摘要：

The transcription factor NF-κB exists in unstimulated cells as a cytoplasmic homo- or heterodimer bound to inhibitory IκB protein. NF-κB has received a great deal of attention since its discovery more than two decades ago, and for good reason. It regulates genes implicated in innate immunity, inflammation, cancer, and apoptosis. And the molecules associated with the NF-κB signaling pathway are prime drug targets. This issue's Hot Papers focus on distinct parts of the NF-κB pathway. An interdisciplinary approach combining computer modeling of IκB isoform activity with experimental data has positioned the NF-κB signaling pathway at the forefront of systems biology. A second more conventional study explored what controls the bivalent nature of NF-κB as both gene activator and suppressor. A third study revealed a new role for an IκB kinase. Building a model NF-κB is regulated by three isoforms of the inhibitor IκB: IκBα, IκBβ, and IκBε. IκB binding keeps NF-κB localized to the cytoplasm. In the so-called canonical pathway, activation of NF-κB by a stimulus such as TNF-α leads to phosphoryla-tion, ubiquitination, and degradation of the IκB isoforms. This in turn permits NF-κB translocation to the nucleus, where it binds DNA and activates target genes, including the gene for IκBα. Newly synthesized IκBα then binds to NF-κB, inhibiting it.

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