Molecular cell biology of androgen receptor signalling

Bennett, Nigel C.; Gardiner, Robert A.; Hooper, John D.; Johnson, David W.; Gobé, Glenda C.

doi:10.1016/j.biocel.2009.11.013

Cited by 239 publications

(263 citation statements)

References 162 publications

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“…The androgen receptor exhibits interacting slow (30 min or more) and fast (seconds to minutes) mechanisms of action, respectively genomic and non-genomic (Bennett et al, 2010;Michels and Hoppe, 2008). This receptor is typically translocated from the cytoplasm to the nucleus when bound by androgen ligands, testosterone or its metabolite, 5a-dihydrotestosterone.…”

Section: Discussionmentioning

confidence: 99%

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Poirier

Imamura

Zanoletti

et al. 2014

Journal of Psychiatric Research

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a b s t r a c tAdolescence is increasingly recognized as a critical period for the development of the social system, through the maturation of social competences and of their underlying neural circuitries. The present study sought to test the utility of resveratrol, a dietary phenol recently reported to have mood lifting properties, in modulating social interaction that is deficient following early life adversity. The main aims were to 1) pharmacologically restore normative social investigation levels dampened by peripubertal stress in rats and 2) identify neural pathways engaged by this pharmacological approach. Following peripubertal (P28e42) stress consisting of unpredictable exposures to fearful experiences, at adulthood the subjects' propensity for social exploration was examined in the three-chamber apparatus, comparing time invested in social or non-social investigation. Administered intraperitoneally 30 min before testing, resveratrol (20 mg/kg) normalized the peripubertal stress-induced social investigation deficit seen in the vehicle group, selectively altering juvenile but not object exploration. Examination of prefrontal cortex subregion protein samples following acute resveratrol treatment in a separate cohort revealed that while monoamine oxidase A (MAOA) enzymatic activity remained unaltered, nuclear AKT activation was selectively increased in the infralimbic cortex, but not in the prelimbic or anterior cingulate cortex. In contrast, androgen receptor nuclear localization was increased in the prelimbic cortex, but not in the infralimbic or anterior cingulate cortex. This demonstration that social contact deficits are reversed by resveratrol administration emphasizes a prosocial role for this dietary phenol, and evokes the possibility of developing new treatments for social dysfunctions.

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Section: Discussionmentioning

confidence: 99%

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Poirier

Imamura

Zanoletti

et al. 2014

Journal of Psychiatric Research

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“…Androgenic action in the prostate is primarily mediated by dihydrotestosterone (DHT), which derives predominantly from the reduction of testicular testosterone but also adrenal dihydroepiandrosterone (DHEA) catalyzed by locally produced 5a-reductase enzymes (Wilson 1996, Mohler et al 2004. The cellular response to androgens is mediated via the AR, a ligand-inducible transcription factor that comprises a C-terminal ligand-binding domain (LBD), a highly conserved DNA-binding domain, a hinge region and N-terminal transactivation domain (Brinkmann 2011, Bennett et al 2012, Green et al 2012. Upon ligand binding, cytosolic AR undergoes conformational changes, including interaction of the N-and C-terminal domains and dissociation from heat shock proteins, enabling the AR to interact with coregulatory molecules such as ARA70 and importin-a, which facilitate nuclear translocation and dimerization ( Fig.…”

Section: The Armentioning

confidence: 99%

In vitro model systems to study androgen receptor signaling in prostate cancer

Sampson

Neuwirt

Puhr

et al. 2013

Endocrine-Related Cancer

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Prostate cancer (PCa) is one of the most common causes of male cancer-related death in Western nations. The cellular response to androgens is mediated via the androgen receptor (AR), a ligand-inducible transcription factor whose dysregulation plays a key role during PCa development and progression following androgen deprivation therapy, the current mainstay systemic treatment for advanced PCa. Thus, a better understanding of AR signaling and new strategies to abrogate AR activity are essential for improved therapeutic intervention. Consequently, a large number of experimental cell culture models have been established to facilitate in vitro investigations into the role of AR signaling in PCa development and progression. These different model systems mimic distinct stages of this heterogeneous disease and exhibit differences with respect to AR expression/status and androgen responsiveness. Technological advances have facilitated the development of in vitro systems that more closely reflect the physiological setting, for example via the use of three-dimensional coculture to study the interaction of prostate epithelial cells with the stroma, endothelium, immune system and tissue matrix environment. This review provides an overview of the most commonly used in vitro cell models currently available to study AR signaling with particular focus on their use in addressing key questions relating to the development and progression of PCa. It is hoped that the continued development of in vitro models will provide more biologically relevant platforms for mechanistic studies, drug discovery and design ensuring a more rapid transfer of knowledge from the laboratory to the clinic.

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“…This is in accordance with earlier studies reporting increased AR expression in endometrium of PCOS patients (Apparao et al 2002, Villavicencio et al 2006, as well as in ovaries in a rat PCOS model (Zurvarra et al 2009). It is known that AR signaling can be both genomic and nongenomic and may, in turn, activate other signaling pathways (Bennett et al 2010). Thus, it is tempting to suggest that an increased AR signaling may underlie the reduced endothelial function (i.e.…”

Section: Ros Inhibition and Enos Uncouplingmentioning

confidence: 99%

Analysis of the vascular responses in a murine model of polycystic ovary syndrome

Labruijere

Houten

Vries

et al. 2013

Journal of Endocrinology

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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of the reproductive age, but the exact pathophysiological mechanisms involved remain unclear. Cardiovascular disease risk is increased in PCOS patients and endothelial damage has been observed. We recently developed a mouse model of PCOS with reproductive and metabolic characteristics resembling those observed in women with PCOS. In this model we studied vascular function with particular emphasis on markers of vascular endothelial function. Animals were treated for 90 days with dihydrotestosterone (DHT; 27.5 mg/day) or placebo using subcutaneous continuous-release pellets. Aortas were isolated for isometric force recordings in organ baths to investigate endothelial and vascular smooth muscle characteristics. Lungs were used to analyze endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Asymmetric dimethylarginine (ADMA) levels were investigated in serum to assess endothelial damage. Expression of androgen receptor (Ar) mRNA was studied in aortas. DHT treatment (compared with placebo) induced i) a significant decrease in acetylcholine-induced aortic relaxations, with no change in calcitonin generelated peptide-or sodium nitroprusside-induced relaxations, as well as 5-hydroxytryptamine-induced contractions; ii) no change in eNOS expression/phosphorylation in lungs or in plasma ADMA levels; and iii) a twofold increase in aortic AR expression. Our results suggest that, in DHT-exposed mice, hyperandrogenemia specifically decreases endotheliumdependent vasorelaxation without deterioration of smooth muscle function. This study may initiate further investigations to elucidate underlying mechanism for the phenotype that is present in these animals, as well as in PCOS patients.

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Molecular cell biology of androgen receptor signalling

Cited by 239 publications

References 162 publications

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

In vitro model systems to study androgen receptor signaling in prostate cancer

Analysis of the vascular responses in a murine model of polycystic ovary syndrome

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