NF-κB, a eukaryotic transcription factor plays an important role in inflammation, autoimmune response, cell proliferation, and apoptosis by regulating the expression of genes involved in these processes. It consists of homo- or heterodimers of different subunits, which belong to a family of Rel/NF-κB proteins. Five different Rel proteins [p50, p52, p65 (Rel A), RelB, and c-Rel] have been identified thus far. The most prevalent activated form of NF-κB is a heterodimer of p50 or p52 subunit and p65, which contains transactivation domains necessary for gene induction. In unstimulated cells, NF-κB is sequestered in the cytoplasm in an inactive form, bound to regulatory proteins called inhibitors of κB (IκB), of which IκBα and IkBb are considered to be the most important. IκBα is associated with transient NF-κB activation, whereas IκBΒ is involved in sustained activation.
The activity of NF-κB is tightly regulated by interaction with inhibitory IκB proteins. In most resting cells, NF-κB is sequestered in the cytoplasm in an inactive form associated with inhibitory molecules, such as IκBα, IκBβ, IκBη, p105, and p100. This interaction blocks the ability of NF-κB to bind to DNA and results in the NF-κB complex being primarily localized to the cytoplasm due to a strong nuclear export signal in IκBα.
Stimulation of cells by inflammatory cytokines, UV light, or reactive oxygen species leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IκB, which frees NF-κB from the NF-κB-IκB complex. NF-κB then translocates to the nucleus where it binds to κB enhancer elements of pro-inflammatory target genes to induce transcription. NF-κB is highly activated at sites of inflammation in diverse diseases and induces transcription of pro-inflammatory cytokines, chemokines, adhesion molecules, MMPs, COX-2, and inducible nitric oxide (iNOS). Hence, NF-κB has been considered as a desirable target for therapy in various inflammatory diseases. In most cancer cells, NF-κB is constitutively active and resides in the nucleus. In some cases, this may be due to chronic stimulation of the IKK pathway, while in others the gene encoding IκBα may be defective. Such continuous nuclear NF-κB activity not only protects cancer cells from apoptotic cell death, but may even enhance their growth activity. Designing antitumor agents to block NF-κB activity or to increase sensitivity to conventional chemotherapy may have great therapeutic value.
Pande, V., and Ramos, M. J. 2005. Curr. Med. Chem. 12, 357.
Bouwnecster, T. et al. 2004. Nat. Cell Biol. 6, 97.
Marienfeld, R., et al. 2003. J. Biol. Chem. 278, 19852.
Ghosh, S., and Karin M. 2002. Cell 109, S81.
Delhase, M., et al. 1999. Science 284, 309.
Rahman, A., et al. 1999. J. Immunol. 162, 5466.
Miyazawa, K., et al. 1998. Am. J. Pathol. 152, 793.
Zandi, E., et al. 1998. Science 281, 1360.
Stancovski, I., and Baltimore, D. 1997. Cell 91, 299.
Baldwin, A.S. Jr. 1996. Annu. Rev. Immunol. 14, 649.
Highlighted below are inhibitors included in InhibitorSelect™ NFkB Signaling Pathway Inhibitor Panel (Cat. No. 481487).