Determinants of DNA Sequence Specificity of the Androgen, Progesterone, and Glucocorticoid Receptors: Evidence for Differential Steroid Receptor Response Elements

Nelson, Colleen C.; Hendy, Stephen C.; Shukin, Robert; Cheng, Helen; Bruchovsky, Nicholas; Koop, Ben F.; Rennie, Paul S.

doi:10.1210/mend.13.12.0396

Cited by 146 publications

(36 citation statements)

References 78 publications

(121 reference statements)

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“…1c, bars 8 and 9). The observed binding of GR to the palindromic and consensus GRE elements correlates with the measured affinity of GR for these sites (32,33).…”

Section: High Affinity Binding Of Gr From Nuclear Extracts As Measurementioning

confidence: 80%

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Accessory Factors Facilitate the Binding of Glucocorticoid Receptor to the Phosphoenolpyruvate Carboxykinase Gene Promoter

Stafford¹,

Wilkinson²,

Beechem³

et al. 2001

Journal of Biological Chemistry

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Glucocorticoid induction of the phosphoenolpyruvate carboxykinase (PEPCK) gene requires a glucocorticoid response unit (GRU) comprised of two non-consensus glucocorticoid receptor (GR) binding sites, GR1 and GR2, and at least three accessory factor elements (gAF1-3). DNA-binding accessory proteins are commonly required for the regulation of genes whose products play an important role in metabolism, development, and a variety of defense responses, but little is known about why they are necessary. Quantitative, real time homogenous assays of cooperative protein-DNA interactions in complex media (e.g. nuclear extracts) have not previously been reported. Here we perform quantitative, real time equilibrium and stopped-flow fluorescence anisotropy measurements of protein-DNA interactions in nuclear extracts to demonstrate that GR binds to the GR1-GR2 elements poorly as compared with a palindromic or consensus glucocorticoid response element (GRE). Inclusion of either the gAF1 or gAF2 element with GR1-GR2, however, creates a high affinity binding environment for GR. GR can undergo multiple rounds of binding and dissociation to the palindromic GRE in less than 100 ms at nanomolar concentrations. The dissociation rate of GR is differentially slowed by the gAF1 or gAF2 elements that bind two functionally distinct accessory factors, COUP-TF/HNF4 and HNF3, respectively.

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“…1c, bars 8 and 9). The observed binding of GR to the palindromic and consensus GRE elements correlates with the measured affinity of GR for these sites (32,33).…”

Section: High Affinity Binding Of Gr From Nuclear Extracts As Measurementioning

confidence: 80%

“…The observed binding of GR from the nuclear extract is not restricted to the palindromic GRE. A consensus GRE with flanking sequences that maximize affinity for GR (26,32) binds GR with a K d of 1.6 nM GR (Fig. 1c, bars 5 and 6, and Fig.…”

Section: High Affinity Binding Of Gr From Nuclear Extracts As Measurementioning

confidence: 99%

Accessory Factors Facilitate the Binding of Glucocorticoid Receptor to the Phosphoenolpyruvate Carboxykinase Gene Promoter

Stafford¹,

Wilkinson²,

Beechem³

et al. 2001

Journal of Biological Chemistry

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“…This serendipitous match to the consensus IR3 half-site allows Lys-563 [22] and Arg-568 [27] of protomer B to recapitulate the hydrogen bonds to the GC base pairs at positions 2 and 5 of the hexameric half-site, as seen in the upstream element. These two ''hooks'' are common elements that position the recognition helix within the major groove of the hexameric half-site (36).…”

Section: Resultsmentioning

confidence: 99%

Structural basis of androgen receptor binding to selective androgen response elements

Shaffer

Jivan

Dollins

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

335

336

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Steroid receptors bind as dimers to a degenerate set of response elements containing inverted repeats of a hexameric half-site separated by 3 bp of spacer (IR3). Naturally occurring selective androgen response elements have recently been identified that resemble direct repeats of the hexameric half-site (ADR3). The 3D crystal structure of the androgen receptor (AR) DNA-binding domain bound to a selective ADR3 reveals an unexpected head-tohead arrangement of the two protomers rather than the expected head-to-tail arrangement seen in nuclear receptors bound to response elements of similar geometry. Compared with the glucocorticoid receptor, the DNA-binding domain dimer interface of the AR has additional interactions that stabilize the AR dimer and increase the affinity for nonconsensus response elements. This increased interfacial stability compared with the other steroid receptors may account for the selective binding of AR to ADR3 response elements.T he androgen receptor (AR) is a ligand-activated transcription factor that plays a central role in male sexual development and in the etiology of prostate cancer (1, 2). It is a member of the steroid and nuclear hormone receptor superfamily, which also includes receptors for glucocorticoids (GR), mineralocorticoids (MR), progesterone (PR), estrogens (ER), and vitamin D (VDR) (3). Members of this family contain conserved, discrete, DNA-binding domains (DBDs) and ligand-binding domains. The amino-terminal domain and the hinge region connecting the central DBD to the C-terminal ligand-binding domain diverge among family members.The hormone receptor DBD consists of a highly conserved 66-residue core made up of two zinc-nucleated modules, shown schematically in Fig. 1 A (4, 5). With VDR as the only reported exception (6), the isolated DBD and associated C-terminal extension are necessary and sufficient to generate the same pattern of DNA response element selectivity, partner selection, and dimerization as the full-length receptor from which it is derived (6-11).Although ligand binding elicits distinct hormone-specific responses, all classical steroid receptors (AR, PR, MR, and GR) recognize identical DNA response elements, which consist of two hexameric half-sites (5Ј-AGAACA-3Ј) arranged as inverted repeats with 3 bp of separating DNA, producing the 2-fold IR3 sequence pattern (Fig. 1B) (12). A question that continues to engage the steroid receptor field is how these transcription factors achieve DNA target specificity despite this degeneracy. As seen in the structures of the GR and ER DBDs bound to IR3 elements (4, 13), the receptors bind as ''head-to-head'' homodimers whose symmetric displacement across the DNA pseudodyad reflects the underlying half-site arrangement. Differences in steroid metabolism, receptor expression, local chromatin structure, and the availability of cofactors all contribute to steroid-specific responses (14-17). However, recent work has now also identified selective androgen response elements (AREs). The AREs consist of two hexameric half-sites a...

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“…These elements are comprised of a palindrome that contains two half-sites based on the 5Ј-TGTTCT-3Ј motif that are separated by a three nucleotide spacer (6). Detailed analysis has demonstrated that both GR and AR bind with highest affinity to a steroid response element that has an imperfect palindrome, 5Ј-GGTACAnnnTGTTCT-3Ј (7). The quandary is that although activated steroid receptors bind to highly homologous response elements on DNA, they still demonstrate an ability to regulate the expression of unique gene sets.…”

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confidence: 99%

RanBPM, a Nuclear Protein That Interacts with and Regulates Transcriptional Activity of Androgen Receptor and Glucocorticoid Receptor

Rao¹,

Cheng²,

Quayle³

et al. 2002

Journal of Biological Chemistry

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The androgen receptor (AR) is a ligand-dependent transcription factor that has an essential role in the normal growth, development, and maintenance of the prostate gland. The AR is part of a large family of steroid receptors that also includes the glucocorticoid, progesterone, and mineralocorticoid receptors. Steroid receptor family members share significant homology at their DNA and ligand-binding domains. However, these receptors exhibit a high degree of sequence variability at their NH 2 -terminal domain, which suggests the possibility of receptor-specific interactions with co-regulator proteins. Transcriptional co-regulators that interact with the AR may have a role in defining AR activity and may be involved in directing AR-specific responses. Here we have identified Ran-binding protein in the microtubule-organizing center (RanBPM) to be a novel AR-interacting protein by yeast two-hybrid assay and have confirmed this interaction by glutathione S-transferase-and His-tagged pull-down assays. In addition, transient overexpression of RanBPM in prostate cancer cell lines resulted in enhanced AR activity in a liganddependent fashion. Glucocorticoid receptor activity was also enhanced when RanBPM was overexpressed, whereas estrogen receptor activity remained unchanged. These data demonstrate that RanBPM interacts with steroid receptors to selectively modify their activity. The androgen receptor (AR)1 is a ligand-dependent transcription factor that belongs to a family of steroid receptors along with the glucocorticoid (GR), progesterone, and mineralocorticoid receptors. These steroid receptors share similar domain structures and mechanism of action. Steroid receptors including the AR have three functional domains: a COOHterminal ligand-binding domain (LBD), a central DNA-binding domain (DBD), and an NH 2 -terminal domain (1). In the absence of androgens, the AR is localized to the cytoplasm in an inactive complex that includes heat shock proteins (HSP). Upon binding to its cognate ligand, the AR undergoes a conformational change that results in a more compact and stable form of the AR. The activated AR dissociates from HSPs and translocates to the nucleus where it interacts with consensus DNA sequences as a homodimer to influence transcription of downstream genes (2). The estrogen receptor (ER) belongs to a different steroid receptor subfamily because it resides predominantly in the nucleus, even in its unliganded form, and does not require translocation across the nuclear membrane following activation (3). There are two major transactivation regions in the AR. 1) The activation function-1 (AF-1) domain is found at the NH 2 terminus. 2) AF-2 is located in the LBD. AF-2 is a weak transactivator that is dependent on the presence of androgens for its activation. AF-1, on the other hand, is capable of ligand-independent transactivation, and fragments of the AR that contain AF-1 show high levels of transcriptional activity when ectopically expressed in cell lines that are devoid of endogenous AR (4, 5).Upon DNA binding,...

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Determinants of DNA Sequence Specificity of the Androgen, Progesterone, and Glucocorticoid Receptors: Evidence for Differential Steroid Receptor Response Elements

Cited by 146 publications

References 78 publications

Accessory Factors Facilitate the Binding of Glucocorticoid Receptor to the Phosphoenolpyruvate Carboxykinase Gene Promoter

Accessory Factors Facilitate the Binding of Glucocorticoid Receptor to the Phosphoenolpyruvate Carboxykinase Gene Promoter

Structural basis of androgen receptor binding to selective androgen response elements

RanBPM, a Nuclear Protein That Interacts with and Regulates Transcriptional Activity of Androgen Receptor and Glucocorticoid Receptor

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