A paradigm for gene regulation: inflammation, NF-kappaB and XXXX .

@entity9135 @entity4284 @entity25612 @entity3419 @entity5601 @entity18793 @entity29772
The onset of inflammatory gene expression is driven by the transcription factor NF-kappaB, whose transcriptional activity is regulated at multiple levels. First, NF-kappaB activity is regulated by cytoplasmic degradation of the IkappaB inhibitor and nuclear translocation. Second, the nuclear @entity9135 transactivation potential can be further influenced by posttranslational modifications, such as phosphorylation and/or acetylation. The @entity9135 phosphorylation is a process highly regulated by both cell- and stimulus-dependent activating kinases. Ser276 phosphorylation seems to be highly important considering its crucial role in the interaction with and the engagement of the cofactor @entity18793 . We have identified @entity29772 as an acting kinase in the TNF-signalling pathway, where it is responsible for @entity9135 phosphorylation at Ser276, as well as for H3 phosphorylation of Ser10 in IL-6 promoter-associated chromatin (Fig. 1) (Saccani et al., 2002; Vermeulen et al., 2002, 2003). To our knowledge, this was the first report that identifies one particular kinase involved in transcription factor phosphorylation and histone modification at the level of a single promoter in order to establish gene activation. The question of which element takes the initial step to recruit and to assemble the activated transcription complex still remains unanswered (Vanden Berghe et al., 2002). @entity5601 negatively interferes with inflammatory gene expression by up-regulation of the cytoplasmic inhibitor molecule @entity4284 , thus establishing an autoregulatory loop (Fig. 1). This induction takes place in the absence of a PPRE, but requires the presence of NF-kappaB and @entity3419 elements in the @entity4284 promoter sequence as well as @entity25612 cofactors. The detailed mechanism how @entity5601 can activate genes in a non-DNA-binding way needs further investigation; moreover, it is at present not clear whether this upregulation, unlike the inhibitory effect of glucocorticoids, is a cell type- or a @entity5601 -specific phenomenon.
