help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Molecular Endocrinology, doi:10.1210/me.2008-0017
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Centenera, M. M.
Right arrow Articles by Butler, L. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Centenera, M. M.
Right arrow Articles by Butler, L. M.
Molecular Endocrinology 22 (11): 2373-2382
Copyright © 2008 by The Endocrine Society

Minireview

Minireview: The Contribution of Different Androgen Receptor Domains to Receptor Dimerization and Signaling

Margaret M. Centenera, Jonathan M. Harris, Wayne D. Tilley and Lisa M. Butler

Dame Roma Mitchell Cancer Research Laboratories (M.M.C., W.D.T., L.M.B.), Discipline of Medicine, The University of Adelaide and Hanson Institute, Adelaide, Discipline of Physiology (M.M.C.), School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5000, Australia; and Institute of Health and Biomedical Innovation (J.M.H.), Brisbane, Queensland 4059, Australia

Address all correspondence and requests for reprints to: Wayne D. Tilley, Ph.D., Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide and Hanson Institute, PO Box 14, Rundle Mall, Adelaide, South Australia 5000, Australia. E-mail: wayne.tilley{at}imvs.sa.gov.au.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 AR DIMERIZATION THROUGH THE...
 N/C INTERACTION
 LBD DIMERIZATION
 SUMMARY
 REFERENCES
 
The androgen receptor (AR) is a ligand-activated transcription factor of the nuclear receptor superfamily that plays a critical role in male physiology and pathology. Activated by binding of the native androgens testosterone and 5{alpha}-dihydrotestosterone, the AR regulates transcription of genes involved in the development and maintenance of male phenotype and male reproductive function as well as other tissues such as bone and muscle. Deregulation of AR signaling can cause a diverse range of clinical conditions, including the X-linked androgen insensitivity syndrome, a form of motor neuron disease known as Kennedy’s disease, and male infertility. In addition, there is now compelling evidence that the AR is involved in all stages of prostate tumorigenesis including initiation, progression, and treatment resistance. To better understand the role of AR signaling in the pathogenesis of these conditions, it is important to have a comprehensive understanding of the key determinants of AR structure and function. Binding of androgens to the AR induces receptor dimerization, facilitating DNA binding and the recruitment of cofactors and transcriptional machinery to regulate expression of target genes. Various models of dimerization have been described for the AR, the most well characterized interaction being DNA-binding domain- mediated dimerization, which is essential for the AR to bind DNA and regulate transcription. Additional AR interactions with potential to contribute to receptor dimerization include the intermolecular interaction between the AR amino terminal domain and ligand-binding domain known as the N-terminal/C-terminal interaction, and ligand-binding domain dimerization. In this review, we discuss each form of dimerization utilized by the AR to achieve transcriptional competence and highlight that dimerization through multiple domains is necessary for optimal AR signaling.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
AR DIMERIZATION THROUGH THE...
 N/C INTERACTION
 LBD DIMERIZATION
 SUMMARY
 REFERENCES
 
PROTEIN DIMERIZATION PLAYS an important role in the function of many proteins (1). For the nuclear receptor family of proteins, dimerization influences nuclear localization, cofactor binding, DNA binding, and transactivation potential (2, 3). The major subgroups of the nuclear receptor family are divided based on the nature of the dimers they form and their ligand- and DNA-binding specificity (4). Group I is composed of the steroid receptors including the androgen receptor (AR), estrogen receptor-{alpha} (ER{alpha}), estrogen receptor-β (ERβ), glucocorticoid receptor (GR), progesterone receptor (PR), and mineralocorticoid receptor (MR). Upon activation by steroid ligand, the steroid receptors bind DNA as homodimers to two hexameric half-sites of the consensus sequence 5'-TGTTCT-3', arranged as inverted repeats separated by three nucleotides (2). ER{alpha} and ERβ diverge slightly from the other steroid receptors in that they bind to an alternative consensus sequence, 5'-AGGTCA-3' (2). Group II nuclear receptors make up the remaining ligand-activated receptors, including thyroid hormone receptor, vitamin D receptor, and retinoid X receptor (RXR). These receptors form heterodimers and characteristically bind to half-sites composed of direct repeats. Group III and IV nuclear receptors are mostly made up of the orphan receptors, for which no ligand is known. Group III nuclear receptors typically bind as homodimers to response elements comprised of a direct repeat, whereas Group IV nuclear receptors typically bind DNA as monomers.

The AR is a modular protein organized into functional domains (5), consisting of an amino-terminal domain (NTD), a DNA-binding domain (DBD), a small hinge region (H), and a ligand-binding domain (LBD) (Fig. 1AGo). Upon androgen binding, the activated AR dissociates from its cytoplasmic chaperone complex and undergoes a conformational change inducing phosphorylation (6), nuclear translocation (7), and dimerization. It is only subsequent to these events that the AR dimer binds to androgen response elements (AREs) located in the regulatory regions of target genes (8), and actively recruits essential cofactors and assembles the transcriptional machinery required to regulate the expression of androgen-regulated genes (9, 10). A critical component of this signaling axis is the ability of the receptor to undergo dimerization.


Figure 1
View larger version (47K):
[in this window]
[in a new window]

  		Fig. 1. Structural Elements of the AR Involved in Dimerization and DNA Binding

A, Structure of the wild-type AR. The AR is a 917-amino acid protein divided into three broad functional domains; an NTD containing TAU-1 and -5 and the two motifs FxxLF and WxxLF, a DBD and an LBD containing AF-2. Located between the DBD and LBD is a small hinge region (H). B, Structure of the AR-DBD. The AR-DBD is comprised of two cysteine-rich zinc finger motifs and a CTE. The first zinc finger mediates DNA recognition through the P-box. The second zinc finger mediates DNA-dependent dimerization through the D-box along with the first 12 amino acids of the CTE. C, Amino acid sequence alignment of the steroid receptor DBDs. The sequence of the human AR-DBD was aligned with sequences of the other steroid receptors using AlignX, which aligns sequences according to the ClustalW algorithm (102 ). Amino acids that are conserved among most of the steroid receptors are shaded in blue, and amino acids conserved among all of the steroid receptors are shaded in yellow.

 
Three forms of protein dimerization have been described for the AR, including DNA-dependent dimerization mediated through the DBD, the androgen-induced N-terminal/C-terminal (N/C) interaction occurring between specific surfaces in the AR-NTD and AR-LBD, and LBD-LBD dimerization. In this review, we outline the various forms of dimerization that have been described for the AR and discuss how each interaction may contribute to optimal AR signaling.


   AR DIMERIZATION THROUGH THE DBD
TOP
 ABSTRACT
 INTRODUCTION
 AR DIMERIZATION THROUGH THE...
N/C INTERACTION
 LBD DIMERIZATION
 SUMMARY
 REFERENCES
 
Whereas steroids induce specific physiological responses, steroid receptors recognize and bind to related response elements of a common consensus sequence, posing the question of how steroid receptors acquire specific DNA binding (11, 12). A number of mechanisms have been suggested to contribute to steroid receptor specificity; these include the relative level of receptor and hormone within a cell (13, 14), receptor associations with chromatin (15, 16), interaction with other transcription factors (17, 18), receptor dimerization, and DNA target recognition (8, 19).

Upon binding DNA, the AR undergoes DNA- dependent dimerization mediated by its DBD (18, 20). The DBD of all nuclear receptors is a highly conserved region arranged into three {alpha}-helices containing two cysteine-rich zinc finger-like motifs and a C-terminal extension (CTE) (2) (Fig. 1BGo). Coordination of the zinc fingers is essential for structural integrity and function of the DBD (21). The first zinc finger contains a stretch of five amino acids called the P-box that directly interacts with the major groove of DNA, conferring responsibility for sequence recognition and DNA binding (22). Within the second zinc finger resides a five-amino acid region called the D-box, which contains the major residues involved in DNA-dependent dimerization between receptor monomers (20, 22). In addition to these primary motifs, interactions outside of the P- and D-boxes are involved in steroid receptor DNA binding and dimerization (23, 24, 25). In particular, residues in the CTE (amino acids 625–636) provide an additional dimer interface for the AR-DBD that acts in concert with amino acids in the second zinc finger to mediate specific and high-affinity DNA binding (25, 26, 27).

Role of the CTE in Dimerization and AR Specificity
There is considerable evidence supporting a role for the AR-CTE in dimerization and binding specificity of the AR. Whereas the core DBD of nuclear receptors is a highly conserved region, sequence homology is reduced within the CTE, resulting in unique residues that may potentiate specificity (Fig. 1CGo). The demonstration that the CTE is necessary for AR-specific DNA binding is unique among the steroid receptors, because structural studies of the ER- and GR-DBDs indicate that the CTE is not involved in DNA binding of those receptors (23, 28, 29, 30, 31). For members of the nuclear receptor family that form heterodimers, including RXR and TR, the CTE of the DBD forms a so-called T-box that provides an additional dimerization interface important in ligand specificity and dimer stability (32, 33, 34).

The Importance of Dimerization for DNA Binding
The established model for DBD-mediated dimerization is such that the first zinc finger of each AR monomer binds to one half-site of the ARE, whereas the second zinc finger binds to the partner monomer. The three nucleotides located between the half-sites play a key role in spatial orientation (28, 35). In this way, receptor monomers assemble on specific DNA targets to achieve cooperative dimerization necessary for DNA binding (19, 33, 36). Wong et al. (37) previously demonstrated that the AR does not bind to a single half-site consensus sequence, which is consistent with the above model of dimerization, and provides evidence that the AR preferentially binds DNA as a dimer. In contrast, recent genome-wide studies (chromatin immunoprecipitation-chip) have revealed that more than 50% of AR binding sites contain noncanonical AREs, including single ARE half-sites or half-sites separated by more than 3 bp (38, 39, 40). Whereas these findings suggest an increased diversity of mechanisms through which the AR binds DNA, the dimeric state of the AR on these elements is unknown, and further studies are required to determine the functional relevance of these noncanonical AR binding sites in AR signaling.

The consensus DNA sequence for steroid receptor binding is typically organized as an inverted repeat; however, the AR is unique in that it also binds to an additional set of response elements that are organized as direct repeats of the consensus sequence, known as specific AREs (41, 42, 43, 44). Subtle amino acid differences between the direct repeat and inverted repeat ARE prevent the remaining steroid receptors from binding to direct repeat elements, thus providing specificity for the AR (27, 45). Consequently, it was expected that the AR would bind parallel to the underlying DNA in a head-to-tail dimer arrangement, thus distinguishing the AR dimer from that of other steroid receptors. However, the resolved crystal structure of an AR-DBD dimer bound to DNA revealed that the AR-DBD binds direct repeat elements in the classic head-to-head arrangement, as seen for the inverted repeat element (35). This dimer formation results in one AR-DBD binding to its cognate half-site with high affinity and the partner DBD with low affinity, thereby reducing specific interactions with the target DNA. That the AR-DBD preferentially binds DNA in this formation despite reduced binding affinity highlights that the nature of the dimer formed is of critical importance for AR-specific DNA binding.

The importance of the DBD dimer interface is further highlighted by the frequency and phenotype of AR mutations identified in prostate cancer and androgen insensitivity syndrome (AIS). Figure 2Go shows the relative distribution of mutations over the DBD (see http://androgendb.mcgill.ca/). It is striking that mutations occur more frequently in residues forming the interface between AR-DBD monomers, with an average of 2.5 mutations per residue in the dimer interface compared with 0.76 mutations per residue for the remainder of the DBD.


Figure 2
View larger version (37K):
[in this window]
[in a new window]

  		Fig. 2. The AR-DBD Dimerization Interface

A, Lateral view of the AR-DBD dimer binding to a consensus ARE from a previously solved crystal structure [1I4R (35 )]. Monomer-A is depicted with a semitransparent molecular surface, whereas monomer-B is shown in ribbon form. Residues with mutations described in the McGill database of prostate cancer or androgen insensitivity (http://androgendb.mcgill.ca) are visible on monomer-B (other residues are omitted) and colored according to the number of described mutations ranging from one mutation described (purple) to 10 or more mutations (red). Those residues forming the dimer interface are shown in space-filling mode, whereas other residues are shown in stick form. B, Axial view of the complex with monomer-B removed. The molecular surface has been colored blue at contact points between receptors. Residues responsible for these contacts are shown in stick form and colored according to mutational frequency as above. DNA has been reduced to a double ribbon representing the phosphate backbone for the sake of clarity. Structures have been visualized using SPDBV V3.7 (103 ), and views have been ray traced using the program PovRay (www.povray.org).

 

   N/C INTERACTION
TOP
 ABSTRACT
 INTRODUCTION
 AR DIMERIZATION THROUGH THE...
 N/C INTERACTION
LBD DIMERIZATION
 SUMMARY
 REFERENCES
 
Another potential contributor to AR dimerization is the AR N/C interaction. The N/C interaction was first identified using the mammalian two-hybrid assay system as an androgen-dependent interaction between the AR-LBD and the AR-NTD that results in receptor stabilization (46). Subsequently, the N/C interaction has been extensively characterized by Wilson and co-workers (37, 47, 48, 49, 50, 51) and others (52) and is considered to be necessary for androgen-dependent activation of the AR in vivo. Upon androgen binding, the AR-LBD undergoes a conformational rearrangement that results in the formation of a highly conserved protein-protein interaction surface known as activation function 2 (AF-2) (53, 54). For most members of the steroid receptor family, the AF-2 surface in the LBD is the primary mediator of transcriptional activity through binding coregulatory proteins that contain LxxLL-like motifs (where x is any amino acid), such as members of the p160 cofactor family (9, 55). However, the AR differs in this regard, as the AR AF-2 domain has evolved such that it preferentially interacts with FxxLF-like motifs contained in the AR-NTD (23FQNLF27 and 433WHTLF437) over LxxLL-like motifs in coregulatory proteins (47, 49, 56). As a result, AR coregulator binding is conferred to transactivation unit 1 (TAU-1) and transactivation unit 5 (TAU-5) in the AR-NTD, thereby making the NTD the primary mediator of AR transcriptional activity (47, 49, 57, 58).

Models of N/C Interactions
Several models have been developed to describe the AR N/C interaction, and although each is unique, these models are not mutually exclusive. Moreover, it is likely that the cellular context determines the nature of the N/C interaction formed and the role it plays in AR signaling. The direct model of N/C interaction describes a ligand-dependent intermolecular interaction between AF-2 in the AR-LBD and 23FQNLF27 in the AR-NTD (49). AF-2 can also interact with 433WHTLF437 in the AR-NTD but with a much lower affinity than 23FQNLF27 (49). The contribution of 433WHTLF437 to the N/C interaction was initially thought to be stabilization of the receptor-ligand complex through additional interactions with the LBD independent of AF-2 (49). However the activity of 433WHTLF437 is independent of ligand (49), whereas the N/C interaction is ligand dependent; thus, the contribution of 433WHTLF437 to the N/C interaction remains unclear. Interestingly, recent studies show that 433WHTLF437 may influence AR signaling by acting as an autonomous activation domain (59).

FxxLF-like motifs are also present in a number of putative AR coregulators, including the AR-associated coactivators ARA70, ARA54, and ARA55 (60, 61). These coactivators bind to AF-2 in regions that are distinct from but overlapping with regions that bind to 23FQNLF27, which suggests that interactions with AF-2 must occur in a temporal sequence. Whereas formation of the N/C interaction typically precludes binding of LxxLL-containing coregulators with AF-2, modulation of the N/C interaction can influence the contribution of AF-2 to AR transcriptional activity. For example, the coregulators melanoma antigen gene protein 11 and cyclin D1 competitively bind to 23FQNLF27 in the NTD, thereby exposing AF-2 to p160 binding (62, 63, 64). In a similar way, increased cellular levels of p160 coactivators compete for AF-2 binding and increase AR transcriptional activity (60, 65), and somatic mutations in the AR can also increase AR activity by enhancing coregulator recruitment to AF-2 (66).

Whereas the AR N/C interaction has traditionally been investigated using partial proteins in the mammalian two-hybrid assay, recent innovative studies have used tagged full-length AR molecules to investigate the N/C interaction in live cells by fluorescence resonance energy transfer. Direct dimerization between the NTD and LBD of distinct AR molecules was observed in the nucleus of cells treated with ligand (67, 68). Furthermore, the N/C interaction was only observed until the AR bound DNA, at which time interactions with the coregulator ARA54 were significantly increased (68). These findings suggest that the N/C interaction may regulate AR interactions with coregulators by preventing access to the essential cofactor binding surfaces when not associated with DNA. In addition to the intermolecular N/C interaction, these fluorescence resonance energy transfer studies observed a conformational change within AR monomers occurring in the cytoplasm that brought the AR-LBD and -NTD into close proximity, described as an intramolecular N/C interaction (67).

The second model of AR N/C interaction is described as an indirect interaction facilitated by receptor cofactors that bridge the LBD and the NTD (bridging N/C). Early work by Ikonen et al. (69) described enhanced N/C interaction in the presence of some AR coactivators (cAMP-responsive element-binding protein) but not others (steroid receptor coactivator 1). More recent analysis of the role coactivators play in the N/C interaction reveal that the AR coactivator GR-interacting protein 1 (GRIP-1) enhances the N/C interaction 10-fold. Furthermore, GRIP-1 restores N/C interaction to an AR-NTD fragment in which the FxxLF motif is mutated to FxxAA. In the absence of GRIP-1, the mutated NTD fragment is unable to elicit an N/C interaction (70), thereby providing evidence for the indirect (bridging) model of N/C interaction. This finding is consistent with reports that the GRIP-1 binding surface(s) in the AR-NTD is located in TAU-5 and distinct from the FxxLF motif (71), which supports a critical role for TAU-5 in the indirect model of AR N/C interaction.

Functional Role for the N/C Interaction
The N/C interaction is only induced upon binding of classic AR agonists, which suggests that the N/C interaction is an essential feature of and may confer specific androgen action (51). Physiologically, the N/C interaction stabilizes the AR by slowing the rate of ligand dissociation and preventing receptor degradation (46, 58, 72, 73, 74). Whereas the N/C interaction may enhance AR activity by maintaining the receptor in an active state, in vitro studies have shown that the AR N/C interaction may not be an absolute requirement for AR signaling (48, 75) or may only be required for a subset of target genes (49, 76). However, a recent study by Li and co-workers (52) indicated that the N/C interaction is critical in vivo for activating chromatin-integrated AR target genes. In addition to facilitating chromatin binding, the authors found that the N/C interaction was required for the AR to recruit chromatin remodeling complexes and thereby directly modulating chromatin structure and transcription. The functional significance of the N/C interaction in AR signaling in vivo is further supported by studies of naturally occurring AR mutations that result in AIS. Inactivating mutations in AF-2 of the AR-LBD that disrupt the N/C interaction without affecting ligand binding affinity have been identified in AIS patients, indicating that N/C interaction is required for normal androgen signaling (77, 78, 79).


   LBD DIMERIZATION
TOP
 ABSTRACT
 INTRODUCTION
 AR DIMERIZATION THROUGH THE...
 N/C INTERACTION
 LBD DIMERIZATION
SUMMARY
 REFERENCES
 
LBD dimerization occurs before DNA binding and is thought to influence DNA-dependent dimerization by restricting DBD-mediated interactions only to those receptors that have already formed dimers through their LBD (2, 4, 80, 81, 82). For the nuclear receptors that bind DNA as heterodimers, LBD dimerization influences heterodimer formation mediating cooperative binding to DNA (82, 83). LBD dimerization has been described for all of the steroid receptors (80, 81, 84, 85, 86), and although the functional role of this interaction in steroid receptor signaling has not been fully elucidated, a correlation between the ability to form dimers in solution and the ability to bind DNA has been observed for both ER (81, 87) and PR (88). For the AR, a model of LBD dimerization is supported by the finding that the AR-DBD preferentially binds AREs as a head-to-head dimer (35). Furthermore, although LBD dimerization contradicts the antiparallel model of intermolecular AR N/C interaction (46), it does not exclude the formation of an intramolecular N/C interaction (67).

The LBD Dimer Interface
Although AR-LBD dimerization has been reported (86, 89), little is known about the specific motifs involved except that they are distinct from those of the N/C interaction, as shown by the E895Q mutation that inhibits the N/C interaction but does not affect LBD homodimerization (90). LBD-LBD dimerization domains have been resolved through crystallographic studies for the RXR, ER, PR, and GR. For ER and RXR dimers (81, 91, 92, 93), LBD dimerization occurs in a similar manner and through common motifs in helix 10 of these receptors. For the PR and GR this differs significantly (80, 84, 85, 94). The central GR dimer interface is composed of reciprocal interactions between residues P625 and I628, surrounded by an extensive network of hydrogen bonds between residues in helices 1, 3, and 5 (84). A functional role for this dimer interface is supported by reports that mutation of the P625 and I628 residues of the GR results in receptors that are defective in transactivation capacity compared with wild-type GR (84, 95). Superimposition of the reported AR-LBD (Protein Data Bank identification no. 1I37 in Ref. 54) with the GR-LBD dimer (1M2Z in Ref. 84) by structural and sequence alignment (Fig. 3Go) shows a high level of conservation of amino acids forming the interface between GR monomers with spatially equivalent residues in AR (Fig. 3Go) and mineralocorticoid receptor (data not shown). One of these residues is the critical P625, which is conserved among the steroid receptors and corresponds with amino acid P766 in the AR. Analysis of the AR gene mutations database (http://androgendb.mcgill.ca/) reveals that this residue has functional significance for the AR because mutation of the proline to either alanine (P766A) or serine (P766S) causes complete AIS (96, 97, 98, 99). Molecular studies in our laboratory (our unpublished data) have shown that the P766A mutation functions in a similar manner to the structurally equivalent GR mutant, P625A, which exhibits compromised transactivation capacity without reducing ligand binding (84). To date, the AR-LBD has only been crystallized as a monomer; however, these studies did not rule out the possibility that AR-LBDs may form dimers in vivo (53, 54). Future studies of AR-LBD dimerization are required to firmly establish this mode of interaction for the AR and its contribution to AR signaling.


Figure 3
View larger version (55K):
[in this window]
[in a new window]

  		Fig. 3. Homology Modeling of the AR-LBD with the GR-LBD Dimer

The reported GR-LBD dimer (1M2Z in Ref. 84 ) and reported AR-LBD (Protein Data Bank identification no. 1I37 in Ref. 54 ) were superimposed via structural and sequence alignment. The GR dimer is shown as a magenta ribbon with those side chains forming the dimer interface (residues <4 Å from the opposite monomer) depicted in stick form and colored blue. Superimposed AR is shown as a cyan ribbon. Aligned sequences for both LBDs in single-letter code show high levels of positional conservation. Identical side chains are denoted with an asterisk, whereas similar side chains are represented by points. Those residues forming the dimer interface are highlighted in cyan. Amino acids are numbered according to the GR sequence from Ref. 84 .

 

   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 AR DIMERIZATION THROUGH THE...
 N/C INTERACTION
 LBD DIMERIZATION
 SUMMARY
REFERENCES
 
Dimerization mediated through the AR-DBD is an absolute requirement for AR signaling. By assembling on DNA targets, the AR homodimer specifically binds DNA to regulate the expression of AR target genes. Developing antagonists of AR dimerization may be effective in inhibiting AR function and therefore provides an alternative strategy to conventional receptor antagonists that typically target ligand binding. Evidence to support this strategy has already been provided through studies that target the AR in prostate cancer cells using dominant-negative ARs (100, 101), which have been shown to act through the dimerization domains in the AR-DBD and -LBD (100). The N/C interaction is characteristic of agonist-induced AR activity and may occur as an intramolecular interaction and/or as a dimerization event between two AR monomers either directly or indirectly via mutual interactions with cofactors. Whereas the N/C interaction provides a potential mechanism for regulation of AR activity, further studies are necessary to determine the precise role and contribution of each model of AR N/C interaction to AR signaling. Finally, based on evidence that AR-LBD dimerization can occur, it is likely that this interaction also contributes to AR signaling. This review highlights that the formation of an AR homodimer is not necessarily a single molecular event mediated through the AR-DBD, and that interaction of multiple AR domains is required for optimal signaling. Moreover, the contribution of these AR domain interactions may occur in a temporal manner, the nature of which may vary depending on the cellular context.


   ACKNOWLEDGMENTS
 
We thank Dr. Eleanor Need for critical evaluation of the manuscript.


   FOOTNOTES
 
This work was supported by grants from the National Health and Medical Research Council of Australia (Grant 453662 to W.D.T. and L.M.B.) and the U.S. Department of Defense (Grant PCO60443 to W.D.T.). M.M.C. is the recipient of a University of Adelaide Postgraduate Award, and L.M.B. holds a senior research fellowship from the Cancer Council of South Australia.

Disclosure Statement: The authors have nothing to disclose.

First Published Online July 10, 2008

Abbreviations: AF-2, Activation function 2; AIS, androgen insensitivity syndrome; AR, androgen receptor; ARE, androgen response element; CTE, C-terminal extension; DBD, DNA-binding domain; ER, estrogen receptor; GR, glucocorticoid receptor; GRIP, GR-interacting protein; LBD, ligand-binding domain; MR, mineralocorticoid receptor; N/C interaction, N-terminal/C-terminal interaction; NTD, N-terminal domain; PR, progesterone receptor; RXR, retinoid X receptor; TAU, transactivation unit.

Received for publication January 15, 2008. Accepted for publication July 2, 2008.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 AR DIMERIZATION THROUGH THE...
 N/C INTERACTION
 LBD DIMERIZATION
 SUMMARY
 REFERENCES
 

  1. Jones S, Thornton JM 1995 Protein-protein interactions: a review of protein dimer structures. Prog Biophys Mol Biol 63:31–65[CrossRef][Medline]
  2. Glass CK 1994 Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev 15:391–407[Abstract/Free Full Text]
  3. Forman BM, Samuels HH 1990 Dimerization among nuclear hormone receptors. New Biol 2:587–594[Medline]
  4. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM 1995 The nuclear receptor superfamily: the second decade. Cell 83:835–839[CrossRef][Medline]
  5. Brinkmann AO, Faber PW, van Rooij HC, Kuiper GG, Ris C, Klaassen P, van der Korput JA, Voorhorst MM, van Laar JH, Mulder E, Trapman J 1989 The human androgen receptor: domain structure, genomic organization and regulation of expression. J Steroid Biochem 34:307–310[CrossRef][Medline]
  6. Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, White FM, Christian RE, Settlage RE, Shabanowitz J, Hunt DF, Weber MJ 2002 Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem 277:29304–29314[Abstract/Free Full Text]
  7. Marcelli M, Stenoien DL, Szafran AT, Simeoni S, Agoulnik IU, Weigel NL, Moran T, Mikic I, Price JH, Mancini MA 2006 Quantifying effects of ligands on androgen receptor nuclear translocation, intranuclear dynamics, and solubility. J Cell Biochem 98:770–788[CrossRef][Medline]
  8. Claessens F, Verrijdt G, Schoenmakers E, Haelens A, Peeters B, Verhoeven G, Rombauts W 2001 Selective DNA binding by the androgen receptor as a mechanism for hormone-specific gene regulation. J Steroid Biochem Mol Biol 76:23–30[CrossRef][Medline]
  9. Glass CK, Rosenfeld MG 2000 The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14:121–141[Free Full Text]
  10. Rosenfeld MG, Lunyak VV, Glass CK 2006 Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 20:1405–1428[Abstract/Free Full Text]
  11. Ham J, Thomson A, Needham M, Webb P, Parker M 1988 Characterization of response elements for androgens, glucocorticoids and progestins in mouse mammary tumour virus. Nucleic Acids Res 16:5263–5276[Abstract/Free Full Text]
  12. Beato M 1989 Gene regulation by steroid hormones. Cell 56:335–344[CrossRef][Medline]
  13. Cleutjens CB, Steketee K, van Eekelen CC, van der Korput JA, Brinkmann AO, Trapman J 1997 Both androgen receptor and glucocorticoid receptor are able to induce prostate-specific antigen expression, but differ in their growth-stimulating properties of LNCaP cells. Endocrinology 138:5293–5300[Abstract/Free Full Text]
  14. Funder JW 1993 Mineralocorticoids, glucocorticoids, receptors and response elements. Science 259:1132–1133[Free Full Text]
  15. Lambert JR, Nordeen SK 1998 Steroid-selective initiation of chromatin remodeling and transcriptional activation of the mouse mammary tumor virus promoter is controlled by the site of promoter integration. J Biol Chem 273:32708–32714[Abstract/Free Full Text]
  16. Beato M, Herrlich P, Schutz G 1995 Steroid hormone receptors: many actors in search of a plot. Cell 83:851–857[CrossRef][Medline]
  17. Adler AJ, Scheller A, Robins DM 1993 The stringency and magnitude of androgen-specific gene activation are combinatorial functions of receptor and nonreceptor binding site sequences. Mol Cell Biol 13:6326–6335[Abstract/Free Full Text]
  18. Truss M, Beato M 1993 Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocr Rev 14:459–479[Abstract/Free Full Text]
  19. Tsai SY, Carlstedt-Duke J, Weigel NL, Dahlman K, Gustafsson JA, Tsai MJ, O'Malley BW 1988 Molecular interactions of steroid hormone receptor with its enhancer element: evidence for receptor dimer formation. Cell 55:361–369[CrossRef][Medline]
  20. Dahlman-Wright K, Wright A, Gustafsson JA, Carlstedt-Duke J 1991 Interaction of the glucocorticoid receptor DNA-binding domain with DNA as a dimer is mediated by a short segment of five amino acids. J Biol Chem 266:3107–3112[Abstract/Free Full Text]
  21. Freedman LP, Luisi BF, Korszun ZR, Basavappa R, Sigler PB, Yamamoto KR 1988 The function and structure of the metal coordination sites within the glucocorticoid receptor DNA binding domain. Nature 334:543–546[CrossRef][Medline]
  22. Umesono K, Evans RM 1989 Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell 57:1139–1146[CrossRef][Medline]
  23. Remerowski ML, Kellenbach E, Boelens R, van der Marel GA, van Boom JH, Maler BA, Yamamoto KR, Kaptein R 1991 1H NMR studies of DNA recognition by the glucocorticoid receptor: complex of the DNA binding domain with a half-site response element. Biochemistry 30:11620–11624[CrossRef][Medline]
  24. Nazareth LV, Stenoien DL, Bingman III WE, James AJ, Wu C, Zhang Y, Edwards DP, Mancini M, Marcelli M, Lamb DJ, Weigel NL 1999 A C619Y mutation in the human androgen receptor causes inactivation and mislocalization of the receptor with concomitant sequestration of SRC-1 (steroid receptor coactivator 1). Mol Endocrinol 13:2065–2075[Abstract/Free Full Text]
  25. Schoenmakers E, Verrijdt G, Peeters B, Verhoeven G, Rombauts W, Claessens F 2000 Differences in DNA binding characteristics of the androgen and glucocorticoid receptors can determine hormone-specific responses. J Biol Chem 275:12290–12297[Abstract/Free Full Text]
  26. Schoenmakers E, Alen P, Verrijdt G, Peeters B, Verhoeven G, Rombauts W, Claessens F 1999 Differential DNA binding by the androgen and glucocorticoid receptors involves the second Zn-finger and a C-terminal extension of the DNA-binding domains. Biochem J 341:515–521[CrossRef][Medline]
  27. Haelens A, Verrijdt G, Callewaert L, Peeters B, Rombauts W, Claessens F 2001 Androgen-receptor-specific DNA binding to an element in the first exon of the human secretory component gene. Biochem J 353:611–620[CrossRef][Medline]
  28. Luisi BF, Xu WX, Otwinowski Z, Freedman LP, Yamamoto KR, Sigler PB 1991 Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature 352:497–505[CrossRef][Medline]
  29. Hard T, Kellenbach E, Boelens R, Maler BA, Dahlman K, Freedman LP, Carlstedt-Duke J, Yamamoto KR, Gustafsson JA, Kaptein R 1990 Solution structure of the glucocorticoid receptor DNA-binding domain. Science 249:157–160[Abstract/Free Full Text]
  30. Schwabe JW, Chapman L, Finch JT, Rhodes D 1993 The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements. Cell 75:567–578[CrossRef][Medline]
  31. Aumais JP, Lee HS, DeGannes C, Horsford J, White JH 1996 Function of directly repeated half-sites as response elements for steroid hormone receptors. J Biol Chem 271:12568–12577[Abstract/Free Full Text]
  32. Wilson TE, Paulsen RE, Padgett KA, Milbrandt J 1992 Participation of non-zinc finger residues in DNA binding by two nuclear orphan receptors. Science 256:107–110[Abstract/Free Full Text]
  33. Rastinejad F, Perlmann T, Evans RM, Sigler PB 1995 Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature 375:203–211[CrossRef][Medline]
  34. Lee MS, Kliewer SA, Provencal J, Wright PE, Evans RM 1993 Structure of the retinoid X receptor {alpha} DNA binding domain: a helix required for homodimeric DNA binding. Science 260:1117–1121[Abstract/Free Full Text]
  35. Shaffer PL, Jivan A, Dollins DE, Claessens F, Gewirth DT 2004 Structural basis of androgen receptor binding to selective androgen response elements. Proc Natl Acad Sci USA 101:4758–4763[Abstract/Free Full Text]
  36. Verrijdt G, Haelens A, Claessens F 2003 Selective DNA recognition by the androgen receptor as a mechanism for hormone-specific regulation of gene expression. Mol Genet Metab 78:175–185[CrossRef][Medline]
  37. Wong CI, Zhou ZX, Sar M, Wilson EM 1993 Steroid requirement for androgen receptor dimerization and DNA binding. Modulation by intramolecular interactions between the NH2-terminal and steroid-binding domains. J Biol Chem 268:19004–19012[Abstract/Free Full Text]
  38. Wang Q, Li W, Liu XS, Carroll JS, Janne OA, Keeton EK, Chinnaiyan AM, Pienta KJ, Brown M 2007 A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell 27:380–392[CrossRef][Medline]
  39. Massie CE, Adryan B, Barbosa-Morais NL, Lynch AG, Tran MG, Neal DE, Mills IG 2007 New androgen receptor genomic targets show an interaction with the ETS1 transcription factor. EMBO Rep 8:871–878[CrossRef][Medline]
  40. Bolton EC, So AY, Chaivorapol C, Haqq CM, Li H, Yamamoto KR 2007 Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21:2005–2017[Abstract/Free Full Text]
  41. Claessens F, Alen P, Devos A, Peeters B, Verhoeven G, Rombauts W 1996 The androgen-specific probasin response element 2 interacts differentially with androgen and glucocorticoid receptors. J Biol Chem 271:19013–19016[Abstract/Free Full Text]
  42. Rennie PS, Bruchovsky N, Leco KJ, Sheppard PC, McQueen SA, Cheng H, Snoek R, Hamel A, Bock ME, MacDonald BS 1993 Characterization of two cis-acting DNA elements involved in the androgen regulation of the probasin gene. Mol Endocrinol 7:23–36[Abstract/Free Full Text]
  43. Verrijdt G, Schoenmakers E, Alen P, Haelens A, Peeters B, Rombauts W, Claessens F 1999 Androgen specificity of a response unit upstream of the human secretory component gene is mediated by differential receptor binding to an essential androgen response element. Mol Endocrinol 13:1558–1570[Abstract/Free Full Text]
  44. Kasper S, Rennie PS, Bruchovsky N, Sheppard PC, Cheng H, Lin L, Shiu RP, Snoek R, Matusik RJ 1994 Cooperative binding of androgen receptors to two DNA sequences is required for androgen induction of the probasin gene. J Biol Chem 269:31763–31769[Abstract/Free Full Text]
  45. Haelens A, Verrijdt G, Callewaert L, Christiaens V, Schauwaers K, Peeters B, Rombauts W, Claessens F 2003 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. Biochem J 369:141–151[CrossRef][Medline]
  46. Langley E, Zhou ZX, Wilson EM 1995 Evidence for an anti-parallel orientation of the ligand-activated human androgen receptor dimer. J Biol Chem 270:29983–29990[Abstract/Free Full Text]
  47. He B, Gampe Jr RT, Kole AJ, Hnat AT, Stanley TB, An G, Stewart EL, Kalman RI, Minges JT, Wilson EM 2004 Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol Cell 16:425–438[CrossRef][Medline]
  48. He B, Kemppainen JA, Voegel JJ, Gronemeyer H, Wilson EM 1999 Activation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH2-terminal domain. J Biol Chem 274:37219–37225[Abstract/Free Full Text]
  49. He B, Kemppainen JA, Wilson EM 2000 FXXLF and WXXLF sequences mediate the NH2-terminal interaction with the ligand binding domain of the androgen receptor. J Biol Chem 275:22986–22994[Abstract/Free Full Text]
  50. He B, Wilson EM 2002 The NH2-terminal and carboxyl-terminal interaction in the human androgen receptor. Mol Genet Metab 75:293–298[CrossRef][Medline]
  51. Kemppainen JA, Langley E, Wong CI, Bobseine K, Kelce WR, Wilson EM 1999 Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone. Mol Endocrinol 13:440–454[Abstract/Free Full Text]
  52. Li J, Fu J, Toumazou C, Yoon HG, Wong J 2006 A role of the amino-terminal (N) and carboxyl-terminal (C) interaction in binding of androgen receptor to chromatin. Mol Endocrinol 20:776–785[Abstract/Free Full Text]
  53. Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S, Otto N, Joschko S, Scholz P, Wegg A, Basler S, Schafer M, Egner U, Carrondo MA 2000 Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. J Biol Chem 275:26164–26171[Abstract/Free Full Text]
  54. Sack JS, Kish KF, Wang C, Attar RM, Kiefer SE, An Y, Wu GY, Scheffler JE, Salvati ME, Krystek Jr SR, Weinmann R, Einspahr HM 2001 Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proc Natl Acad Sci USA 98:4904–4909[Abstract/Free Full Text]
  55. Heery DM, Kalkhoven E, Hoare S, Parker MG 1997 A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387:733–736[CrossRef][Medline]
  56. Hur E, Pfaff SJ, Payne ES, Gron H, Buehrer BM, Fletterick RJ 2004 Recognition and accommodation at the androgen receptor coactivator binding interface. PLoS Biol 2:E274
  57. Jenster G, van der Korput HA, Trapman J, Brinkmann AO 1995 Identification of two transcription activation units in the N-terminal domain of the human androgen receptor. J Biol Chem 270:7341–7346[Abstract/Free Full Text]
  58. He B, Bowen NT, Minges JT, Wilson EM 2001 Androgen-induced NH2- and COOH-terminal Interaction Inhibits p160 coactivator recruitment by activation function 2. J Biol Chem 276:42293–42301[Abstract/Free Full Text]
  59. Dehm SM, Regan KM, Schmidt LJ, Tindall DJ 2007 Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion independent prostate cancer cells. Cancer Res 67:10067–10077[Abstract/Free Full Text]
  60. He B, Minges JT, Lee LW, Wilson EM 2002 The FXXLF motif mediates androgen receptor-specific interactions with coregulators. J Biol Chem 277:10226–10235[Abstract/Free Full Text]
  61. Hsu CL, Chen YL, Yeh S, Ting HJ, Hu YC, Lin H, Wang X, Chang C 2003 The use of phage display technique for the isolation of androgen receptor interacting peptides with (F/W)XXL(F/W) and FXXLY new signature motifs. J Biol Chem 278:23691–23698[Abstract/Free Full Text]
  62. Burd CJ, Petre CE, Moghadam H, Wilson EM, Knudsen KE 2005 Cyclin D1 binding to the androgen receptor (AR) NH2-terminal domain inhibits activation function 2 association and reveals dual roles for AR corepression. Mol Endocrinol 19:607–620[Abstract/Free Full Text]
  63. Bai S, He B, Wilson EM 2005 Melanoma antigen gene protein MAGE-11 regulates androgen receptor function by modulating the interdomain interaction. Mol Cell Biol 25:1238–1257[Abstract/Free Full Text]
  64. Bai S, Grossman G, Yuan L, Lessey BA, French FS, Young SL, Wilson EM 2008 Hormone control and expression of androgen receptor coregulator MAGE-11 in human endometrium during the window of receptivity to embryo implantation. Mol Hum Reprod 14:107–116[Abstract/Free Full Text]
  65. Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS, Wilson EM 2001 A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61:4315–4319[Abstract/Free Full Text]
  66. He B, Gampe Jr RT, Hnat AT, Faggart JL, Minges JT, French FS, Wilson EM 2006 Probing the functional link between androgen receptor coactivator and ligand-binding sites in prostate cancer and androgen insensitivity. J Biol Chem 281:6648–6663[Abstract/Free Full Text]
  67. Schaufele F, Carbonell X, Guerbadot M, Borngraeber S, Chapman MS, Ma AA, Miner JN, Diamond MI 2005 The structural basis of androgen receptor activation: intramolecular and intermolecular amino-carboxy interactions. Proc Natl Acad Sci USA 102:9802–9807[Abstract/Free Full Text]
  68. van Royen ME, Cunha SM, Brink MC, Mattern KA, Nigg AL, Dubbink HJ, Verschure PJ, Trapman J, Houtsmuller AB 2007 Compartmentalization of androgen receptor protein-protein interactions in living cells. J Cell Biol 177:63–72[Abstract/Free Full Text]
  69. Ikonen T, Palvimo JJ, Janne OA 1997 Interaction between the amino- and carboxyl-terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators. J Biol Chem 272:29821–29828[Abstract/Free Full Text]
  70. Shen HC, Buchanan G, Butler LM, Prescott J, Henderson M, Tilley WD, Coetzee GA 2005 GRIP1 mediates the interaction between the amino- and carboxyl-termini of the androgen receptor. Biol Chem 386:69–74[CrossRef][Medline]
  71. Irvine RA, Ma H, Yu MC, Ross RK, Stallcup MR, Coetzee GA 2000 Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length. Hum Mol Genet 9:267–274[Abstract/Free Full Text]
  72. Langley E, Kemppainen JA, Wilson EM 1998 Intermolecular NH2-/carboxyl-terminal interactions in androgen receptor dimerization revealed by mutations that cause androgen insensitivity. J Biol Chem 273:92–101[Abstract/Free Full Text]
  73. Zhou ZX, Lane MV, Kemppainen JA, French FS, Wilson EM 1995 Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Mol Endocrinol 9:208–218[Abstract/Free Full Text]
  74. Dubbink HJ, Hersmus R, Verma CS, van der Korput HA, Berrevoets CA, van Tol J, Ziel-van der Made AC, Brinkmann AO, Pike AC, Trapman J 2004 Distinct recognition modes of FXXLF and LXXLL motifs by the androgen receptor. Mol Endocrinol 18:2132–2150[Abstract/Free Full Text]
  75. Buchanan G, Yang M, Cheong A, Harris JM, Irvine RA, Lambert PF, Moore NL, Raynor M, Neufing PJ, Coetzee GA, Tilley WD 2004 Structural and functional consequences of glutamine tract variation in the androgen receptor. Hum Mol Genet 13:1677–1692[Abstract/Free Full Text]
  76. Callewaert L, Verrijdt G, Christiaens V, Haelens A, Claessens F 2003 Dual function of an amino-terminal amphipatic helix in androgen receptor-mediated transactivation through specific and nonspecific response elements. J Biol Chem 278:8212–8218[Abstract/Free Full Text]
  77. Thompson J, Saatcioglu F, Janne OA, Palvimo JJ 2001 Disrupted amino- and carboxyl-terminal interactions of the androgen receptor are linked to androgen insensitivity. Mol Endocrinol 15:923–935[Abstract/Free Full Text]
  78. Ghali SA, Gottlieb B, Lumbroso R, Beitel LK, Elhaji Y, Wu J, Pinsky L, Trifiro MA 2003 The use of androgen receptor amino/carboxyl-terminal interaction assays to investigate androgen receptor gene mutations in subjects with varying degrees of androgen insensitivity. J Clin Endocrinol Metab 88:2185–2193[Abstract/Free Full Text]
  79. Jaaskelainen J, Deeb A, Schwabe JW, Mongan NP, Martin H, Hughes IA 2006 Human androgen receptor gene ligand-binding-domain mutations leading to disrupted interaction between the N- and C-terminal domains. J Mol Endocrinol 36:361–368[Abstract/Free Full Text]
  80. Savory JG, Prefontaine GG, Lamprecht C, Liao M, Walther RF, Lefebvre YA, Hache RJ 2001 Glucocorticoid receptor homodimers and glucocorticoid-mineralocorticoid receptor heterodimers form in the cytoplasm through alternative dimerization interfaces. Mol Cell Biol 21:781–793[Abstract/Free Full Text]
  81. Fawell SE, Lees JA, White R, Parker MG 1990 Characterization and colocalization of steroid binding and dimerization activities in the mouse estrogen receptor. Cell 60:953–962[CrossRef][Medline]
  82. Perlmann T, Umesono K, Rangarajan PN, Forman BM, Evans RM 1996 Two distinct dimerization interfaces differentially modulate target gene specificity of nuclear hormone receptors. Mol Endocrinol 10:958–966[Abstract/Free Full Text]
  83. Mangelsdorf DJ, Evans RM 1995 The RXR heterodimers and orphan receptors. Cell 83:841–850[CrossRef][Medline]
  84. Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE 2002 Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110:93–105[CrossRef][Medline]
  85. Williams SP, Sigler PB 1998 Atomic structure of progesterone complexed with its receptor. Nature 393:392–396[CrossRef][Medline]
  86. Nemoto T, Ohara-Nemoto Y, Shimazaki S, Ota M 1994 Dimerization characteristics of the DNA- and steroid-binding domains of the androgen receptor. J Steroid Biochem Mol Biol 50:225–233[CrossRef][Medline]
  87. Lees JA, Fawell SE, White R, Parker MG 1990 A 22-amino-acid peptide restores DNA-binding activity to dimerization-defective mutants of the estrogen receptor. Mol Cell Biol 10:5529–5531[Abstract/Free Full Text]
  88. DeMarzo AM, Beck CA, Onate SA, Edwards DP 1991 Dimerization of mammalian progesterone receptors occurs in the absence of DNA and is related to the release of the 90-kDa heat shock protein. Proc Natl Acad Sci USA 88:72–76[Abstract/Free Full Text]
  89. Doesburg P, Kuil CW, Berrevoets CA, Steketee K, Faber PW, Mulder E, Brinkmann AO, Trapman J 1997 Functional in vivo interaction between the amino-terminal, transactivation domain and the ligand binding domain of the androgen receptor. Biochemistry 36:1052–1064[CrossRef][Medline]
  90. Berrevoets CA, Doesburg P, Steketee K, Trapman J, Brinkmann AO 1998 Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2). Mol Endocrinol 12:1172–1183[Abstract/Free Full Text]
  91. Gampe RT, Jr., Montana VG, Lambert MH, Miller AB, Bledsoe RK, Milburn MV, Kliewer SA, Willson TM, Xu HE 2000 Asymmetry in the PPAR{gamma}/RXR{alpha} crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell 5:545–555[CrossRef][Medline]
  92. Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D 1995 Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-{alpha}. Nature 375:377–382[CrossRef][Medline]
  93. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist M 1997 Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758[CrossRef][Medline]
  94. Tanenbaum DM, Wang Y, Williams SP, Sigler PB 1998 Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains. Proc Natl Acad Sci USA 95:5998–6003[Abstract/Free Full Text]
  95. Caamano CA, Morano MI, Dalman FC, Pratt WB, Akil H 1998 A conserved proline in the hsp90 binding region of the glucocorticoid receptor is required for hsp90 heterocomplex stabilization and receptor signaling. J Biol Chem 273:20473–20480[Abstract/Free Full Text]
  96. Marcelli M, Zoppi S, Wilson CM, Griffin JE, McPhaul MJ 1994 Amino acid substitutions in the hormone-binding domain of the human androgen receptor alter the stability of the hormone receptor complex. J Clin Invest 94:1642–1650[CrossRef][Medline]
  97. Bouvattier C, Carel JC, Lecointre C, David A, Sultan C, Bertrand AM, Morel Y, Chaussain JL 2002 Postnatal changes of T, LH, and FSH in 46, XY infants with mutations in the AR gene. J Clin Endocrinol Metab 87:29–32[Abstract/Free Full Text]
  98. Boehmer AL, Brinkmann O, Bruggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MC, Niermeijer MF, Brunner HG, Rouwe CW, Waelkens JJ, Oostdijk W, Kleijer WJ, van der Kwast TH, de Vroede MA, Drop SL 2001 Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 86:4151–4160[Abstract/Free Full Text]
  99. Ahmed SF, Cheng A, Dovey L, Hawkins JR, Martin H, Rowland J, Shimura N, Tait AD, Hughes IA 2000 Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. J Clin Endocrinol Metab 85:658–665[Abstract/Free Full Text]
  100. Butler LM, Centenera MM, Neufing PJ, Buchanan G, Choong CS, Ricciardelli C, Saint K, Lee M, Ochnik A, Yang M, Brown MP, Tilley WD 2006 Suppression of androgen receptor signaling in prostate cancer cells by an inhibitory receptor variant. Mol Endocrinol 20:1009–1024[Abstract/Free Full Text]
  101. Ikonen T, Palvimo JJ, Janne OA 1998 Heterodimerization is mainly responsible for the dominant negative activity of amino-terminally truncated rat androgen receptor forms. FEBS Lett 430:393–396[CrossRef][Medline]
  102. Thompson JD, Higgins DG, Gibson TJ 1994 CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680[Abstract/Free Full Text]
  103. Guex N, Peitsch MC 1997 SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723[CrossRef][Medline]

NURSA Molecule Pages Link:

Nuclear Receptors:   AR
Coregulators:   SRC-1  |  GRIP1  |  AIB1
Ligands:   Dihydrotestosterone



This article has been cited by other articles:


Home page
 EndocrinologyHome page
P. Lim, M. Robson, J. Spaliviero, K. J. McTavish, M. Jimenez, J. D. Zajac, D. J. Handelsman, and C. M. Allan
Sertoli Cell Androgen Receptor DNA Binding Domain Is Essential for the Completion of Spermatogenesis
Endocrinology, October 1, 2009; 150(10): 4755 - 4765.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
J. Yang and M. J Young
The mineralocorticoid receptor and its coregulators
J. Mol. Endocrinol., August 1, 2009; 43(2): 53 - 64.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
K. E. Knudsen and H. I. Scher
Starving the Addiction: New Opportunities for Durable Suppression of AR Signaling in Prostate Cancer
Clin. Cancer Res., August 1, 2009; 15(15): 4792 - 4798.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Centenera, M. M.
Right arrow Articles by Butler, L. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Centenera, M. M.
Right arrow Articles by Butler, L. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals