NF-κB Activation: The IκB Kinase Revealed?

More than a decade ago, the transcriptional activator NF- Kappa B was described as a protein that bound to a specific DNA site in the intronic enhancer of the immunoglobulin Kappa light chain gene. Following the cloning of genes encoding the p50 and p65 subunits of NF- Kappa B, it became evident that both subunits are members of the larger NF- Kappa B/Rel family of transcriptional regulator proteins. Since its initial description, our view of the role of NF- Kappa B in immune and inflammatory responses has broadened significantly. NF- Kappa B regulation is part of a cellular response system to many different noxious stimuli. NF- Kappa B is activated by a vast number of agents including cytokines like tumor necrosis factor alpha (TNF alpha ) and interleukin-1 (IL-1), bacterial LPS, viral infection and expression of certain viral proteins like Tax of human T-cell leukemia virus, (HTLV-1), antigen receptor cross-linking of T and B cells, calcium ionophores, phorbol esters, UV radiation, free radicals, endoplasmic reticulum overloading, and others. The genes regulated by the NF- Kappa B family of transcription factors are diverse and include those involved in immune function, inflammatory response, cell adhesion, and growth control. Recently, the activation of NF- Kappa B has also been linked to the regulation of cell death. NF- Kappa B was initially believed to be lymphoid-specific because of its constitutive presence in the nuclei of mature B cells. In almost all other cells, however, NF Kappa B is sequestered in the cytoplasm by tightly bound inhibitory proteins called I Kappa BS. In the family of I Kappa Bs, the most important appear to be I Kappa B alpha , I Kappa B beta , and the newly discovered I Kappa B epsilon . Many of the signals known to activate NF- Kappa B result in phosphorylation and subsequent degradation of the I Kappa Bs, allowing NF- Kappa B to translocate into the nucleus and activate target genes. Early studies implicated the phosphorylation of I Kappa B as a central event of this activation and identified potential kinases that were able to phosphorylate the inhibitor protein in vitro.