Human Glucocorticoid Receptor β Binds RU-486 and Is TranscriptionallyActive

Lewis‐Tuffin, Laura J.; Jewell, Christine M.; Bienstock, Rachelle J.; Collins, Jennifer B.; Cidlowski, John A.

doi:10.1128/mcb.01439-06

Cited by 152 publications

(163 citation statements)

References 41 publications

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“…2), which suggests that the binding of RU486 to the GR protein does not bring about translocation in the rainbow trout zygote as it appears to do in several mammalian cell lines (murine fibroblast cells: Pariante et al (2001), primate kidney and osteosarcoma cells: Lewis-Tuffin et al (2007), and murine pituitary cells: Peeters et al (2008) and Spiga et al (2011)). Moreover, RU486 does not appear to inhibit cortisolactivated translocation.…”

Section: K1mentioning

confidence: 99%

Glucocorticoid receptor activation following elevated oocyte cortisol content is associated with zygote activation, early embryo cell division, and IGF system gene responses in rainbow trout

Li¹,

Leatherland²,

Vijayan³

et al. 2012

Journal of Endocrinology

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Increased in ovo cortisol content of rainbow trout oocytes from w3 . 5 to w5 . 0 ng.oocyte K1 before fertilization enhances the growth of embryos and juveniles and changes the long-term expression pattern of IGF-related genes. This study used embryos reared from oocytes enriched with cortisol and the glucocorticoid receptor (GR) antagonist, RU486, to determine whether the growth-promoting actions of cortisol involve GR protein activation and modulation of gr expression. Whole-mount in situ immunohistofluorescence studies of zygotes showed that enhanced oocyte cortisol increased the immunofluorescent GR signal and activated the relocation of GR from a general distribution throughout the cytoplasm to an accumulation in the perinuclear cytoplasm. In ovo cortisol treatment increased the number of embryonic cells within 48-h post-fertilization, and RU486 partially suppressed this cortisol stimulation of cell duplication. In addition, there was complex interplay between the expression of gr and igf system-related genes spatiotemporally in the different treatment groups, suggesting a role for GR in the regulation of the expression of development. Taken together, these findings indicate an essential role for GR in the regulation of epigenomic events in very early embryos that promoted the long-term growth effects of the embryos and juvenile fish. Moreover, the pretreatment of the oocyte with RU486 had a significant suppressive effect on the maternal mRNA transcript number of gr and igf system-related genes in oocytes and very early stage embryos, suggesting an action of antagonist on the stability of the maternal transcriptome.

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Section: K1mentioning

confidence: 99%

Glucocorticoid receptor activation following elevated oocyte cortisol content is associated with zygote activation, early embryo cell division, and IGF system gene responses in rainbow trout

Li¹,

Leatherland²,

Vijayan³

et al. 2012

Journal of Endocrinology

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“…These increased HDAC activities in IL-8 promoter site by GRβ may influence the transcription of genes such as IL-8 and benefit to suppress the inflammatory condition, especially in the situation of shortage of glucocorticoid. Recently it was confirmed that GRβ bind RU-486, glucocorticoid antagonist, as an ligand and GRβ bound with RU-486 can regulate gene expression, suggesting that GRβ may have some physiological roles other than as an just bystander or inhibitor of GRα (Lewis-Tuffin et al, 2007). The effect of GRβ on IL-8 secretion was not significant in our experiments, which may be due to insufficient ability of GRβ to interact with DNA or be recruited to the area near inflammatory cytokine gene.…”

Section: Discussionmentioning

confidence: 41%

Repression of TNF-α-induced IL-8 expression by the glucocorticoid receptor-β involves inhibition of histone H4 acetylation

Kim

Lavender

et al. 2009

Exp Mol Med

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Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)β, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRα. However, recent data suggest that GRβ is not a dominant negative inhibitor of GRα in the transrepressive process and has its own functional role. We investigated the functional role of GRβ expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-α-induced IL-8 release in an airway epithelial cell line. GRβ expression was induced by treatment of epithelial cells with either dexamethasone or TNF-α. GRβ was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-α-induced IL-8 transcription was not affected by GRβ overexpression, rather GRβ had its own weak suppressive activity on TNF-α-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRβ overexpression, but TNF-α-induced histone H4 acetylation at the IL-8 promoter was decreased with GRβ overexpression. This study suggests that GRβ overexpression does not affect glucocorticoid-induced suppression of IL-8 expression in airway epithelial cells and GRβ induces its own histone deacetylase activity around IL-8 promoter site.

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“…In support of a dominant-negative function for GRb, resistance to glucocorticoid therapy in leukemia has been associated with high cellular levels of GRb (78). Recent studies, however, suggest that GRb may have a previously unappreciated role in cell signaling and the contribution of relative GRb levels in determining cellular sensitivity to glucocorticoids in individuals undergoing glucocorticoid therapy for malignancies remains unclear (79). The GRg isoform contains a three base insertion in the DBD between exons 3 and 4 that results in addition of arginine between the two zinc fingers of the DBD (80).…”

Section: Glucocorticoid Receptor Isoformsmentioning

confidence: 99%

Glucocorticoid Receptor in Health and Disease

Dunđerski¹,

Matić²

2009

Journal of Medical Biochemistry

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Glucocorticoid Receptor in Health and DiseaseGlucocorticoid hormones are essential for life, have a vital place in the treatment of inflammatory and autoimmune diseases and are increasingly implicated in the pathogenesis of a number of common disorders. Their action is mediated by an intracellular receptor protein, the glucocorticoid receptor (GR), functioning as a ligand-inducible transcription factor. Multiple synthetic glucocorticoids are used as potent antiinflammatory and immunosuppressive agents, but their therapeutic usefulness is limited by a wide range and severity of side-effects. One of the most important pharmaceutical goals has been to design steroidal and non-steroidal GR ligands with profound therapeutic efficacy and reduced unwanted effects. The therapeutic benefit of glucocorticoid agonists is frequently compromised by resistance to glucocorticoids, which may depend on: access of the hormones to target cells, steroid metabolism, expression level and isoform composition of the GR protein, mutations and polymorphisms in the GR gene and association of the receptor with chaperone proteins. The major breakthrough into the critical role of glucocorticoid signaling in the maintenance of homeostasis and pathogenesis of diseases, as well as into the molecular mechanisms underlying the therapeutic usefulness of antiinflammatory drugs acting through the GR is expected to result from the current progress in large-scale gene expression profiling technologies and computational biology.

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Human Glucocorticoid Receptor β Binds RU-486 and Is TranscriptionallyActive

Cited by 152 publications

References 41 publications

Glucocorticoid receptor activation following elevated oocyte cortisol content is associated with zygote activation, early embryo cell division, and IGF system gene responses in rainbow trout

Glucocorticoid receptor activation following elevated oocyte cortisol content is associated with zygote activation, early embryo cell division, and IGF system gene responses in rainbow trout

Repression of TNF-α-induced IL-8 expression by the glucocorticoid receptor-β involves inhibition of histone H4 acetylation

Glucocorticoid Receptor in Health and Disease

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