Tuesday, November 17, 2009

NF-kB/Transcription Factors Related Peptides

Definition
NF-?B, a eukaryotic transcription factor plays an important role in inflammation, autoimmune response, cell proliferation, and apoptosis by regulating the expression of genes involved in these processes. It consists of homo- or heterodimers of different subunits, which belong to a family of Rel/NF-?B proteins1.

Related Peptides
The Rel/NF- B transcription factor family is comprised of several structurally-related proteins that exist in organisms from insects to humans. The vertebrate family includes five cellular proteins: c-Rel, RelA, RelB, p50/p105, and p52/p100 2.

Discovery
NF- B was originally identified as a B-cell nuclear factor by Sen and Baltimore in 1986 3.

Structural Characteristics
Structurally, Rel/NF- B proteins are related through an approximately 300 amino acid domain, called the Rel homology (RH) domain, which contains sequences essential for dimerization, DNA binding, and nuclear transport. C-terminal to the RH domain, one class of Rel proteins (c-Rel, RelA and RelB) has transactivation domains. The second class of Rel proteins can exist either as short, active DNA-binding proteins (p50 and p52) or inactive proteins (p105 and p100), which contain additional C-terminal inhibitory domains related to the I B proteins. All I B proteins have a core domain, which consists of multiple, ankryin repeats necessary for protein ? protein interactions with Rel proteins. The best-studied I B protein, I B , has an N-terminal regulatory domain containing the two Serine residues that are phosphorylated by IKK and lysine residues to which ubiquitin is conjugated 2.

Mode of Action
NF-?B activation is stimulated by a pro-oxidative cell status, especially by an increased presence of H2O21. As homodimers or heterodimers, vertebrate Rel/NF- B proteins bind to a set of related DNA target sites, collectively called B sites, and directly regulate gene expression. Thus, even a single cell can have a combinatorially diverse array of dimeric complexes, the most common of which is called NF- B and consists of a p50/RelA heterodimer. The different Rel/NF- B proteins show distinct abilities to form dimers, distinct preferences for different B sites, and distinct abilities to bind to I B inhibitor proteins. Thus, different Rel/NF- B complexes can be induced in different cell types and by distinct signals, can interact in distinct ways with other transcription factors and regulatory proteins, and can regulate the expression of distinct gene sets. These types of considerations are likely to be responsible for the sometimes opposite effects of Rel/NF- B complexes in different cell types.

The regulation of Rel/NF- B transcription complexes is now known in some detail. In most cell types, these complexes exist in a latent, inactive form in the cytoplasm where they are bound to any of several related I B inhibitor proteins. The vertebrate I B proteins include I B , I B , I B , I B , p105, p100, and Bcl-3, among others. Although activation of Rel/NF- B proteins can follow a variety of pathways, the most common proximal step appears to occur via induced phosphorylation of I B at two N-terminal Ser residues by a large I B kinase complex (IKK), and phosphorylation of I B leads to its degradation by the proteasome. The freed Rel/NF- B complex can then enter the nucleus and bind to DNA 2.

Functions
Rel/NF- B transcription factors are induced in response to many signals that lead to cell growth, differentiation, inflammatory responses, the regulation of apoptosis, and neoplastic transformation. The pivotal role played by these transcription factors is illustrated not only by the great diversity of genes that they regulate, but also by the large variety of stimuli that lead to their activation. In diverse cell types, Rel/NF-kappaB transcription factors have been shown to have a role in regulating the apoptotic program, either as essential for the induction of apoptosis or, perhaps more commonly, as blockers of apoptosis. Whether Rel/NF-kappaB promotes or inhibits apoptosis appears to depend on the specific cell type and the type of inducer 2.

References
1.Pande V, Ramos MJ (2005). NF- kappaB in Human Disease: Current Inhibitors and Prospects for De Novo Structure Based Design of Inhibitors. Curr Med Chem., 12(3):357-374.
2.Barkett M, Gilmore TD (1999). Control of apoptosis by Rel/NF-?B transcription factors. Oncogene, 18(49):6910-6924
3.Sen R, Baltimore D (1986) .Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell, 46(5):705-716.


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