N-Terminal Activation Function Is Dominant in Ligand-Dependent Transactivation of Medaka Estrogen Receptor α in Human Cells

2001 ◽  
Vol 289 (3) ◽  
pp. 763-768 ◽  
Author(s):  
Yoshihiro Mezaki ◽  
Tasuku Yoshida ◽  
Junn Yanagisawa ◽  
Shigeaki Kato
Keyword(s):  
Estrogen Receptor ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Human Cells

scholarly journals Rapid Estrogen-Induced Phosphorylation of the SRC-3 Coactivator Occurs in an Extranuclear Complex Containing Estrogen Receptor

2005 ◽  
Vol 25 (18) ◽  
pp. 8273-8284 ◽  
Author(s):  
Fuzhong F. Zheng ◽  
Ray-Chang Wu ◽  
Carolyn L. Smith ◽  
Bert W. O'Malley
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Direct Interaction ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Phosphorylation Sites ◽  
Binding Domains ◽  
Nongenomic Action ◽  
Binding Groove

ABSTRACT SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM1 is a primary transcriptional coregulator for estrogen receptor (ER). Six SRC-3 phosphorylation sites have been identified, and these can be induced by steroids, cytokines, and growth factors, involving multiple kinase signaling pathways. Using phosphospecific antibodies for six phosphorylation sites, we investigated the mechanisms involved in estradiol (E2)-induced SRC-3 phosphorylation and found that this occurs only when either activated estrogen receptor α (ERα) or activated ERβ is present. Both the activation function 1 and the ligand binding domains of ERα are required for maximal induction. Mutations in the coactivator binding groove of the ERα ligand binding domain inhibit E2-stimulated SRC-3 phosphorylation, as do mutations in the nuclear receptor-interacting domain of SRC-3, suggesting that ERα must directly contact SRC-3 for this posttranslational modification to take place. A transcriptionally inactive ERα mutant which localizes to the cytoplasm supports E2-induced SRC-3 phosphorylation. Mutations of the ERα DNA binding domain did not block this rapid E2-dependent SRC-3 phosphorylation. Together these data demonstrate that E2-induced SRC-3 phosphorylation is dependent on a direct interaction between SRC-3 and ERα and can occur outside of the nucleus. Our results provide evidence for an early nongenomic action of ER on SRC-3 that supports the well-established downstream genomic roles of estrogen and coactivators.

scholarly journals The Human Estrogen Receptor-α Isoform hERα46 Antagonizes the Proliferative Influence of hERα66 in MCF7 Breast Cancer Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5474-5484 ◽  
Author(s):  
Graziella Penot ◽  
Christine Le Péron ◽  
Yohann Mérot ◽  
Eva Grimaud-Fanouillère ◽  
François Ferrière ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cell Growth ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Breast Cancer Cell Lines ◽  
Mcf7 Cells ◽  
Exact Function ◽  
Human Estrogen Receptor

The expression of two human estrogen receptor-α (hERα) isoforms has been characterized within estrogen receptor-α-positive breast cancer cell lines such as MCF7: the full-length hERα66 and the N terminally deleted hERα46, which is devoid of activation function (AF)-1. Although hERα66 is known to mediate the mitogenic effects that estrogens have on MCF7 cells, the exact function of hERα46 in these cells remains undefined. Here we show that, during MCF7 cell growth, hERα46 is mainly expressed in the nucleus at relatively low levels, whereas hERα66 accumulates in the nucleus. When cells reach confluence, the situation reverses, with hERα46 accumulating within the nucleus. Although hERα46 expression remains rather stable during an estrogen-induced cell cycle, its overexpression in proliferating MCF7 cells provokes a cell-cycle arrest in G0/G1 phases. To gain further details on the influence of hERα46 on cell growth, we used PC12 estrogen receptor-α-negative cell line, in which stable transfection of hERα66 but not hERα46 allows estrogens to behave as mitogens. We next demonstrate that, in MCF7 cells, overexpression of hERα46 inhibits the hERα66-mediated estrogenic induction of all AF-1-sensitive reporters: c-fos and cyclin D1 as well as estrogen-responsive element-driven reporters. Our data indicate that this inhibition occurs likely through functional competitions between both isoforms. In summary, hERα46 antagonizes the proliferative action of hERα66 in MCF7 cells in part by inhibiting hERα66 AF-1 activity.

scholarly journals Antagonist-Induced, Activation Function-2-Independent Estrogen Receptor α Phosphorylation

2006 ◽  
Vol 20 (3) ◽  
pp. 516-533 ◽  
Author(s):  
Lorraine Lipfert ◽  
John E. Fisher ◽  
Nan Wei ◽  
Angela Scafonas ◽  
Qin Su ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Activation Function ◽  
Estrogen Receptor Α

scholarly journals Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

2020 ◽  
Vol 21 (12) ◽  
pp. 4193
Author(s):  
Divya Bafna ◽  
Fuqiang Ban ◽  
Paul S. Rennie ◽  
Kriti Singh ◽  
Artem Cherkasov
Keyword(s):  
Estrogen Receptor ◽  
Drug Discovery ◽  
Estrogen Receptor Alpha ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Functional Sites ◽  
Computer Aided ◽  
Ligand Discovery ◽  
Induce Resistance ◽  
Approved Drugs

Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery.

scholarly journals SPBP Is a Phosphoserine-Specific Repressor of Estrogen Receptor α

2005 ◽  
Vol 25 (9) ◽  
pp. 3421-3430 ◽  
Author(s):  
Valentina Gburcik ◽  
Nathalie Bot ◽  
Marcello Maggiolini ◽  
Didier Picard
Keyword(s):  
Estrogen Receptor ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Fine Tuning ◽  
Breast Cancer Cell Lines ◽  
Interaction Domain ◽  
Phosphorylated Form ◽  
Element Binding Protein ◽  
Responsive Element

ABSTRACT Multiple signaling pathways stimulate the activity of estrogen receptor α (ERα) by direct phosphorylation within its N-terminal activation function 1 (AF1). How phosphorylation affects AF1 activity remains poorly understood. We performed a phage display screen for human proteins that are exclusively recruited to the phosphorylated form of AF1 and found the stromelysin-1 platelet-derived growth factor-responsive element-binding protein (SPBP). In a purified system, SPBP bound only the in vitro-phosphorylated form of the ERα AF1 or the phosphoserine mimic S118E, and the interaction domain could be mapped to a 42-amino-acid fragment of SPBP. In cells, SPBP preferentially interacted with liganded and phosphorylated ERα. Functionally, SPBP behaved as a repressor of activated ERα, which extends its previously demonstrated roles as a DNA binding transactivation factor and coactivator of other transcription factors. By targeting the phosphorylated form of AF1, SPBP may contribute to attenuating and fine-tuning ERα activity. A functional consequence is that SPBP inhibits the proliferation of ERα-dependent but not ERα-independent breast cancer cell lines, mirroring a reported negative correlation with the ERα status of breast tumors.

Gene expression profiling reveals novel regulation by bisphenol-A in estrogen receptor-α-positive human cells

2006 ◽  
Vol 100 (1) ◽  
pp. 86-92 ◽  
Author(s):  
David W. Singleton ◽  
Yuxin Feng ◽  
Jun Yang ◽  
Alvaro Puga ◽  
Adrian V. Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Bisphenol A ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Estrogen Receptor Α ◽  
Human Cells

scholarly journals Activation function 2 (AF2) of estrogen receptor-α is required for the atheroprotective action of estradiol but not to accelerate endothelial healing

2011 ◽  
Vol 108 (32) ◽  
pp. 13311-13316 ◽  
Author(s):  
Audrey Billon-Galés ◽  
Andrée Krust ◽  
Coralie Fontaine ◽  
Anne Abot ◽  
Gilles Flouriot ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Activation Function ◽  
Estrogen Receptor Α

The activation function-1 domain of estrogen receptor α in uterine stromal cells is required for mouse but not human uterine epithelial response to estrogen

2005 ◽  
Vol 73 (6) ◽  
pp. 313-322 ◽  
Author(s):  
Takeshi Kurita ◽  
Roanna Medina ◽  
Alex B. Schabel ◽  
Peter Young ◽  
Patricia Gama ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Stromal Cells ◽  
Activation Function ◽  
Estrogen Receptor Α

scholarly journals Full Activation of Estrogen Receptor α Activation Function-1 Induces Proliferation of Breast Cancer Cells

2003 ◽  
Vol 278 (29) ◽  
pp. 26704-26714 ◽  
Author(s):  
Tetsuo Fujita ◽  
Yoko Kobayashi ◽  
Osamu Wada ◽  
Yukiyo Tateishi ◽  
Lina Kitada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Full Activation

scholarly journals Synergistic Activation of the Serotonin-1A Receptor by Nuclear Factor-κB and Estrogen

2001 ◽  
Vol 15 (4) ◽  
pp. 543-552 ◽  
Author(s):  
Sacha Wissink ◽  
Bart van der Burg ◽  
Benita S. Katzenellenbogen ◽  
Paul T. van der Saag
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Factor Κb ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Nuclear Factor ◽  
Serotonin 1A Receptor ◽  
Estrogen Response ◽  
Synergistic Activation ◽  
Serotonin System ◽  
Serotonergic Function

Abstract Estrogen exerts profound effects on mood and mental state. The ability of estrogen to modulate serotonergic function raises the possibility that it may play a role in the mechanism associated with depression and its treatment. A cellular mechanism for estrogen to influence mood might be through the regulation of genes involved at various levels of the serotonin system. Here we report that estrogen can up-regulate the expression of the serotonin-1A receptor via a new mechanism involving synergistic activation by nuclear factor-κB (NF-κB) with estrogen receptor α. Interestingly, we observed that only estrogen receptor-α, and not -β, was able to mediate this effect of estrogens. The partial antiestrogen, 4-hydroxytamoxifen, had the same effect as estrogen. In addition, mutation analysis showed that both the transactivation function of p65 and activation function 1 of estrogen receptor-α were essential for this synergistic regulation. Therefore, we propose that NF-κB complexes cooperate with estrogen receptor-α to recruit cofactors into the complex and thereby synergistically activate the serotonin-1A receptor promoter through nonclassical estrogen response elements by a mechanism that does not involve direct receptor binding to DNA.

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