NF-κB, the first quarter-century: remarkable progress and outstanding questions

Abstract

The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-κB. For the past 25 years, NF-κB has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the κ light chain gene in B cells, research on NF-κB continues to yield new insights into fundamental cellular processes. Advances in understanding the mechanisms that regulate NF-κB have been accompanied by progress in elucidating the biological significance of this transcription factor in various physiological processes. NF-κB likely plays the most prominent role in the development and function of the immune system and, not surprisingly, when dysregulated, contributes to the pathophysiology of inflammatory disease. As our appreciation of the fundamental role of inflammation in disease pathogenesis has increased, so too has the importance of NF-κB as a key regulatory molecule gained progressively greater significance. However, despite the tremendous progress that has been made in understanding the regulation of NF-κB, there is much that remains to be understood. In this review, we highlight both the progress that has been made and the fundamental questions that remain unanswered after 25 years of study.

EGFR and NF-κB: partners in cancer

“…Both p50 and p52 lack any TAD and therefore rely on other members to drive gene expression of NF-kB-target genes. In unstimulated cells, NF-kB proteins are sequestered in the cytoplasm through binding to inhibitory molecules whose prototype is IkBa [81]. Other inhibitory molecules include p100, p105, IkBb, and IkBe, as well as BCL-3, IkBz, and IkBNS.…”

Development of Novel 1,2,3,4-Tetrahydroquinoline Scaffolds as Potent NF-κB Inhibitors and Cytotoxic Agents

“…1 NF-κB is involved in the regulation of many immune and inflammatory responses, cellular growth, and apoptosis. 2,3 At present, NF-κB and its signaling is one of the most exciting and extensively studied research fields since NF-κB dysregulation is associated with many diseases such as cancer, AIDS, asthma, arthritis, diabetes, and inflammatory bowel disease. 4−6 Several natural and synthetic compounds, including some drugs, have been tested for their potential to inhibit NF-κB, but very few of them are suitable for anticancer therapy.…”

Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

“…NF-kB can be activated via at least two different pathways: the so-called canonical and noncanonical pathways. 13 Canonical signaling begins with receptor-ligand stimulation of a kinase cascade that phosphorylates the inhibitor of NF-kB proteins via the inhibitor of NF-kb kinase (IKK) complex. The IKK complex consists of two catalytic subunits, IKKa and IKKb, and the regulatory subunit, NF-kBeessential modulator (also known as IKKg).…”

“…In contrast, the noncanonical pathway is triggered by different stimuli and activation is mediated by an alternative IKK complex (ie, essentially independent of the NF-kBeessential modulator), and leads to transcriptional regulation via the RelB and P52 subunits. 13,16 In normal skin, NF-kB has been shown to be a critical regulator of proliferation and differentiation and is key to overall tissue homeostasis, which is essential for the protective role of this self-renewing organ. 17 Targeted ablation of multiple components of this pathway in mice, coupled with in vitro cellular experimentation, has driven much of our understanding of how NF-kB regulates epidermal homeostasis.…”