NF-kB
From Wikipedia, the free encyclopedia
NF-κB, or Nuclear Factor kappa B, is a nuclear transcription factor found in all cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Consistent with this role, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory (Albensi and Mattson, 35:151 Synapse 2000)
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[edit] Discovery and Characterization
NF-κB was first discovered via its interaction with an 11-base pair sequence in the immunoglobulin light-chain enhancer in B cells (Sen and Baltimore, Cell, 1986). NF-κB family members share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins (Gilmore, Oncogene 2006).
There are five members in the mammalian NF-κB family:
- NF-κB1 (also called p50)
- NF-κB2 (also called p52)
- RelA (also named p65)
- RelB
- c-Rel
In addition, there are NF-κB proteins in lower organisms, such as the fruit fly Drosophila, sea urchins, and sea anenomes. While all the members of the NF-κB family share a Rel homology domain in their N-terminal halves, a subfamily including RelA, RelB and c-Rel also have a trans-activation domain in their C-termini. In contrast, the NF-κB1 and NF-κB2 proteins are synthesized as large precursors, p105 and p100, which undergo processing to generate the mature NF-κB subunits, p50 and p52, respectively. The processing of p105 and p100 is mediated by the ubiquitin/proteasome pathway and involves selective degradation of their C-terminal region containing ankyrin repeats. While the generation of p52 from p100 is a tightly regulated process, p50 is produced from constitutive processing of p105 (Karin and Ben-Neriah, Annu. Rev.Immunol. 2000; Senftleben et al Science 2001).
[edit] Activation of NF-κB
Many bacterial products can activate NF-κB. The identification of Toll-like receptors (TLRs) as specific pattern recognition molecules and the finding that stimulation of TLRs leads to activation of NF-κB improved our understanding of how different pathogens activate NF-κB. For example, studies have identified TLR4 as the receptor for the LPS component of Gram-Negative bacteria. TLRs are key regulators of both innate and adaptive immune responses.
Unlike RelA, RelB, and c-Rel; p50 and p52 do not contain trans-activation domains in their C-termini. Nevertheless, these two NF-κB members play critical roles in modulating the specificity of NF-κB function. Although homodimers of p50 and p52 are generally repressors of κB transcription, both p50 and p52 participate in target gene transactivation by forming heterodimers with RelA, RelB or c-Rel (Li and Verma, Nat. Rev. Immunol., 2002). Additionally, the p50 and p52 homodimers also bind to the nuclear protein Bcl-3, forming potent transcriptional activators (Fujita et al, Genes Dev. 1993; Franzoso et al, Nature, 1992; Bours et al, Cell, 1993).
Inhibitor of kappa B - IκB regulates NF-κB In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a family of inhibitors, called IκBs, which are characterized by the presence of ankyrin repeats. By virtue of their ankyrin repeat domains, the IκB proteins mask the nuclear localization signals (NLS) of NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.
IκBs are a family of related proteins that have an N-terminal regulatory domain, followed by six or more ankyrin repeats and a PEST domain in their C-terminus. Although the IκB family consists of IκBα, IκBβ, IκBγ, IκBε and Bcl-3, the best studied and major IκB protein is IκBα. Due to the presence of ankyrin repeats in their C-termini, p105 and p100 also function as IκB proteins. Of all the IκB members, IκBγ is unique in that it is synthesized from the nf-kb1 gene using an internal promoter, thereby resulting in a protein which is identical to the C terminal half of p105 (Inoue, et all, Cell, 1992).
Activation of the NF-κB complexes occurs primarily via activation of a kinase called the IκB kinase (IKK). When activated by signals, usually coming from the outside of the cell, the IκB kinase phosphorylates two serine residues located in an IκB regulatory domain. When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the IκB inhibitor molecules are targeted for ubiquitin-mediated proteasomal degradation.
With the destruction of the IκB inhibitor, the NF-κB complex is then freed to enter the nucleus where it can 'turn on' the expression of specific genes that have DNA-binding sites for NF-κB nearby. The activation of these genes by NF-κB then leads to the given physiological response, for example, an inflammatory or immune response, a cell survival response, or cellular proliferation. In addition, several viruses, including the AIDS virus HIV, have binding sites for NF-κB that controls the expression of viral genes, which in turn contribute to viral replication or viral pathogenicity. In the case of HIV-1, activation of NF-κB may, at least in part, be involved in activation of the virus from a latent, inactive state.
[edit] NF-κB's Role in Cancer and Other Diseases
NF-κB is widely used by eukaryotic cells as a regulator of cell proliferation and cell survival. As such, many different types of human tumors have mis-regulated NF-κB: that is, NF-κB is chronically active. This continuously active NF-κB turns on the expression of genes that keep the cell proliferating and stop it from dying. In tumor cells, NF-κB is active either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity; in addition, cells can secrete factors that cause NF-κB to be chronically active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the killing action of other anti-tumor agents. Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.
In addition, because NF-κB controls many genes that cause inflammation, it is also found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, among others. Many natural products (including anti-oxidants) that have been promoted to have anti-cancer and anti-inflammatory activity have also been shown to inhibit NF-κB. There is a very controversial US patent (US patent 6,410,516) that applies to the discovery and use of agents that can block NF-κB for therapeutic purposes.
[edit] References
[1] Shehata M, Rel/Nuclear factor-kappaB apoptosis pathways in human cervical cancer cells, Cancer Cell International 2005, 5; 10.
[2] Lindström MT, Bennet R Philip, The role of nuclear factor kappaB in human labor. Reproduction (2005) 130: 569-581.
[3] Buss H, Dörrie A, Schmitz M, Lienhard M, Hoffman E, Resh K, Constitutive and Interleukin-1-inducible Phosphoryltion of p65 NF-κB at Serine 536 Is Mediated by Multiple Protein Kinases Including IκB Kinase (IKK)-α ,IKKβ, IKKЄ, TRAF Family Member-associated (TANK)-binding Kinase 1 (TBK1), and an Unknown Kinase and Couples p65 to TATA-binding Protein-associated Factor II31-mediated Interleukin-8 Transcription. Journal of Biological Chemistry 2000; 279 (53): 55633-55643.
[4] Barnes, Peter J., Karin, Michael. Nuclear Factor-κB -- A Pivotal Transcription Factor in Chronic Inflammatory Diseases. New England Journal of Medicine 1997; 336: 1066-1071
[5] Gilmore, Thomas D. (editor). NF-κB: From Basic Research to Human Disease. Oncogene Oct 2006; 25 (51): 6679 - 6899
[edit] External links
| Cell signaling |
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| Key concepts - Ligand | Receptor | Second messenger | Protein kinase | Transcription factor | Cell signaling networks |
| Pathways - Apoptosis | Ca2+ signaling | Cytokine signaling | Hedgehog | Integrin signaling | JAK/STAT | Lipid signaling | MAPK/ERK pathway | mTOR | NF-kB | Notch | p53 | TGFβ | Wnt |
