![]() The presence of κB sites, however, appears to be a minimal requirement for NF-κB regulation but not sufficient for gene induction ( Wan et al. Increasing evidence suggests that specific chromatin modifications and configurations are required for NF-κB proteins to access the chromosomally embedded cognate κB motifs ( Natoli et al. ![]() How NF-κB selectively recognizes a small subset of relevant κB sites from the large excess of potential binding sites (about 1.4×10 4 estimated in human genome) is a critical step for stimulus-specific gene transcription. NF-κB exerts its fundamental role as transcription factor by binding to variations of the consensus DNA sequence of 5′-GGGRNYY YCC-3′ (in which R is a purine, Y is a pyrimidine, and N is any nucleotide) known as κB sites ( Chen et al. Therefore, the molecular machine known as NF-κB consists of both Rel and non-Rel subunits that actually comprise multiple protein complexes with different gene activation specificities, masquerading as a single NF-κB complex in the nucleus. As an integral component, RPS3 plays a critical role in determining the DNA binding affinity and specificity of NF-κB, which will be discussed in more detail in the following discussion ( Wan et al. A new study shows that another essential subunit of NF-κB complex, ribosomal protein S3 (RPS3), cooperates with Rel dimers to achieve full binding and transcriptional activity ( Wan et al. Moreover, native NF-κB complexes have a >100-fold higher affinity for Ig κB motif DNA than reconstituted p65–p50 heterodimers ( Phelps et al. The native complex of NF-κB from nuclear extracts is more than 200 kDa, significantly higher than that reconstituted from purified p50 and p65 proteins (115 kDa) ( Urban et al. NF-κB complexes have long been thought to function dimerically but functional and biochemical information belied this simple conceptualization. In contrast, the transcription activation domain (TAD) necessary for the target gene expression is present only in the carboxyl terminus of p65, c-Rel, and RelB subunits. Each of these subunits harbors a prototypical amino-terminal sequence of roughly 300 amino acids, termed the Rel homology domain (RHD), that mediates dimerization, DNA-binding, nuclear localization, and cytoplasmic retention by IκBs ( Rothwarf and Karin 1999 Chen and Greene 2004). The best known subunits of mammalian NF-κB consist of five proteins in the Rel family: RelA (p65), RelB, c-Rel, p50, and p52, which are capable forming homo- and hetero-dimeric complexes in almost any combination ( Hayden and Ghosh 2004). ![]() A diverse spectrum of modulating stimuli can activate this pleiotropic transcription factor furthermore, the fundamental use of NF-κB has been highlighted with an ever-increasing array of genetic targets, responsible for diverse biological activities including immune response, inflammation, cell proliferation, and death ( Grilli et al. This adaptability and versatility no doubt underlies its broad use. It provides a pre-established genetic switch that is independent of new protein synthesis and triggered by a biochemical change in the cell. This cytoplasmic “switch” liberates NF-κB complexes for subsequent nuclear translocation and target gene transcription ( Scheidereit 2006). NF-κB induction typically occurs following the activation of the IκB kinase (IKK) signalosome, resulting in the phosphorylation and subsequent dispatch of the inhibitory IκBs to the proteasome for protein degradation ( Hacker and Karin 2006). 1989 Hayden and Ghosh 2004 Hayden and Ghosh 2008). In essentially all unstimulated nucleated cells, NF-κB complexes are retained in latent cytoplasmic form through binding to a member of the inhibitor of NF-κB (IκB) proteins ( Lenardo and Baltimore 1989 Lenardo et al. NF-κB is evolutionarily and structurally conserved and has representative members in a wide range of species. Nuclear factor-κB (NF-κB), a collective term for a family of transcription factors, was originally detected as a transcription-enhancing, DNA-binding complex governing the immunoglobulin (Ig) light chain gene intronic enhancer ( Sen and Baltimore 1986 Lenardo et al.
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