Regulation of NF-kB

Nuclear factor-kB (NF-kB) is a ubiquitous transcription factor that controls the expression of genes involved in immune responses, apoptosis, and cell cycle. Incorrect regulation of NF-kB may cause inflammatory and autoimmune diseases, viral infection and cancer. Five mammalian NF-kB family members have been identified:

• NF-kB1 (also called p50)
• NF-kB2 (also named p52)
• RelA (also known as p65)
• RelB
• c-Rel

They all share a highly conserved Rel homology domain, responsible for their dimerization and binding to DNA and IkB (inhibitor of NF-kB). The transcription factor NF-kB works only when two members form a dimer. The most abundant activated form consists of a p50 or p52 subunit and a p65 subunit.

Figure 4-H-3.  Structure of a NF-kB/DNA complex.  The transcription factor NF-kB consists of two subunits: p50 (green) and p65 (red).

NF-kB can be activated by a variety of stimuli, including cytokines (such as TNF-a and IL-1), T and B cell mitogens, viral proteins, and stress inducers (such as reactive oxygen species or UV radiation).   In the cytoplasm, NF-kB is inhibited by IkB.  Upstream activating signal (e.g., binding of TNF-a to its receptor) may cause phosphorylation of IkB by IKK (IkB kinase).  This triggers the degradation of IkB through the ubiquitin system, where the target molecule is masked by a chain of ubiquitins for degradation by the 26S protesome.  The free NF-kB can then translocate to the nucleus and activate transcription.

Figure 4-H-4.  Activation of NF-kB.

Review Articles:

New Insights into the Role of Nuclear Factor-kB in Cell Growth Regulation - Am J. Pathol., 2001.

NF-kB signaling pathways in mammalian and insect innate immunity - Genes and Development, 2001.

Series from Journal of Clinical Investigation (2001)

1. Series Introduction: The transcription factor NF-kB and human disease
2. NF-kB: a key role in inflammatory diseases
3. Toll-like receptor–mediated NF-kB activation: a phylogenetically conserved paradigm in innate immunity
4. Therapeutic potential of inhibition of the NF-kB pathway in the treatment of inflammation and cancer
5. Hostile takeovers: viral appropriation of the NF-kB pathway
6. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kB
7. NF-kB in neuronal plasticity and neurodegenerative disorders
8. NF-kB: pivotal mediator or innocent bystander in atherogenesis?

A ubiquitin ligase complex essential for the NF-kB, Wnt/Wingless, and Hedgehog signaling pathways - Genes and Development, 1999.

The Beginning of the End: IkB Kinase (IKK) and NF-kB Activation - J. Biol. Chem., 1999.