The NF-kB (Nuclear Factor-kappa B) protein family is important for transcription factors or promoter molecules which are highly significant for the functioning of animal immune systems.
NF-kB was discovered by Baltimore and associates as a special transcription stimulator or activator of specific immunoglobulin genes. Later research showed that many other genes respond to NF-kB stimulation. Dr. Sibenlist's NIAID NIH laboratory, for example, has demonstrated how NF-kB complexes act as DNA signals and activators and how HTLV, HIV and other viruses influence and control this system. Badr and coworkers have used fluorescent-reporter molecules to study NF-kB factors and IF inhibitors and their effects in normal and cancerous cell culture systems.
Dr. Kuehl and associates at the National Cancer Institute are studying multiple myeloma and the significance of the two different NF-kB pathways (classical and alternative). Read more basic information on how this intergated system of proteins works inside the cytoplasm and nucleus of human and animal cells.
Normal functions controls and regulation of NF-kB
The NF-kB complex of proteins has the following features:
- the NF-kB proteins are dimers of various combinations of 5 "Rel" family mammalian polypeptides (proteins): RelA (p65), RelB, c-Rel, p50 (NFKB1) and p52 (NFKB2)
- these subunits can combine in various combinations of two to form different protein "dimers": the NFkB1 classical system is composed of p65 and p50 and the NFkB2 alternative system is composed of p52 and RelB.
- Rel polypeptides have a common homology region near the N-terminal region that promotes homo- and heterodimerization as well as DNA binding. However, only p65, RelB and c-Rel possess the ability to induce gene expression due their very specific transcription activation domain (TAD)
- inhibitor protein molecules (IkB and p100) interact with NF-kB to form inactive, inhibited trimers: NFkB1 reacts with IkB and NFkB2 reacts with p100
- under certain conditions (infection, cell damage, cancer) the inhibitor factor in the trimer is phosphorylated by activation of the cytoplasmic the IKK kinase system (an enzyme complex which phosphorylates). Shortly after phosphorylation each molecule is chemically ubiquitinylated which is an additional marker and factor used for processing proteins
- phosphorylated-ubiquitinylated trimers react with and are processed by proteasomes
- proteasomes degrade IκB and p100 and free the NF-kB dimers
- freed NF-kB dimers can progress into the nucleus. NF-kB molecules translocate into the nucleus and act as a signal-messengers and transcription promoters. These NF-kB activation steps are promoted by cytoplasmic events such as cell damage, stress, and intracellular microbial (bacteria, virus, protozoan) pathogen activity
- NF-kB molecules are strong transcription factors that can stimulate up to 100 different genes related to the immune system, growth and repair genes
- NF-kB activation is self-limiting since inhibitors are transcriptionally upregulated by NF-kB in a negative feed-back loop
- some members of the NF-kB pathway display additional functions in the nucleus as regulators of NF-κB dependent and independent gene expression.
- specific nuclear roles exist for IKK and IκB proteins
Why is NF-kB so important in health and disease?
The NF-kB inhibition and activation cycle is better understood now. An important goal of NF-kB research is to control and regulate the NF-kB system during certain inflammatory processes and viral diseases. Discovering all the ways for activation of the NF-kB system and the specific receptors involved is an important area of research. NF-kB is activated via receptors of the biochemical families of TNF (Tumor Necrosis Factor), IL-1 (Interleukin-1) and Toll, all of which are important molecules of inflammatory responses and both innate and adaptive immune reactions.
Where is the NF-kB found and active in animals?
The NF-kB family of proteins is important to innate immunity humans and occurs to the level of insects such as fruit flies (Drosophila). Therefore, NF-kB molecules are important and biologically ancient and conserved proteins.
Sources
Badr, C. et al. 2009. "Real-time monitoring of NF-kappaB activity in cultured cells and in animal models." Mol Imaging. 8(5): 278–290. Accessed 9 December, 2011 @ ncbi.nlm.nih.gov
Espinosa, L., et al. 2011. "Alternative nuclear functions for NF-κB family members." Am J Cancer Res. 2011; 1(4): 446–459.
Hiscott, J. et al. 2001. "Hostile takeovers: viral appropriation of the NF-kB pathway." J Clin Invest. 107(2): 143–151. doi: 10.1172/JCI11918. Accessed 7 December, 2011 @ ncbi.nlm.nih.gov
Donald Reinhardt - Think, read, write & live well always. DJR has a PhD in Biology/Microbiology & is a Fellow & Diplomate, ASM Amer Acad Micro.
Join the Conversation