Inhibition of the Dihydrotestosterone-Activated Androgen Receptor by Nuclear Receptor Corepressor

Cheng, Shinta; Brzostek, Sabrina; Lee, Suzanne R.; Hollenberg, Anthony N.; Balk, Steven P.

doi:10.1210/mend.16.7.0870

Cited by 88 publications

(36 citation statements)

References 62 publications

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“…These inverted responses were then shown to depend upon the joint actions of the N-and C-terminal domains of each receptor (Song et al, 2001). These results are consistent with the demonstration that corepressors interact with N-terminal regions of both GRs and PRs Wang et al, 2007) in addition to the initially defined requirements of the C-terminal sequences of nuclear (Zamir et al, 1996) and steroid receptors (Cheng et al, 2002;Wang et al, 2004a;Frego and Davidson, 2006;Wu et al, 2006;Kroe et al, 2007;Wang et al, 2007).…”

Section: Introductionsupporting

confidence: 89%

Differential modulation of glucocorticoid and progesterone receptor transactivation

Szapary

Song

et al. 2008

Molecular and Cellular Endocrinology

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The determinants of the different biological activities of progesterone receptors (PRs) vs. glucocorticoid receptors (GRs), which bind to the same DNA sequences, remain poorly understood. The mechanisms by which differential expression of a common target gene can be achieved by PR and GR include unequal agonist steroid concentrations for half maximal induction (EC 50 ) and dissimilar amounts of residual partial agonist activity for antisteroids in addition to the more common changes in total gene induction, or V max . Several factors are known to alter some or all of these three parameters for GR-regulated gene induction and some (i.e., the corepressors NCoR and SMRT) modulate the EC 50 and partial agonist activity for GR and PR induction of the same gene in opposite directions. The current study demonstrates that other factors (GME, GMEB-2, Ubc9, and STAMP) can also differentially interact with PRs and GRs or alter several of the above induction parameters under otherwise identical conditions. These results support the hypothesis that the modulation of EC 50 , partial agonist activity, and V max by a given factor is not limited to one receptor in a specific cell line. Furthermore, the number of factors that unequally modulate PR and GR induction parameters is now greatly expanded, thereby increasing the possible mechanisms for differential gene regulation by PRs vs. GRs.

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Section: Introductionsupporting

confidence: 89%

Differential modulation of glucocorticoid and progesterone receptor transactivation

Szapary

Song

et al. 2008

Molecular and Cellular Endocrinology

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“…In addition, it may well be possible that repression of AR, bound to either agonist or antagonist, by NCoR, occurs through different mechanisms. Repression of agonist (DHT)-activated AR only requires the receptor-interaction domains of N-CoR, possibly through competition for co-activator interaction sites [27]. It might however be postulated that N-CoR repression of antagonist-bound AR does require the N-terminus of N-CoR, and subsequent recruitment of histone deacetylases, resulting in a complete inhibition of transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Co-repressors (N-CoR/SMRT) can be recruited to interacting surfaces located on the LBD surface of nuclear receptors, which partially overlaps with that used by P160 co-activators [34][35][36]. Repression of DHTactivated AR by N-CoR only requires the repressor interaction domains, and is independent of N-CoR domains that can recruit histone deacetylases [27]. Owing to this, N-CoR and TIF2 might be competitors for the same binding site on the liganded AR.…”

Section: Competition Between Tif2 and N-cor Is Ligand-type-dependentmentioning

confidence: 99%

“…Transcriptional repression by these co-repressors involves the recruitment of histone deacetylases to the promoter of target genes [21][22][23][24]. More recently, evidence became available that N-CoR and SMRT are also involved in AR action [25][26][27][28]. Chromatin immunoprecipitation assays demonstrated that BIC-bound AR in LNCaP cells recruit N-CoR and SMRT to the promoter of the PSA (prostate-specific antigen) gene [25].…”

Section: Introductionmentioning

confidence: 99%

“…Chromatin immunoprecipitation assays demonstrated that BIC-bound AR in LNCaP cells recruit N-CoR and SMRT to the promoter of the PSA (prostate-specific antigen) gene [25]. SMRT and N-CoR suppress CPA-and flutamide-bound AR, as well as the DHT-stimulated AR activity [26][27][28]. For a better understanding of the molecular basis of antiandrogen action, we investigated the response of the AR, occupied with different ligands, to overexpression of N-CoR.…”

Section: Introductionmentioning

confidence: 99%

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Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

Berrevoets

Umar

Trapman

et al. 2004

Biochemical Journal

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Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)-and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonistbound AR has a preference for N-CoR. The AR mutation T877A (Thr 877 → Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of NCoR. The agonistic activities of CPA-and hydroxyflutamideoccupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.

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Modulation of the Androgen Receptor Axis

Mohler

Dalton

2021

Burger's Medicinal Chemistry and Drug Discovery

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The androgen receptor (AR) mediates the endocrine functions of endogenous androgens like testosterone and exerts pleiotropic androgenic (male phenotype development, sexual function) and anabolic (growth and maintenance of musculoskeletal system) effects across most tissues. The AR‐axis, i.e. AR and its downstream effects, is extensively targeted to stimulate anabolism or treat prostatic diseases. Tissue‐selective, direct‐acting synthetic AR agonists are limited in scope by their inadequate separation of anabolic from untoward androgenic or virilizing effects and include FDA approved steroidal androgens (anabolic‐androgenic steroids) and investigational nonsteroidal selective AR modulators (SARMs). Gaining in popularity is testosterone replacement therapy in hypogonadal men. Antagonism of the AR‐axis is common in aging males with androgen‐dependent prostate hyperproliferation [prostate cancer or benign prostatic hyperplasia (BPH)]. Androgen ablation (indirect antagonism) and direct AR antagonism have been the mainstays of prostate cancer therapies for many decades including recent approvals. Indirect antagonists of the AR‐axis include gonadotropin‐releasing hormone agonists or antagonists (androgen‐deprivation therapy), which achieve systemic androgen and estrogen ablation for prostate or breast cancers as a monotherapy or sometimes in combination with steroidogenic enzyme (lyase) inhibitors. DHT‐dependent diseases are treated with 5α‐reductase to block intracrine production of DHT for male pattern baldness and BPH; whereas aromatase inhibitors block androgen metabolism to estrogen in breast cancer. Direct AR antagonists (antiandrogens) with improved potency and anti‐androgenic scope continue to be approved for prostate cancer. Research into innovative ways to directly or indirectly modulate the AR‐axis remains robust, suggesting new therapies will likely be introduced regularly for the foreseeable future.

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Inhibition of the Dihydrotestosterone-Activated Androgen Receptor by Nuclear Receptor Corepressor

Cited by 88 publications

References 62 publications

Differential modulation of glucocorticoid and progesterone receptor transactivation

Differential modulation of glucocorticoid and progesterone receptor transactivation

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

Modulation of the Androgen Receptor Axis

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