A Model of Glucocorticoid Receptor Interaction With Coregulators Predicts Transcriptional Regulation of Target Genes.

Regulatory factors that control gene transcription in multicellular organisms are assembled in multicomponent complexes by combinatorial interactions. In this context, nuclear receptors provide well-characterized and physiologically relevant systems to study ligand-induced transcription resulting from the integration of cellular and genomic information in a cell- and gene-specific manner. Here, we developed a mathematical model describing the interactions between the glucocorticoid receptor (GR) and other components of a multifactorial regulatory complex controlling the transcription of GR-target genes, such as coregulator peptides.

Functional analysis reveals no transcriptional role for the glucocorticoid receptor β-isoform in zebrafish.

In humans, two splice variants of the glucocorticoid receptor (GR) exist: the canonical α-isoform, and the β-isoform, which has been shown to have a dominant-negative effect on hGRα. Previously, we have established the occurrence of a GR β-isoform in zebrafish, and in the present study we have investigated the functional role of the zebrafish GRβ (zGRβ). Reporter assays in COS-1 cells demonstrated a dominant-negative effect of zGRβ but no such effect was observed in zebrafish PAC2 cells using induction of the fk506 binding protein 5 (fkbp5) gene as readout.

Glucocorticoid-Induced Attenuation of the Inflammatory Response in Zebrafish.

Glucocorticoids are steroid hormones that are secreted upon stress. Their effects are mediated by the glucocorticoid receptor, which acts as a transcription factor. Because the antiinflammatory activity of glucocorticoids has been well established, they are widely used clinically to treat many inflammatory and immune-related diseases.

Transcriptional and metabolic effects of glucocorticoid receptor α and β signaling in zebrafish.

In humans and zebrafish, 2 glucocorticoid (GC) receptor (GR) splice variants exist: the canonical GR α-isoform (GRα), and the GRβ. In the present study, we have used the zebrafish model system in order to reveal genes affected by each of these 2 receptor isoforms. By injecting zebrafish embryos with different splice-blocking morpholinos, we could knock down both GR isoforms or could target the alternative splicing of the GR pre-mRNA in favor of the GRβ.

The zebrafish as an in vivo model system for glucocorticoid resistance.

Glucocorticoids regulate a wide range of systems in vertebrate organisms, and their effects are mediated by the glucocorticoid receptor (GR). The responsiveness to glucocorticoids differs largely between individuals. Resistance to glucocorticoids is an important medical problem, since it limits the efficacy of glucocorticoids when they are used to treat immune-related diseases like asthma and rheumatoid arthritis.