1. ¹Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, USA
2. ²Signaling Systems Laboratory, University of California at San Diego, La Jolla, CA, USA
3. ³Department of Experimental Oncology, European Institute of Oncology, Milan, Italy

Correspondence: Professor A Hoffmann and Professor G Ghosh, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Dr, La Jolla, CA 92037, USA. E-mails: ahoffmann@ucsd.edu and gghosh@ucsd.edu

Abstract

Stimulus-induced nuclear factor-B (NF-B) 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 B (IB) proteins controls NF-B DNA-binding activity and nuclear localization. IB protein metabolism is intricately regulated through stimulus-induced degradation and feedback re-synthesis, which allows for dynamic control of NF-B activity. This network of interactions has been termed the NF-B signaling module. Here, we summarize the current understanding of the molecular structures and biochemical mechanisms that determine NF-B dimer formation and the signal-processing characteristics of the signaling module. We identify NF-B–B site interaction specificities and dynamic control of NF-B 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-B-mediated gene activation.