The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways.

Beck, Candace A.; Weigel, Nancy L.; Moyer, Marissa L.; Nordeen, Steven K.; Edwards, Dean P.

doi:10.1073/pnas.90.10.4441

Cited by 192 publications

(99 citation statements)

References 35 publications

(66 reference statements)

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“…Hormone antagonists classified into a group of a higher type number more resemble the fully induced receptor after agonist binding. Therefore, the antiglucocorticoid RU486 is often classified as a type II antagonist leading to a mixed agonist/antagonist transcriptional activity (41)(42)(43). Both the estrogen receptor as well as the progesterone receptor bound by a mixed agonist/antagonist have been shown to be associated with the corepressors SMRT or NCoR (18,19,44).…”

Section: Discussionmentioning

confidence: 99%

RU486-induced Glucocorticoid Receptor Agonism Is Controlled by the Receptor N Terminus and by Corepressor Binding

Schulz

Eggert

Baniahmad

et al. 2002

Journal of Biological Chemistry

132

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Glucocorticoid-induced gene transcription has been shown to be mediated by coactivators bound to the glucocorticoid receptor (GR). The glucocorticoid antagonist RU486 interferes with the steroid-mediated activation and can also exhibit partial agonist activity, a response in which corepressors have been implicated. Here we have shown that deletion of the N terminus of GR totally abolishes the agonist activity of RU486. Furthermore, we have demonstrated that corepressors bind directly to the RU486-bound GR as determined by glutathione S-transferase pull-down, mammalian two-hybrid assay, and coimmunoprecipitation. Fine mapping of the interaction regions within GR and the corepressor NCoR reveals a complex interaction profile that involves a number of domains in each protein. Notably, the N and the C termini of GR are both involved in corepressor binding. Thus, the N terminus of GR is a major determinant for RU486-dependent NCoR interaction as well as for RU486-mediated agonist activity.

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Section: Discussionmentioning

confidence: 99%

RU486-induced Glucocorticoid Receptor Agonism Is Controlled by the Receptor N Terminus and by Corepressor Binding

Schulz

Eggert

Baniahmad

et al. 2002

Journal of Biological Chemistry

132

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“…The GR type II agonist RU486 gives rise to nuclear import of GR without stimulating these subsequent events (Beck et al, 1993). Therefore, we pre-treated cells expressing EGFP-GR and p65-dsRed with this agonist in place of dexamethasone.…”

Section: Function Of the Gfp-gr Fusion Proteinmentioning

confidence: 99%

NF-κB signalling is inhibited by glucocorticoid receptor and STAT6 via distinct mechanisms

Nelson

Wilde

Spiller

et al. 2003

Journal of Cell Science

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NF-κB transcription factors are involved in the cellular response to stress, and are regulated by inhibitor (IκB)proteins, which prevent NF-κB-mediated transcription by maintaining NF-κB in the cytoplasm. Proteins from other pathways are also known to regulate NF-κB negatively, notably the glucocorticoid receptor (GR) and IL-4-responsive STAT6. Both pathways were shown to inhibit NF-κB-mediated transcription, by expressing either STAT6 or GR and activating the respective pathways. Using fluorescent fusion proteins, we show that GR alters the timing of activated p65 NF-κB nuclear occupancy by increasing the export rate of p65 and is independent of whether GR is present as a dimer or monomer. Expression of STAT6 was also shown to alter p65 nuclear occupancy but appeared to affect the import rate and hence the overall maximal level of p65 translocation. Activating STAT6 with IL-4 prior to activating NF-κB significantly increased this inhibition. Investigation of IκBa showed that activated STAT6 inhibited TNFα-mediated IκBa phosphorylation and degradation, whereas GR activation did not alter IκBαkinetics. This demonstrates a clear separation of two distinct mechanisms of inhibition by STAT6 and GR upon the NF-κB pathway.

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“…In the field of steroid receptors, most of the recent advances have emerged from transient transfection experiments, including the contributions of cis-acting elements (1,2), of different nucleotides in receptor binding to the hormone-responsive element (3), of various regions of receptors in steroid binding and biological activity (reviewed in Ref. 4), of promoter structure and cell type as determinants for the activity of antisteroid activity (5), and of overlapping signaling systems such as dopamine (6), epidermal growth factor (7), and protein kinase A inducers (8,9). The utility of transient transfections has been further enhanced by the development of the "two-hybrid" (10,11) and similar assays, which allows the direct detection of the interactions of two (or more) proteins (12,13).…”

mentioning

confidence: 99%

Induction Properties of a Transiently Transfected Glucocorticoid-responsive Gene Vary with Glucocorticoid Receptor Concentration

Szapary

Simons

1996

Journal of Biological Chemistry

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Transient transfections of steroid receptors have yielded much of the data used to construct the current models of steroid hormone action. These experiments invariably examine the ability of receptors to regulate transcription when occupied by saturating concentrations of steroid. We now report that other induction properties of a transiently transfected gene are not constant but vary with the concentration of transiently transfected glucocorticoid receptors. Thus, the percentage of maximal induction seen with subsaturating concentrations of glucocorticoid could be dramatically increased, and an antiglucocorticoid could be converted into a partial glucocorticoid, simply by increasing the concentration of glucocorticoid receptors. This behavior was observed in HeLa cells, containing endogenous receptors, or in CV-1 cells, containing almost no endogenous receptor, with either homologous or heterologous receptors. These increases were relatively insensitive to the concentration of reporter gene, suggesting the titration of some transcription factor(s) involved in regulating the position of the glucocorticoid dose-response curve and the agonist activity of an antiglucocorticoid. This property of transfected glucocorticoid receptors required a full-length, functionally active receptor but was retained, albeit reduced in magnitude, in the absence of binding to a glucocorticoid response element. Furthermore, this phenomenon was specific in that the A form of the human progesterone receptor had no effect under the same conditions. These variations in induction properties of antiglucocorticoids and of subsaturating concentrations of glucocorticoid, in a manner that was proportional to the amount of transfected receptor, reveal processes that are not operative with saturating concentrations of glucocorticoid. These variations also demonstrate that caution should be exercised in making mechanistic conclusions based solely on experiments conducted with saturating concentrations of glucocorticoid.The overriding experimental advantage of transient transfections is time. Thus, the biological consequences of altered nucleotide compositions in the cDNAs encoding active proteins, and in genomic sequences, can be examined in a fraction of the time required to establish cell lines with the same sequences stably integrated into the cellular genome. In the field of steroid receptors, most of the recent advances have emerged from transient transfection experiments, including the contributions of cis-acting elements (1, 2), of different nucleotides in receptor binding to the hormone-responsive element (3), of various regions of receptors in steroid binding and biological activity (reviewed in Ref. 4), of promoter structure and cell type as determinants for the activity of antisteroid activity (5), and of overlapping signaling systems such as dopamine (6), epidermal growth factor (7), and protein kinase A inducers (8, 9). The utility of transient transfections has been further enhanced by the development of the "two-hybrid" (10, 11) and...

show abstract

The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways.

Cited by 192 publications

References 35 publications

RU486-induced Glucocorticoid Receptor Agonism Is Controlled by the Receptor N Terminus and by Corepressor Binding

RU486-induced Glucocorticoid Receptor Agonism Is Controlled by the Receptor N Terminus and by Corepressor Binding

NF-κB signalling is inhibited by glucocorticoid receptor and STAT6 via distinct mechanisms

Induction Properties of a Transiently Transfected Glucocorticoid-responsive Gene Vary with Glucocorticoid Receptor Concentration

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