Coactivator function of RIP140 for NF B/RelA-dependent cytokine gene expression

Emmy Noether and Marie Curie Research Group Molecular Metabolic Control, German Cancer Research Center Heidelberg, Heidelberg, Germany.
Blood (Impact Factor: 10.45). 08/2008; 112(2):264-76. DOI: 10.1182/blood-2007-11-121699
Source: PubMed


Inflammatory responses represent a hallmark of numerous pathologies including sepsis, bacterial infection, insulin resistance, and malign obesity. Here we describe an unexpected coactivator function for the nuclear receptor interacting protein 140 (RIP140) for nuclear factor kappaB (NFkappaB), a master transcriptional regulator of inflammation in multiple tissues. Previous work has shown that RIP140 suppresses the expression of metabolic gene networks, but we have found that genetic as well as acute deficiency of RIP140 leads to the inhibition of the proinflammatory program in macrophages. The ability of RIP140 to function as a coactivator for cytokine gene promoter activity relies on direct protein-protein interactions with the NFkappaB subunit RelA and histone acetylase cAMP-responsive element binding protein (CREB)-binding protein (CBP). RIP140-dependent control of proinflammatory gene expression via RelA/CBP may, therefore, represent a molecular rational for the cellular integration of metabolic and inflammatory pathways.

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    • "Thus miR-21 may inhibit the actions of PDCD4 on NF-κB activity and promote the production of anti-inflammatory cytokines. Likewise, receptorinteracting protein 140 (RIP140) is a nuclear protein believed to associate with NF-κB to aid in the transcription of pro-inflammatory cytokines in macrophages [61]. Using an acute septic mouse model, Ho et al. [62] identified that miR-33 targeted the 3′ UTR of RIP140 mRNA. "
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    • "RIP140 is a pleiotropic co-factor that regulates energy homeostasis (Leonardsson et al., 2004; Herzog et al., 2007; Seth et al., 2007) and plays an essential role in ovulation (White et al., 2000; Tullet et al., 2005). Its function seems to vary according to its physiological role, serving as a co-repressor of catabolic gene expression (Christian et al., 2005; Seth et al., 2007) but as a co-activator of inflammatory gene expression (Zschiedrich et al., 2008; Nautiyal et al., 2010). In the ovary, RIP140 is required for the expression of the epidermal growth factor (EGF)-like family of growth factors, "
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    • "The latter results suggest that Robo1 may be involved in maintaining proper lung function and it may become essential when lung epithelium is destroyed during an influenza infection. Nrip1/Rip140 functions as a co-activator for cytokine gene promoter activity via direct protein-protein interactions with the NFkappaB subunit RelA and histone acetylase cAMP-responsive element binding protein (CREB)-binding protein (CBP) [49]. It is involved in modulating pro-inflammatory responses in macrophages [50]. "
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