Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes

Weikum, Emily R.; Vera, Ian Mitchelle S. de; Nwachukwu, Jerome C.; Hudson, William Henry; Nettles, K.W.; Kojetin, D.J.; Ortlund, Eric A.

doi:10.1093/nar/gkx509

Cited by 57 publications

(55 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…38). In support of our view, other studies have demonstrated that activated GR preferentially suppresses the function of AP-1 family members (39,40). In addition, synergistic upregulation of SGK1 expression by E 2 and dexamethasone facilitates maintenance of the homeostasis in the endoplasmic reticulum to antiapoptosis (41,42).…”

Section: Discussionsupporting

confidence: 86%

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Fan

Siwak

Abderrahman

et al. 2019

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Our clinically relevant finding is that glucocorticoids block estrogen (E 2)-induced apoptosis in long-term E 2-deprived (LTED) breast cancer cells. However, the mechanism remains unclear. Here, we demonstrated that E 2 widely activated adipose inflammatory factors such as fatty acid desaturase 1 (FADS1), IL6, and TNFa in LTED breast cancer cells. Activation of glucocorticoid receptor (GR) by the synthetic glucocorticoid dexamethasone upregulated FADS1 and IL6, but downregulated TNFa expression. Furthermore, dexamethasone was synergistic or additive with E 2 in upregulating FADS1 and IL6 expression, whereas it selectively and constantly suppressed TNFa expression induced by E 2 in LTED breast cancer cells. Regarding regulation of endoplasmic reticulum stress, dexamethasone effectively blocked activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) by E 2 , but it had no inhibitory effects on inositol-requiring protein 1 alpha (IRE1a) expression increased by E 2. Consistently, results from reverse-phase protein array (RPPA) analysis demonstrated that dexamethasone could not reverse IRE1a-mediated degradation of PI3K/Akt-associated signal pathways activated by E 2. Unexpectedly, activated GR preferentially repressed nuclear factor-kB (NF-kB) DNA-binding activity and expression of NF-kB-dependent gene TNFa induced by E 2 , leading to the blockade of E 2-induced apoptosis. Together, these data suggest that trans-suppression of NF-kB by GR in the nucleus is a fundamental mechanism thereby blocking E 2-induced apoptosis in LTED breast cancer cells. This study provided an important rationale for restricting the clinical use of glucocorticoids, which will undermine the beneficial effects of E 2-induced apoptosis in patients with aromatase inhibitorresistant breast cancer.

show abstract

Section: Discussionsupporting

confidence: 86%

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Fan

Siwak

Abderrahman

et al. 2019

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Given the strong repressive activity of the GRtetra receptor, we propose that transrepression as previously defined cannot entirely explain GR repressive action. In fact, both JUN-FOS and NFKB1 pathways are most likely modulated by GR in a more complex manner that involves, at least in part, an oligomeric receptor interacting directly with the chromatin landscape (Weikum et al 2017;Hudson et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor quaternary structure drives chromatin occupancy and transcriptional outcome

et al. 2019

View full text Add to dashboard Cite

Most transcription factors, including nuclear receptors, are widely modeled as binding regulatory elements as monomers, homodimers, or heterodimers. Recent findings in live cells show that the glucocorticoid receptor NR3C1 (also known as GR) forms tetramers on enhancers, owing to an allosteric alteration induced by DNA binding, and suggest that higher oligomerization states are important for the gene regulatory responses of GR. By using a variant (GRtetra) that mimics this allosteric transition, we performed genome-wide studies using a GR knockout cell line with reintroduced wild-type GR or reintroduced GRtetra. GRtetra acts as a super receptor by binding to response elements not accessible to the wild-type receptor and both induces and represses more genes than GRwt. These results argue that DNA binding induces a structural transition to the tetrameric state, forming a transient higher-order structure that drives both the activating and repressive actions of glucocorticoids.[Supplemental material is available for this article.] 4 These authors contributed equally to this work. Corresponding authors: hagerg@dce41.nci.nih.gov, presmandm@fbmc.fcen.uba.ar Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/

show abstract

“…Indeed, the analysis of GR occupancy nearby our candidate Dex-sensitive genes of both classes reveals co-localized GR and p65 peaks associated with NF-kB enhancers under repressing LPS + Dex conditions and no GR binding in Dex-only - treated macrophages. Thus, although this is certainly not the only mechanism by which GR affects inflammatory gene expression ( Rao et al, 2011 ; Uhlenhaut et al, 2013 ; Oh et al, 2017 ; Weikum et al, 2017a ), tethering to p65 is a widespread regulatory mechanism that GR relies upon to elicit acute repression of pro-inflammatory genes in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages

Sacta

Tharmalingam

Coppo

et al. 2018

eLife

View full text Add to dashboard Cite

The glucocorticoid receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis in mouse macrophages reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB-binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class; however, it effects repression by targeting distinct temporal events and components of transcriptional machinery.

show abstract

Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes

Cited by 57 publications

References 69 publications

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Glucocorticoid receptor quaternary structure drives chromatin occupancy and transcriptional outcome

Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages

Contact Info

Product

Resources

About