Selectivity of the NF-{kappa}B response

Abstract

NF-kappaB is activated by many stimuli and NF-kappaB binding sites have been identified in a wide variety of genes. Yet, NF-kappaB-dependent gene expression must be stimulus- and cell-type-specific. In others words, the cellular response to different NF-kappaB activating stimuli, such as TNFalpha, IL-1, and LPS, must be different; and the response of different cell types, such as lymphocytes, fibroblasts, or epithelial cells, to the same NF-kappaB-inducing stimulus must also be different. Finally, kinetics of gene expression must be accounted for, so that all NF-kappaB-dependent genes are not activated simultaneously even if cell type and stimulus are constant. Here, we explore the mechanistic framework in which such regulatory aspects of NF-kappaB-dependent gene expression have been analyzed because they are likely to form the basis for physiological responses.

Figure 1.

Mechanisms that contribute to the specificity of gene activation by NF-κB proteins. Homo- and heterodimerization between Rel-homology region (RHR) containing proteins generates a diverse range of κB sequence element binding proteins (top). Typically, several of these may be present in the cell nucleus after an activating stimulus, although the composition varies according to cell type, stimulus, and duration of signaling. The spectrum of genes activated is determined by several factors discussed in the text. (A) Tissue- or signal-specific marking may allow NF-κB binding to some genes (top) but not others (bottom). Gray box represents chromatin constraints that may preclude NF-κB binding. (B) The sequence of the κB element in promoters, represented by blue and red boxes, within DNA may bind specific RHR family proteins. (C) The same κB element (red box) may bind more than one RHR dimer under different circumstances, leading to different transcriptional outcomes. (D) The proximity of κB elements (red box) to other transcription factor binding sites (blue and green boxes) may differentially regulate gene expression by combinatorial mechanisms.

Figure 2.

Mechanisms that regulate duration of NF-κB activation. NF-κB activation via the classical pathway is initiated by degradation of IκB protein (cytosol center), resulting in NF-κB (schematized by a p50/RelA heterodimer here, but could involve many of the homo-/heterodimeric pairs shown in Fig. 1) translocation to the nucleus and gene activation after DNA binding. Mechanisms summarized within the blue box reduce the duration of NF-κB-mediated gene expression. (A) Newly synthesized IκB proteins can remove DNA-bound NF-κB and export the complex out to the cytosol; (B) post-translational modifications of RelA, such as methylation and phosphorylation, can target it for proteasome-mediated degradation within the nucleus. The fate of the heterodimeric partner in the complex is not known; (C) transcription-activating heterodimers (such as p50/RelA or p50/c-Rel) can be replaced by p50 homodimers that have been implicated in repressing transcription (note however, that there is also evidence that p50 homodimers may activate transcription in association with nonclassical IκB-like proteins such as Bcl3 and IκBξ). Mechanisms summarized in the red box can extend the duration of NF-κB-mediated gene expression. (D) De novo c-Rel gene transcription and translation can lead to long-term induction of c-Rel-containing heterodimers, and (E) NF-κB target genes such as TNFα (green hexagon) activated during the initial stimulus may feed back in an autocrine fashion to maintain nuclear NF-κB.