The Search for Safer Glucocorticoid Receptor Ligands

Rosen, Jonathan; Miner, Jeffrey N.

doi:10.1210/er.2005-0002

Cited by 162 publications

(134 citation statements)

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“…Intriguingly, an increasing body of evidence indicates that much of the anti-inflammatory activity of GCs is mediated by the transrepression mechanism, a finding that has been attributed largely to the repression of key inflammatory transcription factors, including AP-1 and NF-B (3-5). Meanwhile, many of the reported side effects of GC treatment have been attributed to a transactivation mechanism (32). Efforts to develop GC-based drugs that can dissociate anti-inflammatory and immunosuppressive effects from side effects have focused largely on establishing a method of dissociating the transrepression activity from the transactivation activity of the GR.…”

Section: Discussionmentioning

confidence: 99%

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Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

Muzikar

Nickols²,

Dervan³

2009

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

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The glucocorticoid receptor (GR) affects the transcription of genes involved in diverse processes, including energy metabolism and the immune response, through DNA-binding dependent and independent mechanisms. The DNA-binding dependent mechanism occurs by direct binding of GR to glucocorticoid response elements (GREs) at regulatory regions of target genes. The DNA-binding independent mechanism involves binding of GR to transcription factors and coactivators that, in turn, contact DNA. A small molecule that competes with GR for binding to GREs could be expected to affect the DNAdependent pathway selectively by interfering with the protein-DNA interface. We show that a DNA-binding polyamide that targets the consensus GRE sequence binds the glucocorticoid-induced zipper (GILZ) GRE, inhibits expression of GILZ and several other known GR target genes, and reduces GR occupancy at the GILZ promoter. Genome-wide expression analysis of the effects of this polyamide on a set of glucocorticoid-induced and -repressed genes could help to elucidate the mechanism of GR regulation for these genes.gene regulation ͉ glucocorticoid response element ͉ nuclear receptor ͉ protein-DNA interface ͉ Py-Im polyamide

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Section: Discussionmentioning

confidence: 99%

“…The oligonucleotide 5Ј-GTATAGCCTGCACTTTGTTCTGTCTAC-3Ј representing a 27-bp section of the GILZ promoter containing GRE1 (underlined) was annealed to its complement and end-labeled with 32 (Fig. S3).…”

Section: Methodsmentioning

confidence: 99%

Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

Muzikar

Nickols²,

Dervan³

2009

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

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“…Therefore, one of the main challenges in glucocorticoid pharmacology is to develop agents that can dissociate anti-inflammatory and immunosuppressive effects from these side effects. One approach was suggested by the notion that GR confers anti-inflammatory effects by transcriptional repression, whereas the side effects reflect transcriptional activation by GR (Rosen and Miner 2005). However, it has been shown that some glucocorticoid-activated genes, such as annexin I, are important in the anti-inflammatory effect Roviezzo et al 2002), whereas some glucocorticoid-repressed genes, such as endothelial nitric oxide synthase (eNOS) (Wallerath et al 1999(Wallerath et al , 2004Schafer et al 2005), are associated with deleterious side effects.…”

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confidence: 99%

Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity

Wang¹,

Shah²,

Pantoja³

et al. 2006

Genes Dev.

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The activities of intracellular receptors are regulated by their cognate ligands. Here we show that a series of related arylpyrazole compounds, which specifically bind the glucocorticoid receptor (GR), selectively modulated GR-regulated biological functions in preadipocyte, preosteoblast, and lung epithelial cell lines. Indeed, when we monitored 17 endogenous GR target genes in one of these cell types, we found that distinct arylpyrazole compounds induced different expression patterns. We showed by chromatin immunoprecipitation that the arylpyrazole compounds regulated, in a gene-specific manner, either GR occupancy of the genomic glucocorticoid response element (GRE) or events after GR association, such as histone modification. Overall, our results establish that subtle differences in ligand chemistry can profoundly influence the transcriptional regulatory activity of GR, and that endogenous genes bearing natural GREs are especially sensitive detectors of these differences.[Keywords: Glucocorticoid receptor; glucocorticoid receptor ligand; arylpyrazole compounds; response element; chromatin immunoprecipitation] Supplemental material is available at http://www.genesdev.org.

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“…Selective nuclear receptor modulators (SNuRMs) which are able to elicit a specific biological response at the expense of the other activities that the natural ligand may induce (Gronemeyer et al, 2004) have been described for the estrogen receptor (Robertson, 2004) and the glucocorticoid receptor (Rosen & Miner, 2005) among others. The nematode has undergone a dramatic expansion in the NHR superfamily with 284 predicted receptors compared with 48 in humans (Sluder et al, 1999).…”

Section: Endocrine Targets For Pharmacological Interventionmentioning

confidence: 99%

Endocrine targets for pharmacological intervention in aging in Caenorhabditis elegans

Gill

2006

Aging Cell

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SummaryStudies in the nematode Caenorhabditis elegans have been instrumental in defining genetic pathways that are involved in modulating lifespan. Multiple processes such as endocrine signaling, nutritional sensing and mitochondrial function play a role in determining lifespan in the worm and these mechanisms appear to be conserved across species. These discoveries have identified a range of novel targets for pharmacological manipulation of lifespan and it is likely that the nematode model will now prove useful in the discovery of compounds that slow aging. This review will focus on the endocrine targets for intervention in aging and the use of C. elegans as a system for high throughput screens of compounds for their effects on aging.

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The Search for Safer Glucocorticoid Receptor Ligands

Cited by 162 publications

References 132 publications

Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity

Endocrine targets for pharmacological intervention in aging in Caenorhabditis elegans

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