Transcriptional regulation via the NF-κB signaling module

Abstract

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

Inhibitors of NF-κB signaling: 785 and counting

“…In principle, agents that can interfere with NF-kB dimerization could also be effective blockers of NF-kB activity, and because the various NF-kB subunits show different dimerization affinities (see Hoffmann et al, 2006), it should be possible to develop agents that selectively disrupt different NF-kB dimers. Although trans-dominant p50 mutants (that can dimerize but not bind DNA) have been used in tissue culture models (Logeat et al, 1991), no chemical or natural product inhibitors of NF-kB dimerization have been described.…”

“…In theory, this should be a step that could provide extreme specificity and efficacy, given that different NF-kB dimers target different promoters/enhancers in tissue-, stimulus-, and promoter-specific manners (Hoffmann et al, 2006). In addition, NF-kB subunit modification can influence their target gene transactivation ability (Perkins, 2006).…”

“…These complexes bind to DNA regulatory sites called kB sites, generally to activate specific target gene expression. The target gene specificity of NF-kB dimers is thought to arise from a number of considerations, including the specific NF-kB complexes that are in different cell types, the distinct kB target site binding specificities of different NF-kB complexes, and the different proteinprotein interactions and posttranslational modifications that NF-kB complexes undergo in different contexts (Hoffmann et al, 2006;Perkins, 2006).…”

“…Similarly, the different IkB proteins have different affinities for the diverse NF-kB dimers. Thus, different IkB proteins can indirectly regulate the expression of distinct sets of genes, which are transcriptional targets of specific NF-kB complexes (Hoffmann et al, 2006). Finally, NF-kB is a family of dimeric transcription factors, which have distinct sets of target genes.…”

NFκB and HIF display synergistic behaviour during hypoxic inflammation

“…NF!B is a family of transcription factors which plays a key role in a wide variety of physiological (such as immunity) and patho-physiological cellular responses (chronic inflammation, diabetes, cancer) [10,11]. Due to its role as a master regulator of immunity and inflammation, its transcriptional activity and regulatory pathway have been an area of intense research [12]. Substantial evidence now exists that hypoxia can activate NF!B in vivo [8,13] and in vitro [5,7,8,14].…”