IκBα (Inhibitor of Nuclear Factor (NF)-κB α isoform) is a member of the IκB protein family with a MW of 40 kDa. IκBα is ubiquitously expressed among mammals. Located at IκBα's N-terminus is a signal response domain which contains serine residues that can be phosphorylated, while the C-terminus contains a PEST domain, a common feature among proteins with high turnover rates. As with all members of the IκB family, IκBα possesses ankyrin repeats approximately 33 amino acids in length, which mediate binding to the Rel homology region of NF-κB. The interaction of IκBα with NF-κB masks the nuclear localization sequence of NF-κB, preventing NF-κB translocation to the nucleus. A variety of stimuli can activate gene expression by liberating NF-κB through the degradation of IκBα. These stimuli include the proinflammatory cytokines TNF-α and IL-1β, chemokines, PMA, growth factors, LPS, UV irradiation, and viral infection, as well as various chemical and physical stresses. The series of events leading to this liberation is well-defined. In response to stimulus, Ser32/36 of IκBα are phosphorylated, which provides a signal for IκBα E3 ligase, a protein complex composed of SKP-1, Cul-1, Roc1, and Fbw1. IκBα E3 ligase polyubiquitinates IκBα at lysine residues 21 and 22, and the polyubiquitinated IκBα is then targeted to the 26S proteasome for degradation. Liberated NF-κB is transported across the nuclear membrane, where it activates transcription by binding to the consensus sequence GGRNNYYCC, which is found in the promoter regions of a large number of genes including IL-6, VEGF, VCAM-1, ICAM-1, HIV long terminal repeat, and many others. The initial event which targets IκBα for degradation is phosphorylation of Ser32/36. This phosphorylation is catalyzed by a protein complex known as IKK (IκB kinase). IKK contains two kinase subunits designated IKKα (MW=85 kDa) and IKKβ (MW=87 kDa), and scaffold protein designated IKKγ/NEMO (MW=48 kDa). The kinetic properties of IKK are regulated by complex formation as well as by phosphorylation events catalyzed by upstream kinases including members of the MAPK cascade, the SAPK/JNK cascade and NIK. Through its regulation of NF-κB, IκBα controls immune and inflammatory responses, cell division, and apoptosis. Numerous disease states including arthritis, asthma, and inflammatory bowel disease are associated with loss of IκBα regulation. The importance of regulation of IκBα in cancer is underscored by the observation that multiple myelomas often possess polymorphisms at IκBα regulatory sites, and certain symptoms can be ameliorated using the proteasome inhibitor PS-341 which favors the sequestration of NF-κB in the cytoplasm.
IKBA; MAD-3; NFKBI; I-kappa-B-alpha; IkappaBalpha; NF-kappa-B inhibitor alpha; ikB-alpha; major histocompatibility complex enhancer-binding protein MAD3; nuclear factor of kappa light chain gene enhancer in B-cells; NFKBIA; nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; MAD 3; IKBA, MAD-3, IkappaBalpha; I kappa B-alpha; Rel-associated pp40; NF-kappaB inhibitor alpha; REL-associated protein pp40