The Hinge Region as a Key Regulatory Element of Androgen Receptor Dimerization DNA Binding and Transactivation

2004 ◽  
Author(s):  
Frank A. Claessens
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Regulatory Element ◽  
Hinge Region ◽  
Receptor Dimerization

scholarly journals DNA recognition by the androgen receptor: evidence for an alternative DNA-dependent dimerization, and an active role of sequences flanking the response element on transactivation

2003 ◽  
Vol 369 (1) ◽  
pp. 141-151 ◽  
Author(s):  
Annemie HAELENS ◽  
Guy VERRIJDT ◽  
Leen CALLEWAERT ◽  
Valerie CHRISTIAENS ◽  
Kris SCHAUWAERS ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Steroid Receptors ◽  
Binding Domain ◽  
Hinge Region ◽  
General Mechanism ◽  
Affinity Binding ◽  
Dna Binding Domain ◽  
Direct Repeats ◽  
Response Element

The androgen receptor has a subset of target DNA sequences, which are not recognized by any other steroid receptors. The androgen selectivity of these sequences was proposed to be the consequence of the ability of the androgen receptor to dimerize on direct repeats of 5′-TGTTCT-3′-like sequences. This is in contrast with the classical non-selective elements consisting of inverted repeats of the 5′-TGTTCT-3′ elements separated by three nucleotides and which are recognized by other steroid receptors in addition to the androgen receptor. We demonstrate that while the DNA-binding domain of the oestrogen receptor is unable to dimerize on direct repeats, dimeric binding can be rescued by replacing the second Zn finger and part of the hinge region by the corresponding fragment of the androgen receptor, but not the glucocorticoid receptor. In this study, we investigate the androgen receptor binding to all natural androgen-selective response elements described so far. We show that a 12-amino acid C-terminal extension of the DNA-binding domain is required for high-affinity binding of the androgen receptor to all these elements. For one androgen-specific low-affinity binding site, the flanking sequences do not contribute to the invitro affinity of the androgen receptor DNA-binding domain. Surprisingly, however, they control the transcriptional activity of the androgen receptor in transient transfection experiments. In conclusion, we give evidence that the alternative DNA-dependent dimerization of the androgen receptor on direct repeats is a general mechanism for androgen specificity in which the second Zn finger and hinge region are involved. In addition, the sequences flanking an androgen-response element can control the activity of the androgen receptor.

scholarly journals Transcriptional Repression of the α-Subunit Gene by Androgen Receptor Occurs Independently of DNA Binding but Requires the DNA-Binding and Ligand-Binding Domains of the Receptor

1997 ◽  
Vol 11 (10) ◽  
pp. 1497-1506
Author(s):  
Leslie L. Heckert ◽  
Elizabeth M. Wilson ◽  
John H. Nilson
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Ligand Binding ◽  
Transcriptional Repression ◽  
Regulatory Element ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Subunit Gene ◽  
Α Subunit ◽  
Binding Domains

Abstract The pituitary glycoprotein hormones LH and FSH regulate the reproductive cycle and are sensitive to feedback by gonadal steroids. The common α-subunit shared by these hormones is transcriptionally repressed by androgen receptor (AR) in the presence of its ligand dihydrotestosterone. This identifies at least one mechanism that contributes to AR-dependent suppression of gonadotropin synthesis. Repression of α-subunit transcription by AR requires only the sequences within the first 480 bp of the promoter. While this region contains a high-affinity binding site for AR, this element does not mediate the suppressive effects of androgens. Instead, two other elements within the promoter-regulatory region (α-basal element and cAMP-regulatory element), which are important for expression of theα -subunit gene in gonadotropes, mediate the effects of AR. This suggests that AR inhibits activity of the α-subunit promoter by interfering with the transcriptional properties of the proteins that bind to α-basal element and the cAMP-regulatory elements. Furthermore, transfection analysis of various mutant ARs identified both the DNA-binding and ligand-binding domains of the receptor as critical for repression. Comparisons with the MMTV promoter revealed distinct structural requirements that underlie the transactivation and transrepression properties of AR.

scholarly journals The Hinge Region Regulates DNA Binding, Nuclear Translocation, and Transactivation of the Androgen Receptor

2007 ◽  
Vol 67 (9) ◽  
pp. 4514-4523 ◽  
Author(s):  
Annemie Haelens ◽  
Tamzin Tanner ◽  
Sarah Denayer ◽  
Leen Callewaert ◽  
Frank Claessens
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Nuclear Translocation ◽  
Hinge Region

Redox-Dependent DNA Binding of the Purified Androgen Receptor:  Evidence for Disulfide-Linked Androgen Receptor Dimers†

Biochemistry ◽  
1999 ◽  
Vol 38 (30) ◽  
pp. 9718-9727 ◽  
Author(s):  
Mingmin Liao ◽  
Zhong-xun Zhou ◽  
Elizabeth M. Wilson
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Receptor Dimers

scholarly journals Intra-domain communication between the N-terminal and DNA-binding domains of the androgen receptor: modulation of androgen response element DNA binding

2005 ◽  
Vol 34 (3) ◽  
pp. 603-615 ◽  
Author(s):  
Jacqueline Brodie ◽  
Iain J McEwan
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Fluorescence Emission ◽  
Progesterone Receptors ◽  
Fluorescence Emission Spectrum ◽  
Response Element ◽  
Amino Terminal ◽  
Binding Domains ◽  
Receptor Modulation

The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone. In vitro, two types of response element have been characterised - non-selective elements that bind the androgen, glucocorticoid and progesterone receptors, and androgen receptor-selective sequences. In the present study, the allosteric effects of DNA binding on the receptor amino-terminal domain (NTD) were studied. Binding to both types of DNA response element resulted in changes in the intrinsic fluorescence emission spectrum for four tryptophan residues within the AR-NTD and resulted in a more protease-resistant conformation. In binding experiments, it was observed that the presence of the AR-NTD reduced the affinity of receptor polypeptides for binding to both selective and non-selective DNA elements derived from the probasin, PEM and prostatin C3 genes respectively, without significantly altering the protein–base pair contacts. Taken together, these results highlight the role of intra-domain communications between the AR-NTD and the DNA binding domain in receptor structure and function.

Response to Treatment in Patients with Partial Androgen Insensitivity due to Mutations in the DNA-Binding Domain of the Androgen Receptor

2000 ◽  
Vol 53 (2) ◽  
pp. 83-88 ◽  
Author(s):  
Yvonne Lundberg Giwercman ◽  
Andrej Nikoshkov ◽  
Kristina Lindsten ◽  
Birgitta Byström ◽  
Åke Pousette ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Binding Domain ◽  
Response To Treatment ◽  
Dna Binding Domain ◽  
Androgen Insensitivity

Comparative analysis of the influence of the high-mobility group box 1 protein on DNA binding and transcriptional activation by the androgen, glucocorticoid, progesterone and mineralocorticoid receptors

2001 ◽  
Vol 361 (1) ◽  
pp. 97-103 ◽  
Author(s):  
Guy VERRIJDT ◽  
Annemie HAELENS ◽  
Erik SCHOENMAKERS ◽  
Wilfried ROMBAUTS ◽  
Frank CLAESSENS
Keyword(s):  
Androgen Receptor ◽  
Comparative Analysis ◽  
Dna Binding ◽  
Mineralocorticoid Receptor ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
High Mobility ◽  
Steroid Hormone Receptors ◽  
High Mobility Group ◽  
Mineralocorticoid Receptors

We performed a comparative analysis of the effect of high-mobility group box protein 1 (HMGB1) on DNA binding by the DNA-binding domains (DBDs) of the androgen, glucocorticoid, progesterone and mineralocorticoid receptors. The affinity of the DBDs of the different receptors for the tyrosine aminotransferase glucocorticoid response element, a classical high-affinity binding element, was augmented up to 7-fold by HMGB1. We found no major differences in the effects of HMGB1 on DNA binding between the different steroid hormone receptors. In transient transfection assays, however, HMGB1 significantly enhances the activity of the glucocorticoid and progesterone receptors but not the androgen or mineralocorticoid receptor. We also investigated the effect of HMGB1 on the binding of the androgen receptor DBD to a subclass of directly repeated response elements that is recognized exclusively by the androgen receptor and not by the glucocorticoid, progesterone or mineralocorticoid receptor. Surprisingly, a deletion of 26 amino acid residues from the C-terminal extension of the androgen receptor DBD does not influence DNA binding but destroys its sensitivity to HMGB1. Deletion of the corresponding fragment in the DBDs of the glucocorticoid, progesterone and mineralocorticoid receptor destroyed their DNA binding. This 26-residue fragment is therefore essential for the influence of HMGB1 on DNA recognition by all steroid hormone receptors that were tested. However, it is dispensable for DNA binding by the androgen receptor.

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