Androgen receptor coregulators: Recruitment via the coactivator binding groove

Wijngaart, Dennis J. van de; Dubbink, Hendrikus J.; Royen, Martin E. van; Trapman, Jan; Jenster, Guido

doi:10.1016/j.mce.2011.08.007

Cited by 103 publications

(77 citation statements)

References 164 publications

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“…Binding of an agonist results in the repositioning of helix 12 and creates a hydrophobic groove formed by helices 3, 4, 5, and 12. This site serves as a binding site for LXXLL-containing coactivators as well as for the amino-terminal domain of the AR (30,38,56).…”

mentioning

confidence: 99%

Evidence for DNA-Binding Domain–Ligand-Binding Domain Communications in the Androgen Receptor

Helsen

Dubois

Verfaillie

et al. 2012

Molecular and Cellular Biology

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DNA binding as well as ligand binding by nuclear receptors has been studied extensively. Both binding functions are attributed to isolated domains of which the structure is known. The crystal structure of a complete receptor in complex with its ligand and DNA-response element, however, has been solved only for the peroxisome proliferator-activated receptor ␥ (PPAR␥)-retinoid X receptor ␣ (RXR␣) heterodimer. This structure provided the first indication of direct interactions between the DNA-binding domain (DBD) and ligand-binding domain (LBD). In this study, we investigated whether there is a similar interface between the DNA-and ligand-binding domains for the androgen receptor (AR). Despite the structural differences between the AR-and PPAR␥-LBD, a combination of in silico modeling and docking pointed out a putative interface between AR-DBD and AR-LBD. The surfaces were subjected to a point mutation analysis, which was inspired by known AR mutations described in androgen insensitivity syndromes and prostate cancer. Surprisingly, AR-LBD mutations D695N, R710A, F754S, and P766A induced a decrease in DNA binding but left ligand binding unaffected, while the DBD-residing mutations K590A, K592A, and E621A lowered the ligand-binding but not the DNA-binding affinity. We therefore propose that these residues are involved in allosteric communications between the AR-DBD and AR-LBD. N uclear receptors (NRs) are involved in many physiological processes, diseases, and therapeutic applications. They are transcription factors that contain a DNA-binding domain (DBD) composed of 2 zinc fingers (40) and a ligand-binding domain (LBD) formed by 12 ␣ helices (60). The structures of the separate DNA-binding and ligand-binding domains of many receptors have already revealed a large amount of information. The structure of the LBD has especially led to a more focused search for new agonists and antagonists for many therapeutic indications where NRs are involved. The exact structure of full-size NRs bound to DNA and ligand will help us in understanding the basic mechanism of nuclear receptor signaling but will also provide new targets for therapeutic strategies. The coordinates of the peroxisome proliferator-activated receptor ␥ (PPAR␥)-retinoid X receptor ␣ (RXR␣) cocrystal bound as a heterodimer to the DNA have been reported (11) and revealed a contact between PPAR␥ and RXR␣ more intimate than expected. The existence of the previously unknown interface between PPAR␥-LBD and RXR␣-DBD was corroborated with a mutation analysis. Since this has not yet been confirmed by other techniques like small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) (49), it is debated whether such a communication exists. There is, however, strong evidence for allosteric communications, e.g., between the DBD and LBD, in nuclear receptors. A most remarkable observation was made for the glucocorticoid receptor (GR) when slightly different response elements were tested in gene reporter assays: small changes in the DNA sequence had an importa...

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confidence: 99%

Evidence for DNA-Binding Domain–Ligand-Binding Domain Communications in the Androgen Receptor

Helsen

Dubois

Verfaillie

et al. 2012

Molecular and Cellular Biology

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“…The (CAG)n and (GGN)n polymorphisms were involved in two specific symptoms (ie, scrotal discomfort and increased skin dryness); for other symptoms, only one of the two polymorphisms was involved, which is likely a reflection of the complex modulation of AR activity. 16,40 Our investigation using a precision medicine approach suggested genetic implications in symptoms of patients with PFS. Much more genetic and non-genetic research is necessary to elucidate the pathophysiologic pathways leading to the onset and persistence of adverse effects in former finasteride users.…”

Section: Resultsmentioning

confidence: 88%

“…16,40,41 The (CAG)n and (GGN)n polymorphisms also are likely to be in linkage disequilibrium with other polymorphic sites in the human genome, which in turn might determine the observed effects. 40 In line with observations made by other investigators, 39 the present findings suggest that the general belief associating long (CAG)n and (GGN)n repeats with a worse androgenic condition 18 should be taken with caution. 39 In general, investigations on the influence of AR polymorphisms on specific clinical features (ie, metabolic profile, bone density, and body composition) typically show very contradictory results.…”

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confidence: 99%

“…18,33 This could be due to the concomitant effect of AR-related genetic cofactors (apart from the two studied polymorphisms), which have not been fully explored thus far and which can exert an independent effect on clinical outcomes. 40,41 It should be noted at this point that the dimension of complexity of the regulation and activities of nuclear receptors is being realized, and that tissue-specific effects and epigenetic changes occurring in a single individual can modulate the action of receptors. 41,42 Therefore, many more investigations are needed to disclose the biological pathways relating molecular findings to phenotypes.…”

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confidence: 99%

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Androgen receptor (AR) gene (CAG)n and (GGN)n length polymorphisms and symptoms in young males with long-lasting adverse effects after finasteride use against androgenic alopecia

Chiriacò¹,

Cauci²,

Cecchin³

et al. 2017

European Urology Supplements

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“…Eventually, cancer becomes androgen-independent and resistant to corepressors [20]. NCoR1/SMRT bind to both agonist-and antagonist-bound ARs, which lessens the receptor's tumor-promoting ability [21,22]. Activated MAPK cascade may attenuate the corepressor recruitment [23].…”

Section: Ncor1/smrtmentioning

confidence: 99%

Targeting transcription factor corepressors in tumor cells

Vaiopoulos

Kostakis

Athanasoula

et al. 2012

Cell. Mol. Life Sci.

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By being the "integration" center of transcriptional control as they move and target transcription factors, corepressors fine-tune the epigenetic status of the nucleus. Many of them utilize enzymatic activities to modulate chromatin through histone modification or chromatin remodeling. The clinical and etiological relevance of the corepressors to neoplastic growth is increasingly being recognized. Aberrant expression or function (both loss and gain of) of corepressors has been associated with malignancy and contribute to the generation of transcriptional "inflexibility" manifested as distorted signaling along certain axes. Understanding and predicting the consequences of corepressor alterations in tumor cells has diagnostic and prognostic value, and also have the capacity to be targeted through selective epigenetic regimens. Here, we evaluate corepressors with the most promising therapeutic potential based on their physiological roles and involvement in malignant development, and also highlight areas that can be exploited for molecular targeting of a large proportion of clinical cancers and their complications.

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Androgen receptor coregulators: Recruitment via the coactivator binding groove

Cited by 103 publications

References 164 publications

Evidence for DNA-Binding Domain–Ligand-Binding Domain Communications in the Androgen Receptor

Evidence for DNA-Binding Domain–Ligand-Binding Domain Communications in the Androgen Receptor

Androgen receptor (AR) gene (CAG)n and (GGN)n length polymorphisms and symptoms in young males with long-lasting adverse effects after finasteride use against androgenic alopecia

Targeting transcription factor corepressors in tumor cells

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