kappaB

Nuclear transcription factor kappaB (NF-kappaB) was first discovered in 1986 in the nucleus of the B cell as an enhancer in the kappa immunoglobulin chain. However, this factor has identified in the cytoplasm in the resting state.

When activated in response to inflammatory stimuli, carcinogens, stress, ionizing radiation, and growth factors, NF-kappaB translocates to the nucleus where it upregulates the expression of over 400 different gene products linked with inflammation, cell survival, proliferation, invasion, and angiogenesis.

The activation of NF-kappaB has now been linked with a variety of inflammatory diseases, including cancer and pulmonary, autoimmune, skin, neurodegenerative, and cardiovascular disorders.

Indeed, constitutive NF-kappaB activation frequently correlates with the proliferation, survival, chemoresistance, radioresistance, and progression of various cancers.

NF-kappaB has both diagnostic and prognostic applications.

NFKB has been detected in numerous cell types that express cytokines, chemokines, growth factors, cell adhesion molecules, and some acute phase proteins in health and in various disease states.

NFKB is activated by a wide variety of stimuli such as cytokines, oxidant-free radicals, inhaled particles, ultraviolet irradiation, and bacterial or viral products.

Inappropriate activation of NF-kappa-B has been linked to inflammatory events associated with autoimmune arthritis, asthma, septic shock, lung fibrosis, glomerulonephritis, atherosclerosis, and AIDS.

In contrast, complete and persistent inhibition of NF-kappa-B has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth.

NFKB1 (MIM.164011) or NFKB2 (MIM.164012) is bound to REL (MIM.164910), RELA (MIM.164014), or RELB (MIM.604758) to form the NFKB complex.

Subunits

The p50 (NFKB1)/p65 (RELA) heterodimer is the most abundant form of NFKB.

The NFKB complex is inhibited by I-kappa-B proteins (NFKBIA) (MIM.164008) or NFKBIB (MIM.604495), which inactivate NFKB by trapping it in the cytoplasm.

Phosphorylation of serine residues on the I-kappa-B proteins by kinases IKBKA (MIM.600664) or IKBKB (MIM.603258) marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NFKB complex.

Activated NFKB complex translocates into the nucleus and binds DNA at kappa-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine).

NFKBs	NFKB1	NFKB2	NFKB3
RELs	REL	RELA	RELB

Pathology

The activation of NF-kappaB has now been linked with a variety of inflammatory diseases, including cancer and pulmonary, autoimmune, skin, neurodegenerative, and cardiovascular disorders.

Indeed, constitutive NF-kappaB activation frequently correlates with the proliferation, survival, chemoresistance, radioresistance, and progression of various cancers.

 Melanoma

• Besides the RAS/MAP kinase pathway, NFκB is another pathway that melanoma tumors use to achieve survival, proliferation and resistance to apoptosis. (22433222)
• Inhibition of NF-κB activation appears to be a very promising option for anti-cancer therapies. (22433222)

Open References

 NF-κB as potential target in the treatment of melanoma. Madonna G, Ullman CD, Gentilcore G, Palmieri G, Ascierto PA. J Transl Med. 2012 Mar 20;10:53. PMID: 22433222 [Free]

References

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