NF-κB Family - Interactive Pathway and Product Listing

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NF-κB: A Therapeutic Target for Inflammation & Cancer

The eukaryotic nuclear factor kB (NF-kB) plays an important role in inflammation, autoimmune response, cell proliferation, and apoptosis by regulating the expression of genes involved in these processes. Five members of the NF-kB family have been identified: NF-kB1 (p50/p105), NF-kB2 (p52/p100), RelA (p65), RelB, and c-Rel. They share a highly conserved Rel homology domain (RHD), which is responsible for DNA binding, dimerization, and interaction with IkB. The p50/RelA(p65) heterodimer is the major Rel/NF-kB complex in most cells. RelB can act as both a transcriptional activator as well as a repressor of NF-kBdependent gene expression. It acts as an activator when it associates with p50 or p52. However, its inhibitory effect has been attributed to the formation of the RelA(p65):RelB heterodimer that does not bind to kB sites. Studies on NIH 3T3 cells have also shown that RelA(p65):RelB heterodimers are not regulated by IkB and are located in both the cytoplasm and the nucleus.

The activity of NF-kB is tightly regulated by its interaction with inhibitory IkB proteins. In most resting cells, NF-kB is sequestered in the cytoplasm in an inactive form associated with inhibitory molecules such as IkBa, IkBb, IkBe, p105, and p100. This interaction blocks the ability of NF-kB to bind to DNA and results in the NF-kB complex being primarily localized to the cytoplasm due to a strong nuclear export signal in IkBa. Following exposure to inflammatory cytokines, UV light, reactive oxygen species, or bacterial and viral toxins, the NF-kB signaling cascade is activated, leading to the complete degradation of IkB. This allows the translocation of unmasked NF-kB to the nucleus where it binds to the enhancer or promoter regions of target genes and regulates their transcription. In the nucleus, acetylation of NF-kB determines its active or inactive state. p300 and CBP acetyltransferases play a major role in the acetylation of RelA(p65), principally targeting Lys^{218, 221, 310} for modification. Acetylated NF-kB is active and is resistant to the inhibitory effects of IkB. However, when histone deacetylase 3 (HDAC3) deacetylates NF-kB, IkB readily binds to NF-kB and causes its translocation into the cytoplasm. Here HDAC3 serves as an intranuclear molecular switch that turns off the biological processes triggered by NF-kB. One of the target genes activated by NF-kB is that encoding IkBa. Newly synthesized IkBa can enter the nucleus, remove NF-kB from DNA, and export the complex back to the cytoplasm to restore its original latent state.

As mentioned above, the activation of NF-kB by extracellular inducers depends on the phosphorylation and subsequent degradation of IkB proteins. Activation of NF-kB is achieved through the action of a family of serine/threonine k (IKK). The IKK contains two catalytic subunits (IKKa and IKKb) and a regulatory/adapter protein NEMO (also known as IKKg). IKKa and IKKb phosphorylate IkB proteins and the members of the NF-kB family. All IkB proteins contain two conserved serine residues within their N-terminal area, which are phosphorylated by IKK. IKKa and IKKb share about 50% sequence homology and can interchangeably phosphorylate Ser^32/36 of IkBa, and Ser^19/23 of IkBb. These phosphorylation events lead to the immediate polyubiquitination of IkB proteins and rapid degradation by the 26S proteasome.

The Rel/NF-kB signal transduction pathway is misregulated in a variety of human cancers, especially those of lymphoid cell origin. Several human lymphoid cancer cells are reported to have mutations or amplifications of genes encoding NF-kB transcription factors. In most cancer cells NF-kB 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 IkBa may be defective. Such continuous nuclear NF-kB activity not only protects cancer cells from apoptotic cell death, but may even enhance their growth activity. Designing anti-tumor agents to block NF-kB activity or to increase their sensitivity to conventional chemotherapy may have great therapeutic value.

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