16 alpha-substituted analogs of the antiprogestin RU486 induce a unique conformation in the human progesterone receptor resulting in mixed agonist activity.

Wagner, Beverly L.; Pollio, Giuseppe; Leonhardt, Susan A.; Wani, Mansukh C.; Lee, Dy-W; Imhof, M O; Dp, Edwards; Cook, Clarence; McDonnell, DP

doi:10.1073/pnas.93.16.8739

Cited by 60 publications

(37 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Numerous studies on estrogen and progesterone receptors have indicated that a range of distinct receptor conformations can be induced by the binding of different ligands. There is a strong correlation between receptor conformations elicited by different ligands and downstream biological activity (9)(10)(11)(12)(13). The hypothesis that different PPA Rligands have distinct downstream effects is supported by our protein profiling experiment that demonstrated differential regulation of gene expression by troglitazone and rosiglitazone in several cell types.…”

Section: A B Csupporting

confidence: 60%

“…It has been postulated that these coactivators act as bridges to transmit the nuclear receptor regulatory signals to the cellular transcriptional machinery. Studies on estrogen and progesterone receptors have suggested that a range of distinct receptor conformations can be induced by the binding of different ligands (9)(10)(11)(12)(13). Although less is known about PPA R-in this regard, it is possible that different PPA R-ligands induce unique conformational changes in the receptor, eliciting distinct downstream biological effects.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone.

Camp¹,

Li²,

Wise³

et al. 2000

Diabetes

214

122

View full text Add to dashboard Cite

The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-a c t i v a t e d receptor (PPA R )-and exert their antihyperglycemic e ffects by regulation of PPA R--responsive genes. We report here that PPA R-activation by troglitazone depends on the experimental setting. Troglitazone acts as a partial agonist for PPA R-in transfected muscle (C2C12) and kidney (HEK 293T) cells, producing a submaximal transcriptional response (1.8-to 2.5-fold activation) compared with rosiglitazone (7.4-to 13-fold activation). Additionally, troglitazone antagonizes rosiglitazone-stimulated PPA R-transcriptional activity. Limited protease digestion of PPA R-suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone. Consistent with this fin d i n g , an in vitro coactivator association assay demonstrated that troglitazone-bound PPA R-recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone-bound receptor. In contrast to these observations, troglitazone behaves as a full agonist of PPA R-in 3T3L1 adipocytes. Tw odimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types. Thus, troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others. These differences could be caused by variations in the amount of specific cofactors, differences in PPA R response elements, or the presence of different isoforms of PPA R-. D i a b e t e s 4 9 :5 3 9-547, 2000 T ype 2 diabetes is characterized by decreased insulin sensitivity of peripheral tissues. Glucose homeostasis is maintained under these circumstances by increased insulin secretion from pancreatic -cells. In some cases, the -cell is unable to maintain increased output. The antidiabetic thiazolidinediones (TZDs), such as troglitazone, improve peripheral insulin sensitivity, leading to reduced blood glucose and insulin levels and the preservation of pancreatic function (1-4). Improvement of insulin sensitivity by TZDs is most likely due to the activation of the peroxisome proliferator-activated receptor (PPA R )-(5). The TZDs are high-affinity ligands for PPA R-in vitro, and the rank order of receptor affinity correlates with their in vivo hypoglycemic activity (6), with one reported exception (7). Although many of the molecular details are not clearly understood, a model has emerged in which activated PPA R-m o dulates the transcriptional activity of a set of genes encoding proteins that are important in glucose and lipid metabolism. H o w e v e r, the identity of these genes and the precise pathways leading to the normalization of insulin sensitivity remain largely unknown.R e c e n t l y, the X-ray crystal structure of the ligand-binding domain of PPA R-has been elucidated (3,8), revealing that ligand binding causes a conformational change within P PA R-such...

show abstract

Section: A B Csupporting

confidence: 60%

mentioning

confidence: 99%

Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone.

Camp¹,

Li²,

Wise³

et al. 2000

Diabetes

214

122

View full text Add to dashboard Cite

show abstract

“…In another study, Fjelldal et al (37) exposed breast cancer and uterine cervix cancer cells to P4 or RU486 and found that, depending on the dose of both agents, the treatments could reduce cell density in vitro and were not due to their actions on the intranuclear P4 receptor. However, there are some data showing that RU486 may not be as highly specific as a P4 antagonist because of its partial PR-agonist activity (41,42). Here, we can also speculate that one of the reasons for its complex and sometimes contradictory effects is that RU486 is a selective blocker of PR-B only and does not block PR-A.…”

Section: Discussionmentioning

confidence: 92%

Progesterone Inhibits the Growth of Human Neuroblastoma: In Vitro and In Vivo Evidence

Atif

Sayeed

Yousuf

et al. 2011

Mol Med

View full text Add to dashboard Cite

“…As with estrogen receptor (ER) mixed agonists, the relative agonist, or antagonist, activity of PR mixed agonists is influenced by the cell and promoter context (7,38). The likely mechanistic basis for the unique activities of the PR mixed agonists was revealed when it was shown by limited protease digestion analysis that these ligands induce a conformational change within PR which is different from that induced by either agonists or antagonists (41). These studies firmly established a link between the overall structure of the PR-ligand complex and its biological activity.…”

mentioning

confidence: 99%

“…In addition to agonists and antagonists, we have recently identified a new class of PR ligands which function as mixed agonists (41). As with estrogen receptor (ER) mixed agonists, the relative agonist, or antagonist, activity of PR mixed agonists is influenced by the cell and promoter context (7,38).…”

mentioning

confidence: 99%

The Nuclear Corepressors NCoR and SMRT Are Key Regulators of Both Ligand- and 8-Bromo-Cyclic AMP-Dependent Transcriptional Activity of the Human Progesterone Receptor

Wagner

Norris

Knotts

et al. 1998

Molecular and Cellular Biology

235

131

View full text Add to dashboard Cite

Previously, we defined a novel class of ligands for the human progesterone receptor (PR) which function as mixed agonists. These compounds induce a conformational change upon binding the receptor that is different from those induced by agonists and antagonists. This establishes a correlation between the structure of a ligand-receptor complex and its transcriptional activity. In an attempt to define the cellular components which distinguish between different ligand-induced PR conformations, we have determined, by using a mammalian two-hybrid assay, that the nuclear receptor corepressor (NCoR) and the silencing mediator for retinoid and thyroid hormone receptor (SMRT) differentially associate with PR depending upon the class of ligand bound to the receptor. Specifically, we observed that the corepressors preferentially associate with antagonistoccupied PR and that overexpression of these corepressors suppresses the partial agonist activity of antagonist-occupied PR. Binding studies performed in vitro, however, reveal that recombinant SMRT can interact with PR in a manner which is not influenced by the nature of the bound ligand. Thus, the inability of SMRT or NCoR to interact with agonist-activated PR when assayed in vivo may relate more to the increased affinity of PR for coactivators, with a subsequent displacement of corepressors, than to an inherent low affinity for the corepressor proteins. Previous work from other groups has shown that 8-bromo-cyclic AMP (8-bromo-cAMP) can convert the PR antagonist RU486 into an agonist and, additionally, can potentiate the transcriptional activity of agonist-bound PR. In this study, we show that exogenous expression of NCoR or SMRT suppresses all 8-bromo-cAMP-mediated potentiation of PR transcriptional activity. Further analysis revealed that 8-bromo-cAMP addition decreases the association of NCoR and SMRT with PR. Thus, we propose that 8-bromocAMP-mediated potentiation of PR transcriptional activity is due, at least in part, to a disruption of the interaction between PR and the corepressors NCoR and SMRT. Cumulatively, these results suggest that NCoR and SMRT expression may play a pivotal role in PR pharmacology.The progesterone receptor is a ligand-activated transcription factor and a member of the nuclear receptor superfamily (15). In the absence of ligand, the receptor exists in a transcriptionally inactive state associated with heat shock proteins and other cellular chaperones (36). Upon binding ligand, the receptor undergoes a conformational change and dissociates from the heat shock proteins, allowing the receptor to dimerize and bind to progesterone-responsive elements (PRE) within regulatory regions of target genes (23). Agonist-bound progesterone receptor (PR) is believed to activate transcription by directly interacting with the general transcription machinery (20) and/or by associating with coactivators such as TIF2 (40), SRC-1 (29), and CBP (35), which act as bridging factors between the receptor and the general transcription machinery. Interestingly, upon bind...

show abstract

16 alpha-substituted analogs of the antiprogestin RU486 induce a unique conformation in the human progesterone receptor resulting in mixed agonist activity.

Cited by 60 publications

References 27 publications

Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone.

Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone.

Progesterone Inhibits the Growth of Human Neuroblastoma: In Vitro and In Vivo Evidence

The Nuclear Corepressors NCoR and SMRT Are Key Regulators of Both Ligand- and 8-Bromo-Cyclic AMP-Dependent Transcriptional Activity of the Human Progesterone Receptor

Contact Info

Product

Resources

About