Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity

Wang, Jen-Chywan; Shah, Nilesh; Pantoja, Carlos; Meijsing, Sebastiaan H.; Ho, Joseph; Scanlan, Thomas S.

doi:10.1101/gad.1400506

Cited by 89 publications

(78 citation statements)

References 34 publications

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“…Much of the work in this area has centered about the development of unique GR-binding ligands that display a more selective gene-regulation pattern than classical GCs. The end result of this body of effort has demonstrated that the problem is complex, because slight alterations in ligand structure and chemical reactivity can have a pronounced influence on the transcriptional regulatory activity of GR (14). An additional complication to mechanistic study of the GR is the fact that examples have been noted in which genes are repressed through DNA-binding dependent GR action, in addition to those in which genes are activated through DNA-binding independent action.…”

Section: Discussionmentioning

confidence: 99%

“…An understanding of the mechanisms of GR activity on target genes has been explored using a variety of approaches, including microarray analysis (10,11); ChIP scanning (12); and modulation of GR activity using siRNA (13), genetic mutants (4), and ligands with modified structures (14). However, these methods would not be expected to differentiate explicitly between the direct and indirect DNA-binding mechanisms of GR action.…”

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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%

mentioning

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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“…The outcome of a potential 9cRA/atRA interaction with pancreas RARs cannot be predicted simply because both retinoids bind to the same receptor. Nuclear receptor action depends on the ligand bound and the nucleotide sequence of the gene's response element-both influence receptor conformation, affinity for a particular response element, and function (48,49).…”

Section: Discussionmentioning

confidence: 99%

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

Kane

Folias

Pingitore

et al. 2010

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

100

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The all-trans-retinoic acid (atRA) isomer, 9-cis-retinoic acid (9cRA), activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in vitro. RARs control multiple genes, whereas RXRs serve as partners for RARs and other nuclear receptors that regulate metabolism. Physiological function has not been determined for 9cRA, because it has not been detected in serum or multiple tissues with analytically validated assays. Here, we identify 9cRA in mouse pancreas by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and show that 9cRA decreases with feeding and after glucose dosing and varies inversely with serum insulin. 9cRA reduces glucose-stimulated insulin secretion (GSIS) in mouse islets and in the rat β-cell line 832/13 within 15 min by reducing glucose transporter type 2 (Glut2) and glucokinase (GK) activities. 9cRA also reduces Pdx-1 and HNF4α mRNA expression, ∼8-and 80-fold, respectively: defects in Pdx-1 or HNF4α cause maturity onset diabetes of the young (MODY4 and 1, respectively), as does a defective GK gene (MODY2). Pancreas β-cells generate 9cRA, and mouse models of reduced β-cell number, heterozygous Akita mice, and streptozotocin-treated mice have reduced 9cRA. 9cRA is abnormally high in glucose-intolerant mice, which have β-cell hypertropy, including mice with diet-induced obesity (DIO) and ob/ob and db/db mice. These data establish 9cRA as a pancreas-specific autacoid with multiple mechanisms of action and provide unique insight into GSIS.retinol | vitamin A | rexinoids I mpaired glucose-stimulated insulin secretion (GSIS) develops through multiple mechanisms, including actions of metabolic hormones and inflammatory cytokines, products of metabolic overload, and endoplasmic reticulum stress; however, mechanisms of GSIS and impaired glucose tolerance remain incompletely understood (1-4). Also uncertain is the contribution of impaired glucose tolerance to diminished pancreatic β-cell function and mass associated with type 2 diabetes (5). GSIS relies on the pancreas, and pancreas development, islet formation, and function require normal vitamin A nutriture (6-8). Vitamin A restriction during development impairs islet development and promotes glucose intolerance in adult rodents. On the other hand, restricting vitamin A in mature diabetes-prone rats reduces diabetes and insulitis, possibly through enhancing glucose sensing and metabolism. Alltrans-retinoic acid (atRA), an activated metabolite of vitamin A, regulates pancreas development, and atRA does not enhance the incidence of diabetes in diabetes-prone rats fed a vitamin Adeficient diet (7, 9, 10). Although the contribution of vitamin A to pancreas development through atRA seems clear, mechanisms whereby vitamin A affects mature pancreas function have not been determined in depth, nor have the specific vitamin A metabolites been identified that contribute to GSIS control.atRA induces differentiation and regulates cell processes by activating the nuclear receptors RAR α, -β, and -γ, which regulate transcription and translation (11...

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“…The mechanism of action of AL-438 involves differential coactivator recruitments of GRIP1/ TIF2 versus PGC-1; the latter seems preferentially used in steroid-mediated glucose upregulation (Coghlan et al, 2003). Third, a series of related arylpyrazole compounds can elicit different expression patterns on 17 endogenous GR target genes in different cell types (i.e., lung, preadipocyte and preosteoblast), demonstrating that subtle differences in ligand structure can have profound effects on transcriptional regulatory activities of NRs (Wang et al, 2006).…”

Section: Selective Nr Modulatorsmentioning

confidence: 99%

Cross-talk between nuclear receptors and nuclear factor κB

2006

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A variety of studies have shown that some activated nuclear receptors (NRs), especially the glucorticoid receptor, the estrogen receptor and peroxisome proliferator-activated receptor, can inhibit the activity of the transcription factor nuclear factor jB (NF-jB), which plays a key role in the control of genes involved in inflammation, cell proliferation and apoptosis. This review describes the molecular mechanisms of cross-talk between NRs and NF-jB and the biological relevance of this crosstalk. The importance and mechanistic aspects of selective NR modulation are discussed. Also included are future research prospects, which will lead to a new era in the field of NR research with the aim of specifically inhibiting NF-jB-driven gene expression for anti-inflammatory, anti-tumor and immune-modulatory purposes.

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Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity

Cited by 89 publications

References 34 publications

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

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

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

Cross-talk between nuclear receptors and nuclear factor κB

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