Mechanisms of androgen receptor activation and function

Brinkmann, Albert O.; Blok, Leen J.; Ruiter, Petra E. de; Doesburg, Paul; Steketee, Karine; Berrevoets, Cor; Trapman, Jan

doi:10.1016/s0960-0760(99)00049-7

Cited by 268 publications

(182 citation statements)

References 30 publications

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“…These hormones function by activating the androgen receptor (AR), a member of the ligand-activated nuclear receptor superfamily of transcription factors (Brinkmann et al, 1999;Lu et al, 2006). The importance of AR in male development is shown by the androgen insensitivity syndromes characterized by mutations in the AR gene (Gottlieb et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells

et al. 2009

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Section: Introductionmentioning

confidence: 99%

Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells

et al. 2009

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“…After ligand binding, heat-shock proteins dissociate from the receptor, and then the AR translocates to the nucleus [3], where it regulates transcription by binding to specific androgen response elements in promoters of target genes. Together with co-regulatory proteins and general transcription factors, a stable transcription initiation complex is formed [4][5][6]. An important feature of ligand binding is that it induces a conformational change in the AR LBD (ligand-binding domain), providing a surface for interactions with co-regulatory proteins.…”

Section: Introductionmentioning

confidence: 99%

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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“…AR also plays a role in the pathogenesis of prostate cancer (PCa), including progression to the androgen-independent state and metastasis (2,3). Upon androgen binding, the AR undergoes conformational changes and translocates from the cytosol to the nucleus (4), where the receptor-hormone complex regulates the expression of target genes (5).…”

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confidence: 99%

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

Cinar

Mukhopadhyay

Meng

et al. 2007

Journal of Biological Chemistry

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The serine-threonine kinase, Akt1/protein kinase B␣ is an important mediator of growth, survival, and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft membranes as a potential site of intersection of androgenic and Akt1 signaling. A subpopulation of androgen receptor (AR) was found to localize to a lipid raft subcellular compartment in LNCaP prostate cancer cells. Endogenous AR interacted with endogenous Akt1 preferentially in lipid raft fractions and androgen substantially enhanced the interaction between the two proteins. The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K). Androgen promoted endogenous Akt1 activity in lipid raft fractions, in a PI3K-independent manner, within 10 min of treatment. Fusion of a lipid raft targeting sequence to AR enhanced localization of the receptor to rafts, and stimulated Akt1 activity in response to androgen, while reducing the cells' dependence on constitutive signaling through PI3K for cell survival. These findings suggest that signals channeled through AR and Akt1 intersect by a mechanism involving formation within lipid raft membranes of an androgen-responsive, extranuclear AR/Akt1 complex. Our results indicate that cholesterol-rich membrane microdomains play a role in transmitting nongenomic signals involving androgen and the Akt pathway in prostate cancer cells. Androgen receptor (AR),3 a member of the nuclear receptor superfamily of transcription factors, is an important regulator of reproductive physiology as a mediator of the biological activities of androgen (1). AR also plays a role in the pathogenesis of prostate cancer (PCa), including progression to the androgen-independent state and metastasis (2, 3). Upon androgen binding, the AR undergoes conformational changes and translocates from the cytosol to the nucleus (4), where the receptor-hormone complex regulates the expression of target genes (5).In addition to this well recognized genomic function, AR has been demonstrated to activate intracellular signaling pathways by a rapid (occurring in minutes) non-genomic process activated in response to hormonal stimulation (6, 7). The mechanisms underlying the non-canonical pathways involving the AR and other nuclear receptors are still poorly understood, however, possible nongenomic roles for the AR have been described (8 -12). For example, androgen promotes oocyte maturation, in both Xenopus (10) and mouse (12), by a transcription-independent mechanism that involves the classical AR (12,14). Another report showed that cells treated with 17␤-estradiol (E2) or androgen resulted in cell proliferation mediated by the rapid formation of a cytosolic signaling complex containing estrogen receptor-␣ or -␤ (ER␣ or ER␤ (depending on the cell type)), AR, and the non-receptor tyrosine kinase, Src (8). Similarly, Kousteni et al. (9) showed that ER␣, ER␤, or AR...

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Mechanisms of androgen receptor activation and function

Cited by 268 publications

References 30 publications

Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells

Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells

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

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

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