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Transcriptional regulation via the NF-κB signaling module

Abstract

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

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Acknowledgements

In the interest of clarity, we have narrowly focused this review and apologize for not citing many important contributions. We thank Amanda Fusco, Soumen Basak, and Shannon Werner for reading the manuscript, and laboratory members and colleagues for interesting discussions. Work on related topics in our laboratories is funded by NIH GM72024 and GM071573 (AH), NIH CA71718 and GM071862 (GG), and the Human Frontier Science Program and Italian Association for Research on Cancer (GN).

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Correspondence to A Hoffmann.

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Hoffmann, A., Natoli, G. & Ghosh, G. Transcriptional regulation via the NF-κB signaling module. Oncogene 25, 6706–6716 (2006). https://doi.org/10.1038/sj.onc.1209933

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