IκBβ enhances the generation of the low-affinity NFκB/RelA homodimer

Tsui, Rachel; Kearns, Jeffrey D.; Lynch, C.; Vu, Don; Ngo, Kim A.; Basak, Soumen; Ghosh, Gourisankar; Hoffmann, Alexander

doi:10.1038/ncomms8068

Cited by 43 publications

(58 citation statements)

References 38 publications

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“…By contrast, the IkBb protein does not support proper negative feedback control even when expressed from IkBa's promoter; we speculate that substantially reduced nucleocytoplasmic transport [25,26] may be a key underlying reason; a second characteristic that may play a role is IkBa's but not IkBb's ability to strip NFkB off the DNA [27]. Indeed, these properties are not required for the NFkB dimer stabilization/chaperone function recently ascribed to IkBb [28]. Our results illustrate the more general point: that negative feedback regulation in cells is a complex process that depends on multiple molecular properties beyond activator-induced expression [29,30].…”

Section: Discussionmentioning

confidence: 92%

Anatomy of a negative feedback loop: the case of I κ B α

Fagerlund

Behar

Fortmann

et al. 2015

J. R. Soc. Interface.

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The magnitude, duration and oscillation of cellular signalling pathway responses are often limited by negative feedback loops, defined as an 'activator-induced inhibitor' regulatory motif. Within the NFkB signalling pathway, a key negative feedback regulator is IkBa. We show here that, contrary to current understanding, NFkB-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NFkB signalling to identify IkBa molecular properties that are critical for proper negative feedback control and test the resulting predictions in biochemical and single-cell live-imaging studies. We identified nuclear import and nuclear export of IkBa and the IkBa-NFkB complex, as well as the free IkBa half-life, as key determinants of post-induction repression of NFkB and the potential for subsequent reactivation. Our work emphasizes that negative feedback is an emergent systems property determined by multiple molecular and biophysical properties in addition to the required 'activator-induced inhibitor' relationship.

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Section: Discussionmentioning

confidence: 92%

Anatomy of a negative feedback loop: the case of I κ B α

Fagerlund

Behar

Fortmann

et al. 2015

J. R. Soc. Interface.

Self Cite

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“…A good example of this approach is a study by Hofmann and coworkers on their NF-κB modeling [40]. Specifically, they tested different hypotheses on NF-κB homo-and heterodimer formation, initially with a very minimal model.…”

Section: Discussionmentioning

confidence: 99%

“…They expanded the model until it explained the experimental observations on for instance dimer abundances. In the end, they altered their already well-established complex model, to include their new findings on dimer formation, and see if it still exhibits the same dynamics [40]. Another option to deal with model complexity is to first construct a complex model and employ reduction algorithms (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…In follow-up work, Hoffman and colleagues have focused on different aspects of the pathway. For example, some of their latest work concerned NF-κB dimer formation and the role of IκBβ as a stabilizer [40], and the role of Toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-β (TRIF) as a posttranscriptional regulator of TNFα [41].…”

Section: Modelingmentioning

confidence: 99%

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Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

Kuijper

Yang

Water

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI. Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver. Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs. ARTICLE HISTORY

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“…These proteins share a highly conserved DNA-binding and dimerization domain called the Rel homology region (RHR). NF-B proteins can form homodimers and heterodimers, and this combinatorial diversity contributes to the regulation of distinct but overlapping sets of genes (3)(4)(5)(6). The activity of NF-B is modulated by many extracellular signals, including cytokines, tumor promoters, and chemotherapeutic agents.…”

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confidence: 99%

A Novel Allosteric Mechanism of NF-κB Dimerization and DNA Binding Targeted by an Anti-Inflammatory Drug

Ashkenazi

Plotnikov

Bahat

et al. 2016

Molecular and Cellular Biology

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The NF-B family plays key roles in immune and stress responses, and its deregulation contributes to several diseases. Therefore its modulation has become an important therapeutic target. Here, we used a high-throughput screen for small molecules that directly inhibit dimerization of the NF-B protein p65. One of the identified inhibitors is withaferin A (WFA), a documented anticancer and anti-inflammatory compound. Computational modeling suggests that WFA contacts the dimerization interface on one subunit and surface residues E285 and Q287 on the other. Despite their locations far from the dimerization site, E285 and Q287 substitutions diminished both dimerization and the WFA effect. Further investigation revealed that their effects on dimerization are associated with their proximity to a conserved hydrophobic core domain (HCD) that is crucial for dimerization and DNA binding. Our findings established NF-B dimerization as a drug target and uncovered an allosteric domain as a target of WFA action. The NF-B family, which consists of p65/RelA, cRel, RelB, p50, and p52, is responsible for transcription activation of a large number of inflammatory genes, immune response genes, and genes promoting the survival of normal and cancer cells (1, 2). These proteins share a highly conserved DNA-binding and dimerization domain called the Rel homology region (RHR). NF-B proteins can form homodimers and heterodimers, and this combinatorial diversity contributes to the regulation of distinct but overlapping sets of genes (3-6). The activity of NF-B is modulated by many extracellular signals, including cytokines, tumor promoters, and chemotherapeutic agents. In unstimulated cells, NF-B is retained in the cytoplasm in an inactive form by IB proteins. Signals that activate NF-B trigger ubiquitination and degradation of IB by the proteasome, resulting in transport of NF-B into the nucleus and activation of responsive genes (7,8). Deregulation of NF-B is tightly linked to chronic inflammation and cancer (9). In normal cells NF-B activity is transient; however, in many lymphoid malignancies, certain solid tumors, and chronic inflammation, NF-B activity becomes persistent and contributes to or causes disease (10-13). Therefore, inhibition of the NF-B pathway has become an important target for drug development related to inflammation and cancer. Thus far, most of the efforts to modulate NF-B have been directed toward the signaling pathway, while few attempts have been made to target NF-B proteins.In the present study, we conducted a screen based on a split-Renilla luciferase (RL) complementation assay for small molecules that can directly disrupt p65 dimerization. Of the 46,000 small molecules analyzed, the natural product withaferin A (WFA), a known anti-inflammatory and anticancer compound, was among the best inhibitors. We confirmed direct inhibition of p65 dimerization by WFA. Computational modeling of a WFA complex with p65-p65 and p65-p50 predicted contact with dimerization interface residues (E211 and E267 in p65 and p50, respecti...

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IκBβ enhances the generation of the low-affinity NFκB/RelA homodimer

Cited by 43 publications

References 38 publications

Anatomy of a negative feedback loop: the case of I κ B α

Anatomy of a negative feedback loop: the case of I κ B α

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

A Novel Allosteric Mechanism of NF-κB Dimerization and DNA Binding Targeted by an Anti-Inflammatory Drug

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