Estrogen Response Elements Alter Coactivator Recruitment through Allosteric Modulation of Estrogen Receptor β Conformation

Loven, Margaret A.; Likhite, Varsha S.; Choi, Inho; Nardulli, Ann M.

doi:10.1074/jbc.m106211200

Cited by 74 publications

(44 citation statements)

References 44 publications

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“…Evidence for intra-domain communication within the oestrogen receptor (ER) comes initially from the use of domain-specific antibodies (Traish & Pavao 1996), while altered protease sensitivity reveals altered receptor conformation on different oestrogen response elements (ERE) for both ER and ER (Wood et al 1998, Klinge et al 2001, Loven et al 2001a). In the case of ER bound to different EREs distinct patterns of recruitment of members of the p160 coactivator family were observed (Loven et al 2001b). With ER it was clear that coactivator binding stabilised interactions with DNA; however differences in coactivator recruitment were less obvious (Wood et al 2001).…”

Section: Discussionmentioning

confidence: 92%

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

Brodie¹,

McEwan

2005

Journal of Molecular Endocrinology

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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.

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Section: Discussionmentioning

confidence: 92%

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

Brodie¹,

McEwan

2005

Journal of Molecular Endocrinology

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“…Notably, PERC seems to prefer promoters with multiple sites, such as the dimerized EREs, or the C3 promoter that has at least three EREs (40). Different response elements may induce distinct nuclear receptor conformations and thereby influence either the recruitment of the coactivators or the activity of the recruited coactivators (45,46). An additional context that reveals differences in PERC and PGC-1 function is the ability of the two coactivators to promote the agonistic effect of the partial agonist tamoxifen.…”

Section: Perc and Pgc-1 Confer Distinct Functional Properties To Ligamentioning

confidence: 99%

The PGC-1-related Protein PERC Is a Selective Coactivator of Estrogen Receptor α

Kressler

Schreiber

Knutti

et al. 2002

Journal of Biological Chemistry

216

191

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Peroxisome proliferator-activated receptor ␥ coactivator-1 (PGC-1) is a tissue-specific coactivator that enhances the activity of many nuclear receptors and coordinates transcriptional programs important for energy metabolism. We describe here a novel PGC-1-related coactivator that is expressed in a similar tissue-specific manner as PGC-1, with the highest levels in heart and skeletal muscle. In contrast to PGC-1, the new coactivator shows high receptor specificity. It enhances potently the activity of estrogen receptor (ER) ␣, while having only small effects on other receptors. Because of its nuclear receptor selectivity, we have termed the new protein PERC (PGC-1 related Estrogen Receptor Coactivator). We show here that the coactivation function of PERC relies on a bipartite transcriptional activation domain and two LXXLL motifs that interact with the AF2 domain of ER␣ in an estrogen-dependent manner. PERC and PGC-1 are likely to have different functions in ER signaling. Whereas PERC acts selectively on ER␣ and not on the second estrogen receptor ER␤, PGC-1 coactivates strongly both ERs. Moreover, PERC and PGC-1 show distinct preferences for enhancing ER␣ in different promoter contexts. Finally, PERC enhances the ER␣-mediated response to the partial agonist tamoxifen, while PGC-1 modestly represses it. The two coactivators are likely to mediate distinct, tissue-specific responses to estrogens.Nuclear receptors are ligand-regulated transcription factors with a broad range of functions in development, physiology, and behavior. They include steroid hormone receptors for glucocorticoids, mineralocorticoids, progestins, estrogens, and androgens, as well as receptors for thyroid hormone, retinoids, vitamin D, and intermediary metabolites (1). They use a conserved DNA binding domain (DBD) 1 to interact with specific sites in the genome, termed hormone response elements (HREs). DNA-bound receptors can activate the expression of genes in the vicinity of HREs, via two transcriptional activation functions, denoted AF1 and AF2. AF1 lies in the N-terminal part of the receptors and varies significantly from one receptor to another. AF2 is located at the conserved ligand binding domain (LBD) and relies on an agonist ligand-induced protein conformation (2-5). Depending on cellular and promoter context, AF1 and AF2 act independently or synergistically to regulate gene expression. A large number of proteins that interact with the AF2 domain and enhance the activity of nuclear receptors have been identified (reviewed in Refs. 6 -8). They include the three members of the p160 steroid receptor coactivator (SRC) family (SRC-1/NcoA-1, TIF2/GRIP1/NcoA-2, AIB1/pCIP/ACTR/RAC3/ SRC-3), the cointegrators CBP and p300, components of the Mediator complex, individual coactivators such as PGC-1, NRIF3, ASC-2/RAP250, PELP1, and CAPER, and the family of CITED proteins (6 -12). Most of these coactivators harbor one or multiple LXXLL motifs (L being leucine and X any amino acid) within short amphipathic helices (13,14). These LXXLL motifs, als...

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“…These experiments combined with our GST-MPG pull-down studies indicate that ERE-containing DNA increases the interaction of ER␣ with MPG. We have previously demonstrated that DNA acts as an allosteric modulator of ER␣ conformation and thereby influences the interaction of the receptor with coregulatory proteins (5,25,27). Our current studies suggest that the interaction of the receptor with the ERE enhances the recruitment of MPG to estrogen-responsive genes.…”

mentioning

confidence: 57%

Interaction of Estrogen Receptor α with 3-Methyladenine DNA Glycosylase Modulates Transcription and DNA Repair

Likhite

Cass

Anderson

et al. 2004

Journal of Biological Chemistry

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Estrogen receptor ␣ (ER␣) interacts with basal transcription factors, coregulatory proteins, and chromatin modifiers to initiate transcription of the target genes. We have identified a novel interaction between ER␣ and the DNA repair protein 3-methyladenine DNA glycosylase (MPG) thereby providing a functional link between gene expression and DNA repair. Interestingly, the ER␣-MPG interaction was enhanced by the presence of estrogen response element (ERE)-containing DNA. In vitro pull-down assays indicated that the interaction of ER␣ with MPG was direct and occurred through the DNAand ligand-binding domains and the hinge region of the receptor. More importantly, endogenously expressed ER␣ and MPG from MCF-7 cells coimmunoprecipitated with ER␣-and MPG-specific antibodies. The ER␣-MPG interaction had functional consequences on the activities of both proteins. ER␣ increased MPG acetylation, stabilized the binding of MPG with hypoxanthine-containing oligos, and enhanced MPG-catalyzed removal of hypoxanthine from DNA. In turn, MPG dramatically stabilized the interaction of ER␣ with ERE-containing oligos, decreased p300-mediated acetylation of the receptor, and reduced transcription of simple and complex ERE-containing reporter plasmids in a dose-dependent manner. Our studies suggest that recruitment of MPG to ERE-containing genes influences transcription and plays a role in maintaining integrity of the genome by recruiting DNA repair proteins to actively transcribing DNA.Estrogen is critical for the growth, development, and homeostasis of neural, skeletal, cardiovascular, and reproductive tissues (1, 2). The actions of estrogen are mediated by two members of the nuclear receptor family, estrogen receptors (ERs) 1 ␣ and ␤. ER␣ is, however, generally a more potent transcriptional activator than ER␤ (3-5). Like other nuclear receptor family members, ER␣ has a modular structure. At the amino terminus is the A/B region with its autonomous activation function 1 (6). Region C encompasses the DNA binding domain and is linked by the hinge domain to region E, which contains the ligand-binding domain (LBD, Ref. 7). The DNAbinding domain has two zinc finger motifs that are involved in DNA binding. The LBD contains a hydrophobic pocket that interacts with estrogens and antiestrogens. The LBD also contains a ligand-dependent activation function 2, which is responsible for interaction of the receptor with coregulatory proteins (8 -10).ER␣ binds to estrogen response elements (EREs) in target genes to initiate changes in transcription. The consensus ERE is comprised of the palindromic sequence GGTCAnnnTGACC and is found in the Xenopus laevis vitellogenin A2 gene (11). In addition to interacting with EREs, ER␣ modulates transcription through its interaction with components of the basal transcription machinery, regulatory proteins, and chromatin modifiers (12). ER␣ interacts with proteins in the basal transcription complex including TATA-binding protein (13). The coregulatory proteins steroid receptor coactivator 1, transcription interm...

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Estrogen Response Elements Alter Coactivator Recruitment through Allosteric Modulation of Estrogen Receptor β Conformation

Cited by 74 publications

References 44 publications

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

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

The PGC-1-related Protein PERC Is a Selective Coactivator of Estrogen Receptor α

Interaction of Estrogen Receptor α with 3-Methyladenine DNA Glycosylase Modulates Transcription and DNA Repair

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