Affinage

ESR2

Estrogen receptor beta · UniProt Q92731

Round 2 corrected
Length
530 aa
Mass
59.2 kDa
Annotated
2026-04-28
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ESR2 (estrogen receptor beta) is a ligand-activated nuclear receptor that binds 17β-estradiol via a conserved ligand-binding domain and regulates transcription through estrogen response elements (EREs), functioning broadly as an antiproliferative modulator of estrogen signaling that opposes ERα-driven cell cycle progression (PMID:8769313, PMID:10579320, PMID:14729654). ESR2 heterodimerizes with ERα and with its own splice isoforms—some of which (e.g., ERβcx) lack ligand binding and act as dominant-negative inhibitors of ERα—to repress cyclin D1 and c-myc while inducing p21 and p27, causing G2 arrest and suppressing tumor growth in breast cancer xenografts (PMID:9671811, PMID:11986316, PMID:14729654, PMID:14745018). Beyond its antiproliferative genomic activity, ESR2 localizes to mitochondria in neurons and cardiomyocytes, activates non-genomic Src/ERK signaling through steroid receptor complexes, suppresses NF-κB nuclear translocation to inhibit inflammation, and protects against cardiac hypertrophy via inhibition of Ca²⁺-calcineurin signaling (PMID:15024130, PMID:11032808, PMID:19447495, PMID:28863192). ESR2 is essential for female fertility—maintaining the primordial follicle reserve by restraining AKT/mTOR activation and regulating Kiss1 and CYP19A1 in granulosa cells—and is required for embryonic cortical neuronal migration and late brain development (PMID:32141511, PMID:30277501, PMID:12515851, PMID:32703416).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    The discovery of a second estrogen receptor (ERβ) established that estrogen signaling operates through two independent receptors with conserved DNA-binding but divergent ligand-binding domains, raising the question of whether ERβ has distinct or redundant functions relative to ERα.

    Evidence Degenerate PCR cloning from rat prostate, ligand-binding assay, ERE-reporter transactivation in transfected cells

    PMID:8769313

    Open questions at the time
    • Tissue-specific functions of ERβ versus ERα not yet defined
    • Endogenous target genes unknown
    • In vivo role not established
  2. 1998 High

    Identification of multiple ERβ splice isoforms and demonstration of ERα–ERβ heterodimerization revealed that ERβ could modulate ERα activity through combinatorial dimer formation, with the dominant-negative isoform ERβcx providing a mechanism for ERα inhibition independent of ligand binding.

    Evidence cDNA screening, EMSA for homodimer/heterodimer DNA binding, GST pull-down and co-immunoprecipitation for ERα–ERβ interaction, ligand-binding assays for ERβcx

    PMID:9473491 PMID:9636657 PMID:9671811

    Open questions at the time
    • In vivo stoichiometry of ERα/ERβ dimers unknown
    • Physiological relevance of ERβcx in tissues not established
    • Crystal structure of ERα–ERβ heterodimer unavailable
  3. 1999 High

    Domain-mapping experiments resolved how ERβ acts as a transdominant inhibitor of ERα: its N-terminal repressor domain and weak AF-1, combined with heterodimerization, reduce estradiol sensitivity and abolish tamoxifen's partial agonist activity through ERα.

    Evidence Domain deletion/chimeric receptor analysis, co-immunoprecipitation, chromatin binding assay, reporter assays in transfected cells

    PMID:10579320

    Open questions at the time
    • Structural basis of the N-terminal repression function unresolved
    • Chromatin-level mechanism of ligand-independent promoter occupancy not defined
  4. 2000 High

    In vivo loss-of-function in BERKO mice demonstrated that ERβ restrains ERα-driven uterine proliferation and gene induction (PR, VEGF, IGF-1), while parallel biochemical studies showed ERβ engages non-ERE pathways through direct Sp1 interaction and participates in non-genomic Src/Raf/ERK signaling.

    Evidence ERβ-knockout mouse uterine phenotyping, co-immunoprecipitation of ER–Sp1 complexes, GST pull-down of Src SH2/SH3 domains with ER, microinjection of dominant-negative Src blocking S-phase entry

    PMID:10681512 PMID:10823946 PMID:11032808

    Open questions at the time
    • Relative contribution of genomic versus non-genomic ERβ signaling in specific tissues unclear
    • Src interaction site on ERβ not mapped at residue level
  5. 2003 High

    ERβ was shown to be required for embryonic cortical neuronal migration and survival, extending its role beyond reproductive tissues and establishing a developmental neurobiology function.

    Evidence ERβ-knockout mice with BrdU birth-dating, TUNEL apoptosis assay, immunofluorescence of fragmented radial glia

    PMID:12515851

    Open questions at the time
    • Direct ERβ transcriptional targets in developing brain not identified
    • Whether mitochondrial ERβ contributes to neuronal survival not tested
  6. 2004 High

    The antiproliferative mechanism of ERβ was molecularly defined: ERβ represses cyclin D1, c-myc, and cyclin A while inducing p21 and p27, causing G2 arrest and inhibiting xenograft tumor growth, and was simultaneously found to reside predominantly in mitochondria in neurons and cardiomyocytes.

    Evidence Adenoviral ERβ expression in MCF-7 cells with flow cytometry and xenograft assays; subcellular fractionation, confocal colocalization with mitochondrial markers, and mass spectrometry of purified heart mitochondria

    PMID:14729654 PMID:14745018 PMID:15024130

    Open questions at the time
    • Mitochondrial ERβ target genes/functions not identified
    • Whether mitochondrial localization is cell-type-restricted remains unclear
    • Mechanism of mitochondrial import unknown
  7. 2006 High

    Structural and functional analysis of ERβ isoforms established that a single functional helix 12 within a dimer is sufficient for transactivation, with ERβ1 serving as the obligatory active partner that is enhanced by heterodimerization with ligand-incompetent isoforms under estrogen stimulation.

    Evidence Molecular modeling, co-immunoprecipitation for isoform-specific dimerization, luciferase reporter assays, ligand-binding assays

    PMID:16938840

    Open questions at the time
    • In vivo isoform ratios in specific tissues not quantified
    • No crystal structures of ERβ isoform heterodimers available
  8. 2009 Medium

    ERβ was shown to suppress NF-κB-mediated inflammation by blocking p65 nuclear translocation in macrophages, establishing a non-genomic anti-inflammatory mechanism distinct from its ERE-dependent transcriptional activity.

    Evidence Selective ERβ agonist ERB-041 in peritoneal macrophages, nuclear fractionation for NF-κB p65, ERK inhibitor controls

    PMID:19447495

    Open questions at the time
    • Direct molecular interaction between ERβ and NF-κB pathway components not demonstrated
    • Not confirmed in genetic ERβ-knockout macrophages
  9. 2018 High

    Genetic models (null and DBD-mutant rats) established that ESR2's canonical DNA-binding function in granulosa cells is required for follicle maturation, ovulation, and direct transcriptional regulation of Kiss1 through ERE binding and cooperation with ERK2-phosphorylated AP-1 factors.

    Evidence Esr2-null and Esr2-DBD mutant rat models, RNA-seq of granulosa cells, ChIP at Kiss1 regulatory regions, ERE mutagenesis/reporter assay, ERK2-ESR2 phosphorylation assay

    PMID:29580824 PMID:30277501

    Open questions at the time
    • Full ERβ cistrome in granulosa cells not mapped
    • Whether Kiss1 regulation by ERβ operates similarly in human granulosa cells not tested
  10. 2020 High

    ESR2 was identified as the specific gatekeeper of the primordial follicle reserve, restraining AKT/mTOR-driven follicle activation through its transcriptional activity; complete gene deletion confirmed female subfertility progressing to infertility with age.

    Evidence Esr2-null and DBD-mutant rats with selective agonist/antagonist pharmacology, follicle counting, AKT/ERK/mTOR signaling Western blots; CRISPR/Cas9 all-exon deletion mice with fertility and histological assessment

    PMID:32141511 PMID:32703416

    Open questions at the time
    • Direct transcriptional targets mediating AKT/mTOR suppression not identified
    • Whether ESR2 acts cell-autonomously in oocytes versus granulosa cells not fully resolved
  11. 2017 Medium

    ESR2 variants (p.Asn181del, p.Leu426Arg) with gain-of-function transcriptional activity were identified in 46,XY DSD patients, implicating ESR2 in human sex development.

    Evidence Whole-exome sequencing of DSD patients, luciferase transactivation assays, protein structure analysis

    PMID:29261182

    Open questions at the time
    • Small patient cohort without replication
    • Mechanism by which gain-of-function ESR2 disrupts male sex development not defined
    • No rescue or animal model recapitulating these specific variants

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of direct ERβ transcriptional targets in mitochondria, the structural basis of ERα–ERβ heterodimer selectivity at specific promoters, the relative contributions of genomic versus non-genomic ERβ signaling in cardiovascular and neuroprotection, and whether the ESR2–AKT/mTOR axis in follicle maintenance operates through direct target gene regulation.
  • Mitochondrial ERβ targets/import mechanism unknown
  • No ERα–ERβ heterodimer crystal structure
  • Cell-autonomous versus paracrine ERβ action in ovarian follicle biology not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 1
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1474165 Reproduction 3 R-HSA-1640170 Cell Cycle 2
Partners
AHRARARNTEP300ESR1NUPR1SP1SRC
Complex memberships
ER/Src/AR signaling complexERα/ERβ heterodimerERβ homodimer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 ESR2 (ERβ) was identified as a novel estrogen receptor with high conservation in the DNA-binding domain (96%) and ligand-binding domain (58%) relative to ERα. Ligand-binding experiments confirmed 17β-estradiol binding, and transient transfection with an ERE-based reporter demonstrated estradiol-dependent transactivation. ICI-164384 (ERα antagonist) also antagonizes ERβ. Degenerate PCR cloning, ligand-binding assay, transient transfection/reporter assay FEBS letters High 8769313
1997 The human ESR2 gene was mapped to a distinct chromosomal locus from ESR1, confirming two independent ER genes exist in humans. ESR2 is expressed in multiple tissues including ovarian granulosa cells and developing spermatids of the testis. Genomic cloning, chromosomal localization, Northern blot, in situ hybridization The Journal of clinical endocrinology and metabolism High 9398750
1998 Multiple ESR2 (ERβ) isoforms (ERβ1–5) were identified, all diverging within the predicted helix 10 of the ligand-binding domain due to differential exon usage. In vitro band-shift studies showed isoforms form DNA-binding homodimers and heterodimers with each other and with ERα. cDNA library screening, RT-PCR, in vitro gel-shift (EMSA) Biochemical and biophysical research communications High 9636657
1998 Full-length human ESR2 (hERβ) was cloned from testis, encoding 53 additional N-terminal amino acids. ERα–ERβ protein interaction was demonstrated in vitro by GST pull-down assay and in vivo by co-immunoprecipitation, showing that ERα and ERβ can interact and cross-signal each other. cDNA cloning, GST pull-down assay, co-immunoprecipitation Biochemical and biophysical research communications High 9473491
1998 A novel ESR2 isoform, ERβcx, was identified that lacks ligand-binding ability (Kd unmeasurable vs ERβ Kd ~0.6 nM for E2), cannot bind ERE in gel-shift assays, and preferentially heterodimerizes with ERα rather than ERβ, acting as a dominant negative inhibitor of ERα transactivation. Molecular cloning/alternative splicing characterization, ligand-binding assay, EMSA, transient transfection/reporter assay Nucleic acids research High 9671811
1999 ERβ contains a functional AF-2 domain but lacks a strong AF-1; instead its N-terminus harbors a repressor domain. ERβ functions as a transdominant inhibitor of ERα transcriptional activity at subsaturating hormone levels by forming ERα/ERβ heterodimers. ERβ abolishes the partial agonist activity of tamoxifen observed through ERα and decreases overall cellular sensitivity to estradiol. ERβ also interacts with target gene promoters in a ligand-independent manner. Domain deletion/chimeric receptor analysis, transient transfection/reporter assay, co-immunoprecipitation (heterodimer detection), chromatin binding assay Endocrinology High 10579320
2000 The activated dioxin receptor (AhR/Arnt heterodimer) directly associates with both ERα and ERβ. This association recruits unliganded ER and co-activator p300 to estrogen-responsive gene promoters, activating transcription. Oestrogenic actions of AhR agonists were absent in AhR−/− or ERα−/− ovariectomized mice, establishing the molecular mechanism by which dioxins exert estrogenic effects through ER. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assay, knockout mouse model Nature High 12774124
2000 In BERKO (ERβ knockout) mice, the immature uterus shows elevated progesterone receptor and Ki-67 levels and exaggerated responsiveness to 17β-estradiol, including enlarged lumen, increased secretion, and enhanced induction of VEGF, IGF-1, complement C3, and IL-1β. E2 failed to downregulate PR in the luminal epithelium of BERKO mice. These findings establish ERβ as a modulator of ERα activity and as having an antiproliferative function in the uterus. ERβ knockout mouse model, immunohistochemistry, ELISA, quantitative gene expression Proceedings of the National Academy of Sciences of the United States of America High 10823946
2000 ERβ and ERα physically interact with Sp1 protein (demonstrated by co-immunoprecipitation and pull-down assays) and bind preferentially to the C-terminal region of Sp1. ERβ/Sp1-mediated transcriptional activation at GC-rich promoter elements is ligand- and cell-context-dependent. Domain-swap experiments showed the ERα AF-1 domain (aa 79–117) is specifically required for activation at Sp1 elements, independently of ER subtype context. Co-immunoprecipitation, GST pull-down, chimeric receptor/deletion analysis, luciferase reporter assay The Journal of biological chemistry High 10681512
2000 ERβ, when expressed in androgen receptor (AR)-positive LNCaP prostate cancer cells, associates with AR and Src upon steroid stimulation, triggering the Src/Raf-1/Erk-2 pathway. Src SH3 domain interacts with a proline-rich stretch of AR; Src SH2 domain interacts with phosphotyrosine 537 of ERα (and analogous site of ERβ). Microinjection of dominant-negative Src abolishes steroid-stimulated S-phase entry, demonstrating that steroid-receptor/Src complexes are required for proliferative signaling. Co-immunoprecipitation, GST fusion pull-down, microinjection of dominant-negative constructs, BrdU S-phase entry assay The EMBO journal High 11032808
2001 ERβ expressed via adenoviral vector in ER-negative MDA-MB-231 breast cancer cells localizes to the nucleus, transactivates ERE reporter constructs in the presence of E2, and inhibits cell proliferation in a ligand-independent manner. ERβ (unlike ERα) cannot regulate c-myc expression but induces p21 (CDKN1A). Both ERα and ERβ decrease cell motility and invasion. Adenoviral overexpression, immunocytochemistry, RT-PCR, Western blot, proliferation assay, invasion assay, reporter assay Endocrinology High 11517191
2002 ERβ opposes ERα at the cyclin D1 promoter: ERα activates cyclin D1 gene transcription via both a CRE element at −57 and an AP-1 site at −954, while ERβ inhibits cyclin D1 expression in the presence of estrogens (activates only with antiestrogens). ERβ completely dominates over ERα or superactive ERαK206A in blocking estrogen/ERα-mediated cyclin D1 induction. Luciferase reporter assay with CRE/AP-1 site mutants, Western blot for endogenous cyclin D1, chimeric receptor analysis in HeLa cells The Journal of biological chemistry High 11986316
2003 ERβ is essential for late embryonic brain development. ERβ knockout mice show smaller brains at E18.5 with fewer cortical neurons. BrdU labeling experiments demonstrated a defect in neuronal migration (fewer BrdUrd-labeled cells in superficial cortical layers by E18.5/P14 when labeled at E14.5–E16.5) and increased apoptosis in the ventricular zone. Radial glia processes guiding migrating neurons were fragmented in ERβ-null mice. ERβ knockout mouse model, BrdU birth-dating/migration assay, TUNEL apoptosis assay, immunofluorescence of radial glia Proceedings of the National Academy of Sciences of the United States of America High 12515851
2004 ERβ expression in ERα-positive MCF-7 breast cancer cells causes G2 cell cycle arrest and inhibits tumor formation in mouse xenografts. ERβ represses transcription of c-myc, cyclin D1, and cyclin A, while increasing p21(Cip1) and p27(Kip1). This is opposite to ERα, which promotes proliferation and tumor formation. Adenoviral ERβ expression, flow cytometry (cell cycle), mouse xenograft model, RT-PCR/Western blot for cell cycle genes Cancer research High 14729654
2004 Induced ERβ expression in T47D breast cancer cells reduces 17β-estradiol-stimulated proliferation when ERβ mRNA equals ERα levels. ERβ decreases cyclin E, Cdc25A, p45(Skp2), reduces Cdk2 kinase activity, and increases p27(Kip1), suggesting ERβ acts on the G1-phase cell-cycle machinery to oppose ERα-driven proliferation. Inducible ERβ expression system, proliferation assay, Western blot, Cdk2 kinase activity assay Proceedings of the National Academy of Sciences of the United States of America High 14745018
2004 ERβ localizes primarily to mitochondria, not to the nucleus, in rat primary neurons, primary cardiomyocytes, and a murine hippocampal cell line. This was established by immunocytochemistry with two independent ERβ antibodies co-localized with mitochondrial markers, immunoblotting of purified human heart mitochondria, and mass spectrometric identification of seven ERβ tryptic fragments in the mitochondrial fraction. No nuclear translocation of ERβ occurred upon 17β-estradiol treatment. Immunocytochemistry, confocal microscopy, subcellular fractionation, immunoblotting of purified mitochondria, MALDI mass spectrometry Proceedings of the National Academy of Sciences of the United States of America High 15024130
2006 ERβ isoforms 2, 4, and 5 do not bind ligand with full activity, cannot form homodimers, and have no innate transcriptional activity due to structural differences in their C-terminus (disrupted helix 12). However, they can heterodimerize with ERβ1 and enhance ERβ1 transactivation in a ligand-dependent manner. ERβ1 is the obligatory active partner; a single functional helix 12 in a dimer is sufficient for gene transactivation. ERβ1 preferentially forms heterodimers with other isoforms under estrogen (but not phytoestrogen) stimulation. Molecular modeling, co-immunoprecipitation (dimerization), luciferase reporter assay, ligand-binding assay Proceedings of the National Academy of Sciences of the United States of America High 16938840
2007 Activation of ESR2 (ERβ) in vivo by the selective agonist 8β-VE2 in ovariectomized spontaneously hypertensive rats lowers systolic blood pressure (−38 mmHg), reduces peripheral vascular resistance, enhances aortic ERβ expression, improves NO-dependent vasorelaxation, augments phosphorylation of vasodilator-stimulated phosphoprotein in isolated aortic rings, and attenuates cardiac hypertrophy without uterotrophic effects. In vivo pharmacological agonist administration, echocardiography, vascular ring relaxation assay, Western blot, immunohistochemistry Cardiovascular research Medium 18056768
2007 AP-2α and AP-2γ (but not AP-2β) regulate ESR2 transcription by binding to the 0N promoter at a methylation hotspot (center 1, a 16-bp AP-2 binding site). ChIP confirmed AP-2α occupancy. Forced AP-2α/γ expression increased ERβ mRNA; siRNA knockdown reduced it. ERβ transcript levels correlate with AP-2α/γ levels across PCa cell lines. Chromatin immunoprecipitation (ChIP), promoter deletion/reporter assay, siRNA knockdown, RT-PCR, forced expression Oncogene High 17525739
2008 ERβ inhibits ERα-mediated induction of progesterone receptor in the neonatal rat ventromedial nucleus of the hypothalamus in an anatomically specific manner. Selective ERα activation in the relative absence of ERβ induces greater PR expression; selective ERβ activation attenuates this ERα-mediated increase in the ventromedial nucleus but not the medial preoptic nucleus, despite high ERα expression in both regions. Selective ER agonist administration in vivo, in situ hybridization/immunohistochemistry for PR as functional readout Endocrinology Medium 18511514
2009 The selective ERβ agonist ERB-041 inhibits LPS-induced iNOS expression in peritoneal macrophages from endometriosis patients by preventing nuclear translocation of NF-κB p65, without affecting the ERK pathway. ERβ (not ERα) is the predominant ER subtype in these macrophages. ERKs are involved in LPS-induced iNOS but are not repressed by ERβ activation. RT-PCR, immunoblot, pharmacological agonist treatment, nuclear fractionation (NF-κB translocation), ERK inhibitor (U0126) Molecular immunology Medium 19447495
2005 Com-1/P8 protein physically interacts with ERβ in breast cancer cells as demonstrated by reciprocal co-immunoprecipitation. Both proteins co-localize in the nucleus. 17β-estradiol stimulation reduces nuclear Com-1 staining, and this reduction is reversed by ubiquitin/proteasome inhibitors (ubiquitin aldehyde, lactacystin), indicating that the ubiquitin-proteasome pathway regulates the Com-1/ERβ complex. Elimination of Com-1 leads to increased estradiol-stimulated growth in ER-negative/ERβ-positive cells. Reciprocal co-immunoprecipitation, immunocytochemistry, proteasome inhibitor treatment, ribozyme transgene knockdown, proliferation assay Biochemical and biophysical research communications Medium 15781258
2016 In adult male rats, ESR2-selective agonist administration reduces sperm counts due to spermiation failure (defects in tubulobulbar complex formation caused by decreased expression of actin remodeling genes) and increased spermatocyte apoptosis associated with elevated oxidative stress and decreased anti-apoptotic gene transcripts. ESR1 agonist causes arrest of round-to-elongated spermatid differentiation. The two receptors regulate distinct aspects of spermatogenesis. In vivo selective ESR agonist administration, histology, gene expression analysis, sperm count, oxidative stress assay Molecular and cellular endocrinology Medium 27004961
2017 E2/ERβ suppresses ISO-induced cardiac cellular hypertrophy in H9c2 cardiomyoblasts by inhibiting Ca2+-calcineurin signaling. ERβ overexpression and/or E2 inhibits ISO-induced elevation of p-CaMKII, calcineurin, p-GATA4, NFATc3, ANP, and BNP. Mechanistically, E2/ERβ suppresses Ca2+ influx, inhibits calcineurin activity to activate I-1 protein, suppresses PP1, then induces PLB phosphorylation and activation, resulting in Ca2+ reuptake into the sarcoplasmic reticulum. NFATc3 nuclear translocation is also inhibited. Calcineurin inhibitor (CsA) confirmed calcineurin as key mediator; Ca2+ chelator (BAPTA) blocked E2/ERβ effects. ERβ overexpression, calcineurin inhibitor (CsA), Ca2+ chelator (BAPTA), Western blot for signaling cascade proteins, immunofluorescence (NFATc3 localization), cell size measurement PloS one Medium 28863192
2018 ESR2 is required for gonadotropin-induced follicle maturation and ovulation in rats. RNA-seq of granulosa cells from Esr2-null and Esr2-DBD mutant rats identified 1,696 differentially expressed genes enriched in steroidogenesis, follicle maturation, and ovulation pathways. Kiss1 was identified as a key ESR2-regulated gene in granulosa cells, indicating an intra-follicular role distinct from hypothalamic Kiss1 regulation by ESR1. Esr2-null and DNA-binding domain mutant rat models, RNA-sequencing of granulosa cells, molecular pathway analysis, exogenous gonadotropin stimulation Molecular and cellular endocrinology High 29580824
2018 ESR2 directly regulates Kiss1 expression in granulosa cells. The Kiss1 promoter, upstream enhancer, and downstream enhancer possess conserved EREs with active histone marks in gonadotropin-stimulated granulosa cells. ChIP revealed ESR2 binding enrichment at these regulatory regions. ERE mutation in the Kiss1 promoter blocked ESR2-mediated induction. Gonadotropins induce ERK2-mediated ESR2 phosphorylation and upregulate AP-1 factors (FOSL2, JUNB), which synergistically activate the Kiss1 promoter with ESR2. ChIP, ERE mutagenesis/reporter assay, ESR2 overexpression, kinase activity assay (ERK2-ESR2 phosphorylation), immunoblot, PMSG/hCG gonadotropin stimulation Endocrinology High 30277501
2017 Biallelic (c.541_543del p.Asn181del, in the DNA-binding domain) and monoallelic (p.Gly84Val in N-terminus; p.Leu426Arg in ligand-binding domain) ESR2 variants were identified in 46,XY DSD patients. Luciferase assays showed significantly increased transcriptional activation for the p.Asn181del and p.Leu426Arg variants, and protein structure analysis demonstrated impact on protein conformation. ERβ immunostaining confirmed expression in the developing human male embryo intestine and eyes. Whole-exome sequencing, luciferase transactivation assay, protein structure analysis, immunostaining of human embryo Genetics in medicine Medium 29261182
2019 miR-186 and miR-135a directly repress ESR2 expression in granulosa cells, verified by luciferase assays and immunoblotting. Reduced ESR2 further inhibits CDKN1A (p21) expression, promoting granulosa cell proliferation and suppressing apoptosis. Estradiol treatment directly increases miR-186 and miR-135a levels in granulosa cells, creating a feedback loop relevant to PCOS pathophysiology. Luciferase 3'UTR reporter assay, immunoblotting, miRNA overexpression/inhibition, primary granulosa cell culture Molecular and cellular endocrinology Medium 31173821
2020 ESR2 (ERβ) acts as a gatekeeper to maintain the primordial follicle reserve. Esr2-null rats show increased primordial follicle activation, premature ovarian senescence, and reduced serum AMH/estradiol. ESR2-selective antagonist PHTPP increases follicle activation in wild-type rats; DPN (selective agonist) decreases it. ESR1 deletion does not increase follicle activation, confirming ESR2-specific regulation. Esr2 DBD mutants also show increased activation, indicating requirement for canonical transcriptional function. Loss of ESR2 augments AKT, ERK, and mTOR pathway activation in both granulosa cells and oocytes. Esr2-null and DBD-mutant rat models, selective agonist/antagonist pharmacology, follicle counting histology, serum hormone ELISA, Western blot for AKT/ERK/mTOR signaling Endocrinology High 32141511
2020 Complete deletion of all Esr2 exons in mice (Esr2ΔE1-10 via CRISPR/Cas9) establishes that female ERβ-null mice are subfertile at young age and become infertile by ~6 months, with smaller ovaries, very few corpora lutea (indicating ovulation failure), and reduced diestrus estradiol levels. Male Esr2ΔE1-10 mice are fertile. This confirms ERβ's essential role in female reproduction likely through regulation of serum estradiol levels. CRISPR/Cas9 all-exon deletion, fertility assessment (litter number/size), ovarian histology/corpora lutea counting, serum estradiol measurement Biochemical and biophysical research communications High 32703416
2019 ERβ (ER-β) regulates FATP1/SLC27A1 expression in breast cancer cells. Experiments with estradiol and PHTPP (ERβ antagonist) demonstrated that ERβ regulates FATP1 mRNA expression, fatty acid uptake, and cell viability in four breast cancer cell lines. Inhibition of FATP1 with arylpiperazine 5k interfered with fatty acid uptake and cell viability. ERβ antagonist (PHTPP) pharmacology, RT-PCR, fatty acid uptake assay, cell viability assay, FATP1 inhibitor Scientific reports Medium 31575907
2021 ESR2-mediated estrogen signaling impairs glycemic homeostasis, antagonizing the beneficial effects of ESR1. In Esr2 transgenic mice, GLUT4 (SLC2A4) expression and translocation are reduced. ESR2 acts as a negative regulator of Slc2a4 transcription by genomic mechanisms involving cooperation with other transcription factors, and estradiol-induced ESR2 activation is associated with detrimental effects on glucose metabolism. Transgenic mouse models (Esr1/Esr2 knockout/overexpression), GLUT4 expression/translocation assays, Slc2a4 promoter analysis, glucose homeostasis measurements Cells Medium 33430527
2024 ESR2 acts as a negative transcription factor that downregulates miR-10a transcription in the prefrontal cortex; miR-10a-5p in turn suppresses BDNF expression. This ESR2→miR-10a-5p⊣BDNF axis contributes to postpartum depression by affecting synaptic plasticity (alterations in SYP, SYN, PSD95, and glutamate receptor expression). Bioinformatics prediction, in vivo animal behavioral studies, cell transfection, and primary neuron culture confirmed the molecular triad. Stereotactic/intranasal antagomir or BDNF administration rescued depressive-like behavior. Bioinformatics, in vivo behavioral assays, cell transfection, luciferase reporter assay, primary neuron culture, stereotactic/intranasal drug delivery Research (Washington, D.C.) Medium 39588356
2024 LXA4 activates ESR2 in fibroblast-like synoviocytes (FLSs) to inhibit ferroptosis via upregulation of LPAR3, which in turn activates the Nrf2/GPX4/SOD1 axis. LPAR3 overexpression upregulated GPX4, Nrf2, SOD1 and downregulated MMP13/MMP3; LPAR3 knockdown reversed these effects. ESR2-selective antagonist PHTPP partially reversed the improvement in synovial and cartilage pathology induced by exercise in KOA rats, confirming ESR2 involvement in this protective pathway. Cell co-culture, LPAR3 overexpression/knockdown, Western blot, in vivo KOA rat model with PHTPP antagonist, dataset analysis (GSE29746) Redox biology Medium 38754271
2021 In chicken ovarian theca cells, ESR2 (along with ESR1 and NR5A2) forms a functional transcriptional network regulating CYP19A1 (aromatase) expression. Overexpression of ESR1, ESR2, and NR5A2 in DF-1 cells upregulates CYP19A1 protein and the three factors mutually restrict each other. ESR2 participates in cross-talk regulating theca cell CYP19A1 expression. Immunofluorescence, Western blot, theca cell culture model, luciferase promoter assay, overexpression in DF-1 cells General and comparative endocrinology Medium 34710471

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 ER beta: identification and characterization of a novel human estrogen receptor. FEBS letters 1838 8769313
1986 The c-erb-A gene encodes a thyroid hormone receptor. Nature 1503 2879243
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1986 The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature 1316 2879242
1997 Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 1255 9267036
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
1997 Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. The Journal of clinical endocrinology and metabolism 961 9398750
1999 The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 878 10579320
2012 Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 871 22460952
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2012 Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 672 22460951
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 610 12774124
1993 The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements. Cell 586 8221895
2005 Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. Journal of biological rhythms 569 16267379
1994 Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription. Science (New York, N.Y.) 569 8197458
2000 Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. The EMBO journal 560 11032808
2004 Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer research 503 14729654
2012 Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nature genetics 490 22544366
2014 REV-ERB and ROR nuclear receptors as drug targets. Nature reviews. Drug discovery 467 24577401
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proceedings of the National Academy of Sciences of the United States of America 449 14745018
1998 Cloning and characterization of human estrogen receptor beta isoforms. Biochemical and biophysical research communications 447 9636657
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2008 Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocrine reviews 436 18216219
2006 Nature of functional estrogen receptors at the plasma membrane. Molecular endocrinology (Baltimore, Md.) 429 16645038
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