Selective glucocorticoid receptor translational isoforms reveal glucocorticoid-induced apoptotic transcriptomes

Wu, Indira; Shin, Soon Cheon; Cao, Yun; Bender, Ingrid; Jafari, Nadereh; Feng, Gang; Lin, Simon; Cidlowski, John A.; Schleimer, Robert P.; Lu, Nanxi

doi:10.1038/cddis.2012.193

Cited by 49 publications

(41 citation statements)

References 53 publications

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“…GRα-A, GRα-B, GRα-C1, GRα-C2, GRα-C3, GRα-D1, GRα-D2 and GRα-D3) with distinct gene expression profiles (Oakley & Cidlowski, 2011;Wu et al, 2013). Given this complexity of transcriptional and translational isoforms, understandably, the proportion of different GR isoforms in a cell modulates the final effects of a presented GC or SEGRM (Gronemeyer et al, 2004;Rhen & Cidlowski, 2005 Furthermore, it has been found that a rise in the ratio of GRβ/GRα levels appears to be a mechanism involved in the development of glucocorticoid resistance in multiple organs (Lewis-Tuffin & Cidlowski, 2006).…”

Section: Structure Of Glucocorticoid Receptorsmentioning

confidence: 99%

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Sundahl

Bridelance

Libert

et al. 2015

Pharmacology & Therapeutics

186

171

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Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies.

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Section: Structure Of Glucocorticoid Receptorsmentioning

confidence: 99%

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Sundahl

Bridelance

Libert

et al. 2015

Pharmacology & Therapeutics

186

171

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“…GAS5 could suppress glucocorticoid receptor (GR)-induced transcriptional activity of endogenous glucocorticoid-responsive genes by competing with DNA glucocorticoid receptor response element (GRE) for binding to the GR since it is structurally similar to GRE (34,43). The GR regulates cell survival by binding the promoters of various glucocorticoid-responsive genes, including apoptosis-related genes (50).…”

Section: Molecular Mechanism and Action Of Gas5mentioning

confidence: 99%

Long non-coding RNA growth arrest-specific transcript 5 in tumor biology

2015

Oncology Letters

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Abstract. The recognition of the biological relevance of long non-coding RNA (lncRNA) molecules has only recently been recognized as one of the most significant advances in contemporary molecular biology. A growing body of evidence indicates that lncRNAs act not only as the intermediary between DNA and protein but also as significant protagonists of cellular functions. The dysregulation of lncRNAs has increasingly been linked to numerous human diseases, particularly cancers. Recent studies have demonstrated that the lncRNA growth arrest-specific transcript 5 (GAS5) was pervasively downexpressed in most human cancers compared with non-cancerous adjacent tissues including gastric, breast, lung and prostate cancer. In addition, patients with decreased GAS5 expression have a significantly poorer prognosis than those with higher expression. Furthermore, GAS5 is involved in the control of cell apoptosis, proliferation, metastasis, angiogenesis, DNA repair and tumor cell metabolism. This review provides an overview of the current knowledge concerning the role of GAS5 in tumor expression and biology function.

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“…Each isoform, when expressed in Jurkat T-lymphoblastic leukemia cells or U2OS osteosarcoma cells, was shown to influence the transcription of a specific set of genes. 40,41 Only a small percentage of target genes (less than 10%) was found to be commonly regulated by these isoforms. 40,41 Not only do they have a unique transcription profile, but they also possess different subcellular localization.…”

Section: Glucocorticoid Receptor: From the Nr3c1 Gene To Protein Isofmentioning

confidence: 99%

“…40,41 Only a small percentage of target genes (less than 10%) was found to be commonly regulated by these isoforms. 40,41 Not only do they have a unique transcription profile, but they also possess different subcellular localization. For example, GRα-D was found constitutively in the nuclear compartment, whereas GRα-A, GRα-B and GRα-C were seen to reside primarily in the cytoplasm and to translocate to the nucleus following ligand-induced activation.…”

Section: Glucocorticoid Receptor: From the Nr3c1 Gene To Protein Isofmentioning

confidence: 99%

Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes

Nicolaides

Charmandari

2017

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Glucocorticoids play a fundamental role in many physiologic functions and contribute substantially to the achievement of homeostasis. These pleiotropic glucocorticoid actions are mediated by a ubiquitously expressed transcription factor, the human glucocorticoid receptor (hGR), which may influence the transcription rate of numerous target genes, interact with other transcription factors, trigger the activation of several kinase pathways or modulate mitochondrial DNA expression. Any genetic defects in the NR3C1 gene that encodes the hGR may cause Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes, two rare allostatic endocrinologic conditions characterized by partial impaired tissue sensitivity to glucocorticoids. However, there are patients who present with clinical manifestations suggestive of the above syndromes and do not harbor an inactivating or activating point mutation, insertion or deletion in the NR3C1 gene. In these cases, several other factors might influence the glucocorticoid signal transduction. In this review, we discuss the numerous glucocorticoid functions and the multiple hGR isoforms, we present the genomic, nongenomic and mitochondrial glucocorticoid signaling cascade and we summarize the clinical manifestations and pathogenesis of Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes. Finally, we speculate that the next generation sequencing technologies will undoubtedly enable us to gain a deeper understanding of the GR "interactome".

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Selective glucocorticoid receptor translational isoforms reveal glucocorticoid-induced apoptotic transcriptomes

Cited by 49 publications

References 53 publications

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Long non-coding RNA growth arrest-specific transcript 5 in tumor biology

Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes

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