The IκB-NF-κB Signaling Module: Temporal Control and Selective Gene Activation

Hoffmann, Alexander; Levchenko, Andre; Scott, Martin; Baltimore, David

doi:10.1126/science.1071914

Cited by 1,662 publications

(1,921 citation statements)

References 18 publications

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“…Consistent with this, at intermediate levels of IL18, we observed induction of cytokine gene expression and induction of Rel family members encoding activating subunits of NFkB. A model for dampening cytokine responses was recently proposed by Hoffmann et al, 29 who described distinct NFkB responses comparing transient and prolonged stimuli. These authors observed that transient TNF stimulation resulted in degradation of IkB-a whereas IkB-b and IkB-e were resistant.…”

Section: Cis-element Clustering D Leyfer Et Alsupporting

confidence: 89%

cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18

et al. 2004

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We examine the effects of IL18 on monocytes by performing microarray experiments using cell line KG1. Based on sensitivity to IL18, we identified three functionally distinct gene expression clusters (EC). We see little proinflammatory gene induction at low IL18 concentrations, but instead observe induction of diverse NFkB signaling inhibitors. Conversely, intermediate concentrations of IL18 induced proinflammatory genes including the activating subunits of NFkB. At the highest IL18 concentration, we observe a third gene cluster containing the proapoptotic Fas gene among others. Clustering of IL18-responsive genes based on cis-elements in their promoters agreed well with the ECs. We conclude that IL18 produces a dosedependent transcriptional response that can in part be attributed to the composition of cis-elements in the promoters of IL18-responsive genes. These results also support a model for regulatory mechanisms that prevent spurious immune response due to weak cytokine fluctuations and a separate mechanism enabling induction of proinflammatory functions by higher levels of cytokine.

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Section: Cis-element Clustering D Leyfer Et Alsupporting

confidence: 89%

cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18

et al. 2004

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“…All IkB proteins (IkBa, -b, -e, p105/IkBg and p100/IkBd) have been reported to be NF-kB target genes, providing for potential negative feedback, yet with distinct temporal control. In recognition that these dynamic molecular interactions are critical for NF-kB signaling, the small network of IKK, IkB and NF-kB proteins has been termed the NF-kB signaling module (Figure 2) (Hoffmann et al, 2002;Basak et al, 2006). Indeed, NF-kB activation dynamics may be stimulusspecific (Werner et al, 2005) and can be a critical mechanism for stimulus-specific gene expression programs (Barken et al, 2006).…”

Section: Molecular Components Of the Nf-kb Familymentioning

confidence: 99%

Transcriptional regulation via the NF-κB signaling module

2006

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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.

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“…A detailed understanding of these biochemical events has allowed for the construction of a mathematical model that recapitulates the experimentally observed NF-κB activation dynamics during the TNF response (Hoffmann et al, 2002;Kearns et al, 2006). This mathematical model provided an in silico confirmation that the known biochemical mechanisms, such as stimulus-responsive degradation and resynthesis of IκBs, its association/dissociation with the RelA:p50 dimer, nuclear import and export of free and IκB-bound RelA:p50 dimers, are sufficient to explain the observed NF-κB regulation in response to the canonical pathway activation (Fig.…”

Section: Nf-κb Signaling Dynamics and A Mathematical Modelmentioning

confidence: 99%

“…To further address the relationship between canonical and non-canonical signaling, a set of ordinary differential equations, that describe synthesis, degradation and molecular interactions of p100, was included into a mathematical model that was already accounted for NF-κB activation dynamics in inflammatory settings (Hoffmann et al, 2002). The resulting model (Basak et al, 2007) included 98 biochemical reactions, which were parameterized based on biochemical measurements and parameter fitting algorithms.…”

Section: A "Four Iκb" Containing Mathematical Modelmentioning

confidence: 99%

Crosstalk via the NF-κB signaling system

Basak¹,

Hoffmann²

2008

Cytokine & Growth Factor Reviews

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152

117

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The NF-κB family of transcription factors consists of fifteen possible dimers whose activity is controlled by a family of inhibitor proteins, known as IκBs. A variety of cellular stimuli, many of them transduced by members of the TNFR superfamily, induce degradation of IκBs to activate an overlapping subset of NF-κB dimers. However, generation and stimulus-responsive activation of NF-κB dimers are intimately linked via various cross-regulatory mechanisms that allow crosstalk between different signaling pathways through the NF-κB signaling system. In this review, we summarize these mechanisms and discuss physiological and pathological consequences of crosstalk between apparently distinct inflammatory and developmental signals. We argue that a systems approach will be valuable for understanding questions of specificity and emergent properties of highly networked cellular signaling systems.

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The IκB-NF-κB Signaling Module: Temporal Control and Selective Gene Activation

Cited by 1,662 publications

References 18 publications

cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18

cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18

Transcriptional regulation via the NF-κB signaling module

Crosstalk via the NF-κB signaling system

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