Functional Differences between the Amino-Terminal Domains of Estrogen Receptors α and β

Delaunay, Franck; Pettersson, Katarina; Tujague, Michel; Gustafsson, Jan‐Åke

doi:10.1124/mol.58.3.584

Cited by 139 publications

(124 citation statements)

References 35 publications

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“…However, when coactivation by ARNT was studied in context of the isolated LBDs of ER␣ and ER␤, there were no significant differences in the effect of ARNT on the two ER subtypes, indicating that ARNT may be more efficient in supporting synergy between AF-1 and AF-2 of ER␤, compared with ER␣. This is an interesting observation in view of several reports describing low or absent ER␤ AF-1 activity (12,26). Apparently, ER␤ AF-1 differs from ER␣ in the specificity of interaction with accessory factors, where classic coactivators of the p160 class apparently fail to sustain activity of ER␤ AF-1 in most systems tested.…”

Section: Discussionmentioning

confidence: 64%

“…Deletion of the AF-1 domain of ER␣ has a strong negative effect on ER␣ transcriptional activity; however, a similar deletion in ER␤ causes only a minor effect, suggesting clear functional differences between the AF-1 domains of ER␣ and ER␤ (12).…”

Section: The C-terminal Domain Of Arnt Is Required For Coactivation Omentioning

confidence: 99%

“…We verified these observations with mutant forms of ER␣ and ER␤ with deletions of the N-terminal A͞B domains, ER␣-⌬A͞B or ER␤-⌬A͞B, respectively. These receptor forms retain their ERE-binding ability and activate transcription in a liganddependent manner through the AF-2 region (12).…”

Section: The C-terminal Domain Of Arnt Is Required For Coactivation Omentioning

confidence: 99%

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The basic helix–loop–helix–PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription

Brunnberg

Pettersson

Rydin

et al. 2003

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

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The biological effects of estrogens are mediated by the estrogen receptors ER␣ and ER␤. These receptors regulate gene expression through binding to DNA enhancer elements and subsequently recruiting factors such as coactivators that modulate their transcriptional activity. Here we show that ARNT (aryl hydrocarbon receptor nuclear translocator), the obligatory heterodimerization partner for the aryl hydrocarbon receptor and hypoxia inducible factor 1␣, functions as a potent coactivator of ER␣-and ER␤-dependent transcription. The coactivating effect of ARNT depends on physical interaction with the ERs and involves the C-terminal domain of ARNT and not the structurally conserved basic helixloop-helix and PAS (Per-ARNT-Sim) motifs. Moreover, we show that ARNT͞ER interaction requires the E2-activated ligand binding domain of ER␣ or ER␤. These observations, together with the previous role of ARNT as an obligatory partner protein for conditionally regulated basic helix-loop-helix-PAS proteins like the aryl hydrocarbon receptor or hypoxia inducible factor 1␣, expand the cellular functions of ARNT to include regulation of ER␣ and ER␤ transcriptional activity. ARNT was furthermore recruited to a natural ER target gene promoter in a estrogen-dependent manner, supporting a physiological role for ARNT as an ER coactivator.cross-talk ͉ chromatin immunoprecipitation E strogens regulate important physiological processes, such as development and function of the male and female reproductive system and maintenance of bone mass in women, and represent a protective factor against cardiovascular disease (1). The physiological effects of estrogens are mediated by estrogen receptors ␣ (ER␣) and ␤ (ER␤), which belong to the nuclear receptor superfamily (1, 2). Nuclear receptors are liganddependent transcription factors characterized by a conserved structural arrangement composed of a centrally located DNA binding domain (DBD) containing two highly conserved Zn finger motifs. This domain is flanked in the N terminus by a variable A͞B region, which contains an activation function (AF-1). The ligand binding domain (LBD), located C-terminally of the DBD, contains a second AF (AF-2) and is also responsible for ligand binding, receptor dimerization, and cofactor interaction (3).The ERs are, in the absence of ligand, present in the nucleus in a nonactivated form. The latent ERs interact with corepressors such as N-Cor, SHP, or SMRT, which inhibit constitutive transcriptional activity (1). Binding of agonists induces release of repressor proteins and allows interaction with coactivators of the p160 class like SRC-1 or transcription intermediary factor 2 (TIF-2). These proteins have been shown to increase access to chromatin through acetylation of histones, mediate contact with general transcription factors, and enhance receptor AF-1͞AF-2 synergy (4, 5).Interestingly, p160 coactivators share considerable sequence homology to basic helix-loop-helix (bHLH)-PAS (Per-ARNTSim) transcription factors. This family also includes factors such as the aryl h...

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Section: Discussionmentioning

confidence: 64%

Section: The C-terminal Domain Of Arnt Is Required For Coactivation Omentioning

confidence: 99%

Section: The C-terminal Domain Of Arnt Is Required For Coactivation Omentioning

confidence: 99%

See 1 more Smart Citation

The basic helix–loop–helix–PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription

Brunnberg

Pettersson

Rydin

et al. 2003

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

Self Cite

126

112

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“…The greatest structural disparity between ERα and ERβ lies within the A/B domain which exhibits only 24% homology between the two receptors and is ∼90 nucleotides shorter in the ERβ as compared to ERβ [48] (Figure 1). This divergence likely accounts for the many functional differences that have been revealed from comparative studies of the two ER forms including coactivator interactions with A/B domain as well as ER-protein interactions, such as AP-1, which modify gene transcription through nonclassical pathways [49][50][51]. Notably, the AF-1 domain of ERβ is not constitutive and depends on ligand-activated AF-2 action whereas the ERα AF-1 can function independent of AF-2 and ligand.…”

Section: Estrogen Receptorsmentioning

confidence: 99%

The role of estrogens and estrogen receptors in normal prostate growth and disease

2008

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Keywordsprostate; prostate cancer; estrogens; estradiol; estrogen receptor Estrogens have significant direct and indirect effects on prostate gland development and homeostasis and have been long suspected in playing a role in the etiology of prostatic diseases. Direct effects are mediated through prostatic estrogen receptors alpha (ERα) and beta (ERβ) with expression levels changing over time and with disease progression. The present review examines the evidence for a role of estrogens and specific estrogen receptors in prostate growth, differentiation and disease states including prostatitis, benign prostatic hyperplasia (BPH) and cancer and discusses potential therapeutic strategies for growth regulation via these pathways. Estrogens in the Male and Effects on the Prostate GlandWhile low levels of circulating estrogens are present throughout life in males, there are two time periods, during in utero development and aging, when males are exposed to relatively higher levels of circulating estradiol which have been shown to impact the prostate gland. In addition, estrogens may be produced locally within the prostate via conversion of testosterone to 17β-estradiol by aromatase expressed within the prostate stroma [1,2], thus estrogen action in the prostate may occur independent of serum levels of this steroid.During the third trimester of in utero development in humans, rising maternal estradiol and declining fetal androgen production result in an elevated estrogen/testosterone (E/T) ratio. This relative increase in estradiol has been shown to directly stimulate extensive squamous metaplasia within the developing prostatic epithelium which regresses immediately after birth when estrogen levels rapidly decline [3,4]. Although the natural role for estrogens during prostatic development is unclear, it has been proposed that excessive estrogenization during prostatic development may contribute to the high incidence of BPH and prostatic carcinoma currently observed in the aging male population [5]. African-American men have a two-fold increased risk of prostatic carcinoma as compared to their Caucasian counterparts and it has been suggested that this is related, in part, to elevated levels of maternal estrogens during early gestation in this population [6,7]. Indicators of pregnancy estrogen levels such as length of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

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“…Isolation of Vinexin ␣-We used the AF-1 region of ER␤485 (6,42) as a bait in a screening of a rat brain cDNA library employing the Gal4-based yeast two hybrid system. We thus isolated a 1.5-kb cDNA fragment that showed high degrees of homology at the protein level with two human sequences named SCAM-1 (SH3-containing adaptor molecule-1) (GenBank TM accession number AF037261) and vinexin ␤ (17) and with the mouse sequence for vinexin ␣ (17) (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Focal Adhesion Protein Vinexin α Regulates the Phosphorylation and Activity of Estrogen Receptor α

Tujague

Thomsen

Mizuki

et al. 2004

Journal of Biological Chemistry

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Steroid receptors are transcription factors that regulate hormone-responsive genes and whose activity is controlled by their interaction with numerous other proteins. Observations reported here reveal that estrogen receptors ␣ and ␤ (ER␣ and ER␤), androgen receptor, and glucocorticoid receptor bind in vitro to vinexin ␣, a multiple SH3 motif-containing protein associated with the cytoskeleton. The SH3 domains are not involved in this interaction. Furthermore, we demonstrate that vinexin ␣ stimulates the ligand-induced transactivation function of these receptors, although it is devoid of intrinsic transcriptional activity when tethered to DNA. In addition, the ectopic coexpression of vinexin ␣ and ER␣ results in a loss of ER␣ phosphorylation on serines and the partial redistribution of vinexin ␣ into the nucleus, where it colocalizes with ER␣. These results establish a new model of transcriptional regulation where components of the cell-cell and cellsubstrate adhesion complexes can regulate the phosphorylation and activity of steroid receptors.Estrogen receptors (ERs) 1 are members of the nuclear receptor (NR) superfamily of transcription factors, which includes the closely related steroid receptors, receptors for thyroid hormone, retinoic acids, fatty acids and their metabolites, vitamin D, oxysterols, and a large number of proteins for which a natural ligand has yet to be identified (for review see Refs.

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Functional Differences between the Amino-Terminal Domains of Estrogen Receptors α and β

Cited by 139 publications

References 35 publications

The basic helix–loop–helix–PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription

The basic helix–loop–helix–PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription

The role of estrogens and estrogen receptors in normal prostate growth and disease

The Focal Adhesion Protein Vinexin α Regulates the Phosphorylation and Activity of Estrogen Receptor α

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