Developing Drugs Against a Master Regulator of Cancer Cell Behavior: Targeting NF-kB

Nuclear factor-κB (NF-κB) represents a group of transcription factors (p50, p52, c-Rel, RelA/p65 and RelB) which belong to the Rel family of proteins. These proteins form homo- and heterodimers important in innumerable cellular processes affecting most major growth and survival pathways. To date, at least 400 discrete genes have been shown to be regulated by NF-kB family members, including genes involved in cell cycle control, apoptosis, immune and inflammatory responses, secondary lymphoid organ development and osteoclastogenesis. All NF-kB subunits share an approximately 300 residue long homologous domain near their N termini called the Rel homology domain, which is responsible for mediating the transcription factors binding to DNA, its dimerization with other subunits binding, its interaction with IkB, and in facilitating nuclear localization.

Activation of NF-κB target genes can be achieved via two pathways, the canonical and alternative. Within the canonical pathway, NF-κB transcription factors are sequestered in their bound and inactive state by the IκB family of inhibitory proteins (IκBα, IκBβ, IκBε, p105/γ and p100/δ). Upon activation of cell surface molecules through various interactions,including but not limited to CD40-ligand, tumor necrosis factor (TNF), and numerous cytokines, IκB kinase (IKK) phosphorylates IκB rendering it a substrate for the ubiquitin ligases, and eventual proteasome mediated degradation. Degradation of the bound IκB allows for nuclear translocation of the NF-κB complex, where it then transactivates its target genes. In the alternative pathway, IKK directly phosphorylates p100 which in turn induces the cytoplasmic processing of p100 to p52, a smaller protein which translocates to the nucleus where it activates its repertoire of target genes.