Stimulus-induced nuclear factor-kappaB (NF-kappaB) activity, the central mediator of inflammatory responses and immune function, comprises a family of dimeric transcription factors that regulate diverse gene expression programs consisting of hundreds of genes. A family of inhibitor of kappaB (IkappaB) proteins controls NF-kappaB DNA-binding activity and nuclear localization. IkappaB protein metabolism is intricately regulated through stimulus-induced degradation and feedback re-synthesis, which allows for dynamic control of NF-kappaB activity. This network of interactions has been termed the NF-kappaB signaling module. Here, we summarize the current understanding of the molecular structures and biochemical mechanisms that determine NF-kappaB dimer formation and the signal-processing characteristics of the signaling module. We identify NF-kappaB-kappaB site interaction specificities and dynamic control of NF-kappaB activity as mechanisms that generate specificity in transcriptional regulation. We discuss examples of gene regulation that illustrate how these mechanisms may interface with other transcription regulators and promoter-associated events, and how these mechanisms suggest regulatory principles for NF-kappaB-mediated gene activation.
