Nuclear factor kappa B

Nuclear factor kappa B (NF-κB) is a protein complex that plays a crucial role in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, and bacterial or viral antigens. NF-κB is involved in regulating the expression of a wide variety of genes that control cell proliferation, apoptosis (programmed cell death), and inflammation. Due to its pivotal role in these fundamental biological processes, NF-κB is also implicated in the pathogenesis of several diseases, including cancer, autoimmune diseases, and inflammatory conditions.

Structure and Activation

NF-κB is a family of closely related protein complexes that can form homo- or heterodimers. The most common form of NF-κB is a heterodimer consisting of p50 and p65 (RelA) subunits. These proteins belong to the Rel protein family, which share a Rel homology domain responsible for DNA binding, dimerization, and interaction with inhibitors known as IκBs.

Activation of NF-κB involves the degradation of IκB proteins, which normally bind to NF-κB and retain it in an inactive state in the cytoplasm. Upon stimulation by various signals, IκB kinase (IKK) phosphorylates IκB, leading to its ubiquitination and subsequent degradation by the proteasome. This process frees NF-κB to translocate into the nucleus, where it binds to specific DNA sequences and activates transcription of target genes.

Functions

NF-κB regulates the expression of genes involved in a wide range of biological processes:

• Immune Response: NF-κB plays a key role in the activation of immune cells, promoting the production of cytokines, chemokines, and other molecules involved in the inflammatory response.
• Cell Proliferation and Survival: By inducing the expression of anti-apoptotic genes and genes promoting cell growth, NF-κB contributes to cell survival and proliferation. This function is crucial for normal cellular processes but can also contribute to the development of cancer when dysregulated.
• Development: NF-κB signaling is involved in various aspects of embryonic development and the maintenance of tissue homeostasis.

Regulation

The activity of NF-κB is tightly regulated by various mechanisms to prevent inappropriate activation:

• Inhibitors: IκB proteins bind to NF-κB and sequester it in the cytoplasm, preventing its activation.
• Phosphorylation: Post-translational modifications of NF-κB subunits and IκB proteins modulate their activity and interactions.
• Cellular Localization: The localization of NF-κB, whether in the cytoplasm or nucleus, is a key regulatory mechanism.

Pathology

Dysregulation of NF-κB has been linked to several diseases:

• Cancer: Constitutive activation of NF-κB can lead to increased cell proliferation and survival, contributing to tumor development and resistance to chemotherapy.
• Inflammatory Diseases: Excessive or inappropriate activation of NF-κB can result in chronic inflammation, underlying conditions such as rheumatoid arthritis and inflammatory bowel disease.
• Autoimmune Diseases: NF-κB's role in immune cell activation can contribute to autoimmune responses when misregulated.

Conclusion

NF-κB is a central mediator of immune and inflammatory responses, cell proliferation, and survival. Its activity is finely tuned by various regulatory mechanisms, and its dysregulation is associated with numerous diseases. Understanding the complex roles and regulation of NF-κB continues to be a significant area of research with implications for developing new therapeutic strategies for cancer, inflammatory, and autoimmune diseases.