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The complexity of NF-κB signaling in inflammation and cancer.

Hoesel B, Schmid JA - Mol. Cancer (2013)

Bottom Line: The NF-κB family of transcription factors has an essential role in inflammation and innate immunity.During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways.Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.

ABSTRACT
The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways. Prominent nodes of crosstalk are mediated by other transcription factors such as STAT3 and p53 or the ETS related gene ERG. These transcription factors either directly interact with NF-κB subunits or affect NF-κB target genes. Crosstalk can also occur through different kinases, such as GSK3-β, p38, or PI3K, which modulate NF-κB transcriptional activity or affect upstream signaling pathways. Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs. In this review, we provide an overview of the most relevant modes of crosstalk and cooperativity between NF-κB and other signaling molecules during inflammation and cancer.

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Related in: MedlinePlus

Post-translational modifications of RelA, IκBα and IκBβ. Phosphorylations, acetylations and methylations of RelA are shown, as well as phosphorylations, ubiquitination and sumoylation of IkBα and IkB.
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Figure 3: Post-translational modifications of RelA, IκBα and IκBβ. Phosphorylations, acetylations and methylations of RelA are shown, as well as phosphorylations, ubiquitination and sumoylation of IkBα and IkB.

Mentions: After the liberation of various NF-κB dimers following activation of IKKs, their steady state localization is normally shifted to the nucleus and the Rel Homology Domains are free to bind cognate DNA-sequences in the enhancer elements of target gene promoters. Depending on the accessibility of the genome regulated by epigenetic mechanisms and the cell type, thousands of different target genes can be transcriptionally activated. This activation is further controlled by additional transcription factors, which can either enhance or reduce the effect of NF-κB – establishing another level of complexity and crosstalk with signaling pathways that activate other transcription factors. The manifold post-translation modifications of RelA add another layer of complexity to NF-κB signaling. These have been shown to be necessary for various aspects of RelA functions (Figure 3). Amongst these, phosphorylations at specific serine or threonine residue are known to be particularly important since they often stimulate transcriptional activity. The most important phosphorylations of RelA, their positions and the corresponding kinases are summarized in Table 1. The activity of NF-κB is not only influenced by a variety of phosphorylations, but also by dynamic and complex protein-protein interactions generating a sophisticated network of interdependencies and feedback loops [45]. Besides the very well defined interactions between the various members of the NF-κB family, and the interactions with their inhibitors such as IκBα, IκBβ or IκBϵ [46-49], NF-κB molecules have been shown to interact with upstream kinases, with chromatin-modifiers such as histone deacetylases (HDACs), p300 or CBP and also with other transcription factors [50-53]. The network of protein interactions involving NF-κB molecules is very complex. The interaction database IntAct (http://www.ebi.ac.uk/intact/) currently lists 306 binary interactions for the NF-κB member RelA alone. To illustrate at least part of this interaction network graphically, we performed a STRING database search (at http://string-db.org/) for proteins interacting either physically or functionally with NF-κB molecules using all five family members as input (Figure 4).


The complexity of NF-κB signaling in inflammation and cancer.

Hoesel B, Schmid JA - Mol. Cancer (2013)

Post-translational modifications of RelA, IκBα and IκBβ. Phosphorylations, acetylations and methylations of RelA are shown, as well as phosphorylations, ubiquitination and sumoylation of IkBα and IkB.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750319&req=5

Figure 3: Post-translational modifications of RelA, IκBα and IκBβ. Phosphorylations, acetylations and methylations of RelA are shown, as well as phosphorylations, ubiquitination and sumoylation of IkBα and IkB.
Mentions: After the liberation of various NF-κB dimers following activation of IKKs, their steady state localization is normally shifted to the nucleus and the Rel Homology Domains are free to bind cognate DNA-sequences in the enhancer elements of target gene promoters. Depending on the accessibility of the genome regulated by epigenetic mechanisms and the cell type, thousands of different target genes can be transcriptionally activated. This activation is further controlled by additional transcription factors, which can either enhance or reduce the effect of NF-κB – establishing another level of complexity and crosstalk with signaling pathways that activate other transcription factors. The manifold post-translation modifications of RelA add another layer of complexity to NF-κB signaling. These have been shown to be necessary for various aspects of RelA functions (Figure 3). Amongst these, phosphorylations at specific serine or threonine residue are known to be particularly important since they often stimulate transcriptional activity. The most important phosphorylations of RelA, their positions and the corresponding kinases are summarized in Table 1. The activity of NF-κB is not only influenced by a variety of phosphorylations, but also by dynamic and complex protein-protein interactions generating a sophisticated network of interdependencies and feedback loops [45]. Besides the very well defined interactions between the various members of the NF-κB family, and the interactions with their inhibitors such as IκBα, IκBβ or IκBϵ [46-49], NF-κB molecules have been shown to interact with upstream kinases, with chromatin-modifiers such as histone deacetylases (HDACs), p300 or CBP and also with other transcription factors [50-53]. The network of protein interactions involving NF-κB molecules is very complex. The interaction database IntAct (http://www.ebi.ac.uk/intact/) currently lists 306 binary interactions for the NF-κB member RelA alone. To illustrate at least part of this interaction network graphically, we performed a STRING database search (at http://string-db.org/) for proteins interacting either physically or functionally with NF-κB molecules using all five family members as input (Figure 4).

Bottom Line: The NF-κB family of transcription factors has an essential role in inflammation and innate immunity.During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways.Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.

ABSTRACT
The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways. Prominent nodes of crosstalk are mediated by other transcription factors such as STAT3 and p53 or the ETS related gene ERG. These transcription factors either directly interact with NF-κB subunits or affect NF-κB target genes. Crosstalk can also occur through different kinases, such as GSK3-β, p38, or PI3K, which modulate NF-κB transcriptional activity or affect upstream signaling pathways. Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs. In this review, we provide an overview of the most relevant modes of crosstalk and cooperativity between NF-κB and other signaling molecules during inflammation and cancer.

Show MeSH
Related in: MedlinePlus