The androgen receptor ligand-binding domain stabilizes DNA binding in living cells

Farla, Pascal; Hersmus, Remko; Geverts, Bart; Mari, Pierre-Olivier; Nigg, Alex L.; Dubbink, Hendrikus J.; Trapman, Jan; Houtsmuller, Adriaan B.

doi:10.1016/j.jsb.2004.01.002

Cited by 86 publications

(130 citation statements)

References 39 publications

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“…However, this can likely be ruled out, since the sub-cellular distribution was found to be similar for AR F826L and wild-type AR. Furthermore, after addition of R1881, GFP-AR and GFP-AR F826L displayed a typical punctuate nuclear distribution pattern, as previously shown by Farla et al (2004Farla et al ( , 2005 for the wild-type receptor. This typical speckled pattern overlaps with sites of active transcription (van Royen et al, 2007).…”

Section: Tif2 Co-activation Of Ar Mutants F826lsupporting

confidence: 82%

“…Generation of pGFP-AR constructs, coding for NH 2 -terminally tagged GFP-AR fusion proteins of which the expression is driven by a CMV promoter, has been described previously (Farla et al, 2004). GFP-AR F826L was constructed by replacing an EcoRI-PvuI cDNA fragment encoding the LBD of pGFP-AR by the same fragment of pAR-F826L.…”

Section: Site-directed Mutagenesis and Plasmidsmentioning

confidence: 99%

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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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Section: Tif2 Co-activation Of Ar Mutants F826lsupporting

confidence: 82%

Section: Site-directed Mutagenesis and Plasmidsmentioning

confidence: 99%

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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“…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). Antagonist-bound ARs behave differently, having smaller immobile fractions, resembling that of DNAbinding defective receptors (26).…”

Section: Ligand-induced Intranuclear Behavior Of Mutant Receptorsmentioning

confidence: 71%

“…When the AR is activated by agonists it undergoes a conformational change that leads to close positioning of the NTD and LBD and thus interaction between these two domains (27,43). The enzalutamide-bound AR WT or F877L did not show any N/C interactions.…”

Section: N/c Interactions and Binding To Coregulator Peptidesmentioning

confidence: 94%

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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“…Upon agonist binding, there is a conformational change in LBD, resulting in the stabilization of helix 12 and the formation of a functional activation function 2 (AF2) on the surface of this domain. AF2 plays a pivotal role on intra-and intermolecular N/C interactions, which may further stabilize AR-bound androgen complex and play a role on receptor dimerization (16,21). The LBD is also involved in the recruitment of coregulators during transcriptional activation.…”

Section: Androgen Receptor Gene and Protein Structurementioning

confidence: 99%

Androgens and the male reproductive tract: an overview of classical roles and current perspectives

Patrão

Silva

Avellar

2009

Arq Bras Endocrinol Metab

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Androgens are steroid hormones that play key roles in the development and maintenance of male phenotype and reproductive function. These hormones also affect the function of several non-reproductive organs, such as bone and skeletal muscle. Endogenous androgens exert most of their effects by genomic mechanisms, which involve hormone binding to the androgen receptor (AR), a ligand-activated transcription factor, resulting in the modulation of gene expression. AR-induced non-genomic mechanisms have also been reported. A large number of steroidal and non-steroidal AR-ligands have been developed for therapeutic use, including the treatment of male hypogonadism (AR agonists) and prostate diseases (AR antagonists), among other pathological conditions. Here, the AR gene and protein structure, mechanism of action and AR gene homologous regulation were reviewed. The AR expression pattern, its in vivo regulation and physiological relevance in the developing and adult testis and epididymis, which are sites of sperm production and maturation, respectively, were also presented. Arq Bras Endocrinol Metab. 2009;53(8):934-45Keywords Androgen receptor; male reproductive tract; testis; epididymis RESUMOOs androgênios são hormônios esteroides com papel fundamental no desenvolvimento e na manutenção do fenótipo masculino e da função reprodutiva. Esses hormônios também afetam a função de diversos tecidos não reprodutivos, como, por exemplo, o ósseo e musculoesquelé-tico. Os androgênios endógenos exercem a maioria de suas funções por mecanismo genômico, que envolve a ligação do hormônio ao receptor de androgênio (RA), um fator de transcrição ativado por ligante, o que resulta no controle da expressão gênica. Mecanismos não genômicos também têm sido associados aos efeitos induzidos pelo RA. Um grande número de ligantes do RA, esteroidais e não esteroidais, tem sido desenvolvido para o uso terapêutico, incluindo o tratamento do hipogonadismo masculino (agonistas do RA) e de doenças da próstata (antagonistas do RA), entre outras condições patológicas. Neste trabalho, foram discutidas as caracterís-ticas estruturais básicas do RA (gene e proteína), os mecanismos de ação desse receptor, bem como aspectos relacionados à sua regulação homóloga. O padrão de expressão do RA, sua regulação in vivo e relevância fisiológica durante o desenvolvimento e a vida adulta na função do testículo e epidídimo, tecidos responsáveis pela produção e maturação de espermatozoides, respectivamente, também foram discutidos. Arq Bras Endocrinol Metab. 2009;53(8):934-45 Descritores Receptor de androgênio; trato reprodutor masculino; testículo; epidídimo

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The androgen receptor ligand-binding domain stabilizes DNA binding in living cells

Cited by 86 publications

References 39 publications

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

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

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

Androgens and the male reproductive tract: an overview of classical roles and current perspectives

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