253-52-1, Children learn through play, and they learn more than adults might expect. Science experiments are a great way to spark their curiosity, get their minds active, and encourage them to do something that doesn¡¯t involve a screen. 253-52-1, C8H6N2. A document type is Review, introducing its new discovery.
The Transcription Factor NF-kappaB as Drug Target
Nuclear factor kappaB (NF-kappaB) is recognized to have a crucial role in the regulation of genes involved in pathological processes such as chronic inflammation and tumourigenesis. The pathways leading to the activation of this transcription factor have generated considerable interest within the pharmaceutical industry as providers of targets for drug discovery. NF-kappaB was identified almost 20 years ago as a regulator of immunoglobulin gene expression [1]. Originally thought of as restricted to the B-cell lineage, NF-kappaB has since been found to be ubiquitously expressed and to be a critical component of regulatory networks controlling cell survival, proliferation, and differentiation within as well as outside the immune system. NF-kappaB consists of a pair of proteins of the Rel family (Figure 5.1) which have combined in a specific way to form a homo- or heterodimer [2]. Rel family proteins are characterized by the possession of a Rel homology domain (RHD), which contains two immunoglobulin-like subdomains and shows close to 50% sequence similarity across the family. It mediates DNA binding via its N-terminal subdomain, dimerization via its C-terminal one, and nuclear translocation via at least one nuclear localization sequence. The two classes of Rel proteins are distinguished by the absence (class I) or presence (class II) of a transcriptional activation domain. Class I proteins are synthesized as longer precursor proteins (NF-kappaB1, shown, and NF-kappaB2) which are processed to yield p50 and p52, respectively. The C-terminal portions of these precursors, which are removed by proteolytic processing, resemble the IkappaB proteins, e.g. IkappaBalpha, IkappaBbeta, and IkappaBepsilon, by possessing a series of ankyrin repeats, which mediate their interaction with Rel protein dimers, as well as a PEST (proline-, glutamate-, serine-, and threonine-rich) domain, involved in the regulation of stability. Indeed, that of NF-kappaB1 is identical to IkappaBgamma which is encoded by a separate gene [3]. A glycine-rich region in class I proteins functions as a processing signal. While NF-kappaB1 has only one nuclear localization sequence, NF-kappaB2 has two. Characteristic for class I Rel proteins is the possession of an insert in the RHD of 32 amino acids in p50 and 18 amino acids in p52. Class II Rel proteins are c-Rel, RelA (p65) and RelB (shown). In contrast to the other Rel proteins, RelB has a leucine zipper near its N-terminus but lacks a PKA phosphorylation site in the RHD. A highly simplified, canonical pathway (Figure 5.2) of NF-kappaB activation by certain extracellular stimuli (Table 5.1), such as cytokine binding to a receptor at the plasma membrane, involves phosphorylation followed by polyubiquitinylation, i.e. the attachment of a chain of the 76-amino acid protein ubiquitin, and proteolytic degradation of inhibitor-of-NF-kappaB (IkappaB) which is associated with the transcription factor. Release from IkappaB results in the accumulation of NF-kappaB in the nucleus where it binds to specific DNA sequences (consensus sequence of the kappaB sites: GGGRNYYYCC where R is a purine, Y a pyrimidine, and N any nucleotide) in the regulatory elements of the genes it controls (Table 5.2) [2]. For maximum stimulation of its transactivation function, covalent modification of the Rel proteins themselves by phosphorylation and acetylation is required. Central to the phosphorylation of IkappaB in the canonical pathway is IkappaB kinase (IKK) whose two isoforms, IKKalpha and IKKbeta, are present in a large multiprotein complex. IKKalpha and beta share 52% of their amino acid residues, an N-terminal catalytic domain, a C-terminal helix-loop-helix domain modulating catalytic activity, and a central leucine zipper motif mediating homo- as well as heterodimer formation. An unrelated regulatory protein, IKKgamma, interacts with these dimers by binding to a specific domain in IKKbeta. A zinc finger motif at its C terminus serves to link the IKK complex to upstream activators. Complexes of p50/p65 heterodimers and IkappaBalpha but not IkappaBbeta or IkappaBepsilon constitutively shuttle between cytoplasm and nucleus, where stimulus-induced ubiquitination (and possibly also proteasomal degradation) of IkappaBalpha takes place. This is because, unlike the other two isoforms, IkappaBalpha only incompletely masks the p50 nuclear localization sequence. Expulsion from the nucleus is stimulated by nuclear export sequences in IkappaBalpha and p65. In unstimulated cells, the movement of these complexes is in a dynamic equilibrium with the majority of complexes being present in the cytoplasm at any one moment. Apart from the canonical pathway, there exists at least one other route to NF-kappaB activation [4]. This non-canonical pathway does not involve IkappaB and neither depends on IKKbeta nor IKKgamma (Figure 5.2). It is activated by a much smaller set of stimuli comprising B-cell activating factor of the TNF family (BAFF), CD4…
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