Nuclear factor kB (NF-kB) is one of the key regulators of transcription of a variety of genes involved in immune and in¯ammatory responses. NF-kB activity has long been thought to be regulated mainly by IkB family members, which keep the transcription factor complex in an inactive form in the cytoplasm by masking the nuclear localization signal. Nowadays, the importance of additional mechanisms controlling the nuclear transcription potential of NF-kB is generally accepted. We show that the mitogen-activated protein kinase inhibitors SB203580 and PD98059 or U0126, as well as a potent mitogen-and stressactivated protein kinase-1 (MSK1) inhibitor H89, counteract tumor necrosis factor (TNF)-mediated stimulation of p65 transactivation capacity. Mutational analysis of p65 revealed Ser276 as a target for phosphorylation and transactivation in response to TNF. Moreover, we identi®ed MSK1 as a nuclear kinase for p65, since MSK1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at Ser276. This effect represents, together with phosphorylation of nucleosome components such as histone H3, an essential step leading to selective transcriptional activation of NF-kB-dependent gene expression.
Glucocorticoids (GCs) are steroidal ligands for the GC receptor (GR), which can function as a ligand-activated transcription factor. These steroidal ligands and derivatives thereof are the first line of treatment in a vast array of inflammatory diseases. However, due to the general surge of side effects associated with long-term use of GCs and the potential problem of GC resistance in some patients, the scientific world continues to search for a better understanding of the GC-mediated antiinflammatory mechanisms. The reversible phosphomodification of various mediators in the inflammatory process plays a key role in modulating and fine-tuning the sensitivity, longevity, and intensity of the inflammatory response. As such, the antiinflammatory GCs can modulate the activity and/or expression of various kinases and phosphatases, thus affecting the signaling efficacy toward the propagation of proinflammatory gene expression and proinflammatory gene mRNA stability. Conversely, phosphorylation of GR can affect GR ligand- and DNA-binding affinity, mobility, and cofactor recruitment, culminating in altered transactivation and transrepression capabilities of GR, and consequently leading to a modified antiinflammatory potential. Recently, new roles for kinases and phosphatases have been described in GR-based antiinflammatory mechanisms. Moreover, kinase inhibitors have become increasingly important as antiinflammatory tools, not only for research but also for therapeutic purposes. In light of these developments, we aim to illuminate the integrated interplay between GR signaling and its correlating kinases and phosphatases in the context of the clinically important combat of inflammation, giving attention to implications on GC-mediated side effects and therapy resistance.
Glucocorticoids (GCs) are used to combat inflammatory diseases. Their beneficial effect relies mainly on the inhibition of NF-Band͞or AP-1-driven proinflammatory gene expression. Previously, we have shown that GCs repress tumor necrosis factor-induced IL-6 gene expression by an NF-B-dependent nuclear mechanism without changing the DNA-binding capacity of NF-B or the expression levels of the cytoplasmic inhibitor of NF-B (I B-␣). In the present work, we investigate the effect of GC repression on different natural and͞or recombinant NF-B-driven reporter gene constructs in the presence of increasing amounts of various coactivator molecules, such as CREB-binding protein (CBP), p300, and SRC-1. We found that GCs maintain their repressive capacities, irrespective of the amount of cofactor present in the cell. Similar results were obtained for the reciprocal transrepression of a GC receptor (GR) element-driven reporter gene by p65. We demonstrate that neither the expression levels of p65 and CBP nor their physical association are affected by activated GR. Using Gal4 chimeras, we show that repression by GCs is specific for p65-mediated transactivation, ruling out competition for limiting nuclear factors as the major underlying mechanism of gene repression. In addition, the transactivation potential of a point-mutated Gal4-p65 variant with a decreased CBP interaction capability is still repressed by GR. Finally, we present evidence that the specificity of GC repression on p65-driven gene expression is codetermined by the TATA box context. T he glucocorticoid (GC) receptor (GR) is a ligand-dependenttranscription factor belonging to the superfamily of steroid͞ thyroid hormone receptors. These receptors and their cognate hormones control various aspects of metabolic homeostasis, embryonic development, and physiological stress. Activated GRs modulate transcription by either directly binding to GR elements (GREs) in promoters of positively regulated genes or indirectly binding by association with other transcription factors, such as NF-B or AP-1. The latter function is considered to be very important in the battle against inflammatory and immune diseases, in which GCs are used effectively as therapeutic agents (1, 2).The transcription factor NF-B plays a critical role in immune homeostasis, cell growth, and survival. A persistent activation of this factor compromises health and is associated with inflammatory and neoplastic diseases as well as with viral infection. The mammalian NF-B͞Rel family of proteins consists presently of five members, namely, Rel (c-Rel), p65 (Rel A), Rel B, p50 (NFKB1), and p52 (NFKB2). In general, the designation NF-B refers to the most frequently occurring heterodimeric complex between the p50 and p65 subunits. NF-B activation may be induced by different signals, such as viral infection, the proinflammatory cytokines tumor necrosis factor (TNF) and IL-1, phorbol esters, UV irradiation, and bacterial lipopolysaccharides. These signals lead to phosphorylation and degradation of the inhibitor of NF-B (...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.