Compartmentalization of androgen receptor protein–protein interactions in living cells

Royen, Martin E. van; Cunha, Sónia; Brink, Maartje C.; Mattern, Karin; Nigg, Alex L.; Dubbink, Hendrikus J.; Verschure, Pernette J.; Trapman, Jan; Houtsmuller, Adriaan B.

doi:10.1083/jcb.200609178

Cited by 143 publications

(126 citation statements)

References 38 publications

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“…It is believed that the immobile fraction of AR measured in FRAP assays corresponds to the chromatin-bound receptor during the transcription activation process, because of the overlap of AR locations with the sites of RNA synthesis (17). There is also a strong correlation between AR activity and the immobile fraction, as observed for AR WT and AR T878A stimulated with agonists and antagonists (43).…”

Section: Ligand-induced Intranuclear Behavior Of Mutant Receptorsmentioning

confidence: 53%

“…Acceptor photobleaching fluorescence resonance energy transfer Acceptor photobleaching fluorescence resonance energy transfer (FRET) was performed using a Zeiss LSM510 confocal laser scanning microscope equipped with a Plan-Neofluar 40Â/1.3 NA oil objective (Carl Zeiss) at a lateral resolution of 100 nm (17). For excitation of CFP and YFP, an Argon laser at 358 and 514 nm was used.…”

Section: Double-hybrid Assaymentioning

confidence: 99%

“…Apparent FRET efficiency was estimated according to the instructions described in ref. (17). The abFRET datasets were tested for normality using the Kolmogorov-Smirnov tests, and the datasets were compared using the one-tailed Student t test.…”

Section: Double-hybrid Assaymentioning

confidence: 99%

“…The same cloning strategy as described for the full-length AR constructs was used. The construct containing double-tagged (N-ter YFP and C-ter CFP) WT AR (17) has been used to generate mutations in the LBD using QuikChange II kit (Agilent Technologies). A plasmid containing pCMV-b-Gal was acquired from Stratagene, the luciferase reporter construct driven by 4 copies of a classical ARE and the VP16 AD-NTD(WT) expression vector have been described elsewhere (16,18).…”

Section: Plasmid Constructsmentioning

confidence: 99%

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The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR.

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Section: Ligand-induced Intranuclear Behavior Of Mutant Receptorsmentioning

confidence: 53%

Section: Double-hybrid Assaymentioning

confidence: 99%

Section: Double-hybrid Assaymentioning

confidence: 99%

Section: Plasmid Constructsmentioning

confidence: 99%

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The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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“…In the presence of 1 nM R1881 both GFP-AR and GFP-AR F826L were translocated in a similar way to the nucleus and displayed a typical punctuate nuclear distribution pattern ( Figures 3C and 3D). This typical speckled pattern indicates an active transcription of endogenous genes (Farla et al, 2005;van Royen et al, 2007). It can be concluded that the F826L mutation did not influence the sub-cellular distribution of the AR mutant F826L.…”

Section: Sub-cellular Distribution Of Ar Mutant F826lmentioning

confidence: 92%

A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation

Wong

Hoogerbrugge

Pang

et al. 2008

Molecular and Cellular Endocrinology

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A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH 2 -/COOH-terminal domain interaction and TIF2 co-activation, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abbreviations: aa, amino acid; AD, activation domain; AF2, activation function 2; DHT, 5-dihydrotestosterone; DSD, disorders of sex development; GFP, green fluorescent protein; GSF, genital skin fibroblast; LBD, ligand binding domain; LBP, ligand binding pocket; N-CoR, nuclear receptor co-repressor; NC-TDI, NH 2 -/COOH-terminal domain interaction; NTD, N-terminal transactivation domain; T, testosterone; TIF2, transcriptional intermediary factor 2; wt, wild-type. However, an at least two-fold higher NH 2 -/COOH-terminal domain interaction was found in luciferase and GST pull-down assays. A two-fold increase was also observed for TIF2 (transcription intermediary factor 2) co-activation of the AR F826L COOH-terminal domain. This increase could not be explained by a higher stability of the mutant protein, which was within wild-type range.Repression of transactivation by the nuclear receptor co-repressor (N-CoR) was not affected by the AR F826L mutation. The observed properties of AR F826L would be in agreement with an increased activity rather than with a partial defective AR transcriptional activation. It is concluded that the penoscrotal hypospadias in the present case is caused by an as yet unknown mechanism, which still may involve the mutant AR.

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Targeting the Nuclear Receptor–Cofactor Interaction

Vaz

Möcklinghoff

Brunsveld

2008

Methods and Principles in Medicinal Chemistry

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The developmental and physiological processes regulated by nuclear receptors are the result of the interplay between the receptors, their small-molecule ligands (hormones), their response elements on the DNA and a large set of interacting proteins, the so-called cofactors [1,2]. Up to recently, the modulation of the function of nuclear receptors concentrated mainly on ligands with agonistic, antagonistic or partial (ant)agonistic properties that bind in the binding pocket of the ligand-binding domain (LBD), also occupied by the natural ligands. These types of ligands have proven very beneficial for the treatment of various diseases and the regulation of hormone functioning, as illustrated by many of the chapters in this book. Some of these ligands have even been shown to feature tissue-specific or -selective (ant) agonistic properties, which is often of crucial importance for the separation of the beneficial effects of nuclear receptor stimulation or inhibition from unwanted sideeffects, regulated by the same receptor [2]. Nevertheless, predictability and control over tissue specificity of these classical ligands is difficult. The physiological effects of some of the nuclear receptor ligands are sometimes also altered over a period of time. A typical example of this is the transition of nuclear receptor ligands used for the treatment of specific cancers from an antagonistic profile into an agonistic profile [3]. Interestingly, there are also nuclear receptors for which, up to now, no ligand, neither of natural nor of synthetic origin, has been found. These so-called orphan receptors seem not to be amenable to modulation by classical ligands.The limitations of the current nuclear receptor ligands generate a continuous quest for new ligands with optimized profiles in both industry and academia. The requirements of the effects of these ligands on the level of the organism are usually quite clear; the translation of these requirements to the level of the conformation of the protein and structure of the ligand is, however, usually not evident. This is due to a major extent to the large plethora of protein-protein interactions between nuclear receptors and their many cofactors [1,2]. Binding of a ligand results in a change of the Nuclear Receptors as Drug Targets. Edited by Eckhard Ottow and Hilmar Weinmann

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Compartmentalization of androgen receptor protein–protein interactions in living cells

Cited by 143 publications

References 38 publications

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation

Targeting the Nuclear Receptor–Cofactor Interaction

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