Site-specific Phosphorylation of the p65 Protein Subunit Mediates Selective Gene Expression by Differential NF-κB and RNA Polymerase II Promoter Recruitment

Hochrainer, Karin; Racchumi, Gianfranco; Anrather, Josef

doi:10.1074/jbc.m112.385625

Cited by 61 publications

(74 citation statements)

References 46 publications

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“…Toggling of NF-B through IKK kinase and activation of either canonical or noncanonical pathways possibly contribute to the diverse phenotypes induced through this transcription factor (15,40). Furthermore, phosphorylation of the p65 subunit can occur at numerous sites and drive differential NF-B-dependent gene expression (21). Although we observed decreases in downstream expression of NF-B-dependent cytokines, we did not see any changes in NF-B-related protein expression, suggesting that there were minimal compensatory changes in NF-B-related activity except for the quantitative decrease in the p65 subunit.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

Zhang

Tang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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NF-κB is a well-known transcription factor that is intimately involved with inflammation and immunity. We have previously shown that NF-κB promotes inflammatory events and mediates adverse cardiac remodeling following ischemia reperfusion (I/R). Conversely, others have pointed to the beneficial influence of NF-κB in I/R injury related to its anti-apoptotic effects. Understanding the seemingly disparate influence of manipulating NF-κB is hindered, in part, by current approaches that only indirectly interfere with the function of its most transcriptionally active unit, p65 NF-κB. Mice were generated with cardiomyocyte-specific deletion of p65 NF-κB. Phenotypically, these mice and their hearts appeared normal. Basal and stimulated p65 expression were significantly reduced in whole hearts and completely ablated in isolated cardiomyocytes. When compared with wild-type mice, transgenic animals were protected from both global I/R by Langendorff as well as regional I/R by coronary ligation and release. The protected, transgenic hearts had less cytokine activity and decreased apoptosis. Furthermore, p65 ablation was associated with enhanced calcium reuptake by the sarcoplasmic reticulum. This influence on calcium handling was related to increased expression of phosphorylated phospholamban in conditional p65 null mice. In conclusion, cardiomyocyte-specific deletion of the most active, canonical NF-κB subunit affords cardioprotection to both global and regional I/R injury. The beneficial effects of NF-κB inhibition are related, in part, to modulation of intracellular calcium homeostasis.

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Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

Zhang

Tang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…The function of NF-kB is known to be regulated by a variety of posttranscriptional modifications, including phosphorylation, acetylation, and ubiquitination, which can either enhance or inhibit transcriptional activity, in part, in a gene-specific manner. Notably, p65 phosphorylation at different serine residues plays an important role in fine-tuning NF-kB activity (47)(48)(49)(50) . However, no differences in the phosphorylation pattern was observed upon treatment with IFN-g.…”

Section: Discussionmentioning

confidence: 99%

Early Inhibition of IL-1β Expression by IFN-γ Is Mediated by Impaired Binding of NF-κB to the IL-1β Promoter but Is Independent of Nitric Oxide

Eigenbrod

Bode

Dalpke

2013

The Journal of Immunology

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The significance of bacterial RNA recognition for initiating innate immune responses against invading pathogens has only recently started to be elucidated. Bacterial RNA is an important trigger of inflammasome activation, resulting in caspase-1–dependent cleavage of pro–IL-1β into the active form. It was reported previously that prolonged treatment with IFN-γ can inhibit IL-1β production at the level of both transcription and Nlrp3 inflammasome activation in an NO-dependent manner. As a result of the delayed kinetics of NO generation after IFN-γ stimulation, these effects were only observed at later time points. We report that IFN-γ suppressed bacterial RNA and LPS induced IL-1β transcription in primary murine macrophages and dendritic cells by an additional, very rapid mechanism that was independent of NO. Costimulation with IFN-γ selectively attenuated binding of NF-κB p65 to the IL-1β promoter, thus representing a novel mechanism of IL-1β inhibition by IFN-γ. Transcriptional silencing was specific for IL-1β because expression of other proinflammatory cytokines, such as TNF, IL-6, and IL-12p40, was not affected. Furthermore, by suppressing IL-1β production, IFN-γ impaired differentiation of Th17 cells and production of neutrophil chemotactic factor CXCL1 in vitro. The findings provide evidence for a rapid immune-modulating effect of IFN-γ independent of NO.

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“…Because Tle1 overexpression has been shown to block NF-κB activation (14, 15), we further studied the effect of TLE1 on NF-κB nuclear translocation and phosphorylation (21). Overexpression of TLE1 inhibited both basal as well as LPS-induced NF-κB activation in THP-1 human monocyte cells, as evidenced by a decrease in nuclear NF-κB translocation using ImageStream analysis.…”

Section: Tle1-deficient Mice Have Increased Expression Of Inflammatormentioning

confidence: 99%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1 Δ/Δ ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1 Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1 Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1 Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1 Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.T ransducin-like enhancer of split 1 (TLE1) belongs to a family of corepressor proteins called transducin-like enhancer of split, or TLEs. Groucho, the TLE homolog in Drosophila, has crucial roles in neurogenesis, segmentation, and sex determination (1). These corepressors do not bind directly to DNA but rather interact with many different classes of transcription factors and help create a repressor complex (1, 2).Vertebrates express five different TLEs (TLE1-4, AES), although the distinct functions of each of the TLEs has not been well determined. TLE1, the most studied among the Groucho family proteins in mammalian systems, is widely expressed in different tissues and cell types and has been implicated in neuronal differentiation (3, 4) and pancreatic beta cell development (5). TLE1 has tumor suppressor activity (6-8) as well as oncogenic functions in cancer (9, 10). TLE1 associates with many important transcription factors integral for cell proliferation and differentiation, including Runx2 to block rRNA expression (11), HES1 to suppresses MASH2 expression (12), and TCF/LEF proteins to block Wnt target gene activation (13). TLE1 also represses NF-κB activity (14,15). Involvement in these diverse cellular functions and diseases was studied primarily in vitro or using in vivo overexpression systems. The major physiological function of TLE1, however, remains poorly understood.A few recent studies suggest TLE1 might regulate immune function. For example, a single noncoding nucleotide polymorphism within the TLE1 locus was associated with inflammatory bowel diseases (16), and in human monocytes,...

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Site-specific Phosphorylation of the p65 Protein Subunit Mediates Selective Gene Expression by Differential NF-κB and RNA Polymerase II Promoter Recruitment

Cited by 61 publications

References 46 publications

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

Early Inhibition of IL-1β Expression by IFN-γ Is Mediated by Impaired Binding of NF-κB to the IL-1β Promoter but Is Independent of Nitric Oxide

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

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