Affinage

ESR2

Estrogen receptor beta · UniProt Q92731

Length
530 aa
Mass
59.2 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ESR2 (ERβ) is a ligand-activated nuclear receptor that, upon 17β-estradiol binding, transactivates ERE-containing target genes through a DNA-binding domain that is highly conserved with ERα, but with intrinsically lower transactivation potency (PMID:8769313). Distinct ligand-dependent conformational changes distinguish ERβ from ERα and underlie isoform-specific activity (PMID:10097152). A recurring theme across tissues is that ERβ acts as an antiproliferative modulator that opposes ERα: in the uterus ERβ restrains ERα-driven proliferative responses (PMID:10823946), in ER-negative breast cancer cells reintroduced ERβ induces pS2, TGFα, and p21 while inhibiting proliferation, motility, and invasion (PMID:11517191), and it directly attenuates ERα-mediated transcription by competing at promoter binding sites — repressing the BRCA2 promoter through an ERβ–CBP/p300 complex that displaces the activating ERα complex from Sp1 sites (PMID:18765668), and binding AP-1, Sp1, and ERE motifs in the ERα promoter to suppress ERα expression itself (PMID:19001520). Loss of ERβ produces unopposed ERα signaling and increased proliferation, and a germline ESR2 frameshift mutation (c.948delT) abolishing ERβ expression de-represses the ERE-containing RET promoter (PMID:26945007). Receptor dimerization is constrained by isoform structure: ERβ2/β4/β5 isoforms lack a functional helix 12 and cannot homodimerize or transactivate alone, but heterodimerize with the obligatory ERβ1 partner to enhance its ligand-dependent activity (PMID:16938840). ERβ also signals non-genomically, with the E2–ERβ complex selectively activating p38/MAPK to drive caspase-3-dependent apoptosis while failing to engage the ERK and PI3K/AKT survival pathways activated by ERα (PMID:15389627). In the ovary ERβ is indispensable for follicular maturation and ovulation through its DNA-binding transcriptional activity, directly driving Kiss1 expression via promoter and enhancer EREs in granulosa cells (PMID:29580824, PMID:30277501), and it acts as a gatekeeper of the primordial follicle reserve by suppressing AKT/ERK/mTOR-dependent follicle activation (PMID:32141511). Beyond reproduction, ERβ limits cardiomyocyte hypertrophy and apoptosis by inhibiting Ca²⁺–calcineurin signaling and promoting PI3K/Akt/MDM2-mediated calcineurin degradation (PMID:28863192, PMID:28441761), and mediates pro-myelination neuroprotection in oligodendrocytes through PI3K/Akt/mTOR (PMID:24191028). A germline ESR2 frameshift mutation has been linked to tumor formation through loss of ERα repression (PMID:26945007).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1996 High

    Established that a second estrogen receptor exists, defining ERβ as a ligand-activated transcription factor distinct from ERα with weaker transactivation.

    Evidence Degenerate PCR cloning, sequence homology, and ERE-reporter transactivation in CHO cells with pharmacological antagonism

    PMID:8769313

    Open questions at the time
    • Endogenous target genes not yet identified
    • Physiological tissue role undefined
    • Basis for lower transactivation vs ERα unexplained
  2. 1999 High

    Resolved why ERβ and ERα behave differently by showing each adopts distinct ligand-dependent conformations, providing a structural basis for isoform- and ligand-specific activity.

    Evidence Peptide affinity selection probing apo- and ligand-bound receptor surfaces with estradiol and 4-OH tamoxifen

    PMID:10097152

    Open questions at the time
    • No atomic-resolution structure reported here
    • Functional consequence of conformations in vivo not tested
  3. 2000 High

    Defined ERβ's in vivo role as an antiproliferative modulator opposing ERα-mediated estrogen responses in the uterus.

    Evidence BERKO knockout mice with immunohistochemistry, protein quantification, and hormonal challenge

    PMID:10823946

    Open questions at the time
    • Molecular mechanism of opposition not resolved here
    • Direct vs indirect effects on ERα targets unclear
  4. 2001 High

    Showed ERβ directly suppresses tumor cell proliferation and invasion in an ERα-null context, distinguishing its target gene program (induces p21, pS2, TGFα; not c-myc) from ERα.

    Evidence Adenoviral ERβ expression in MDA-MB-231 cells with reporter, proliferation, and invasion assays

    PMID:11517191

    Open questions at the time
    • Ligand-independent growth inhibition mechanism not defined
    • Single cell line
  5. 2003 Medium

    Consolidated that ERβ forms functional heterodimers with ERα and inhibits ERα-mediated transcription across promoter and cell-type contexts.

    Evidence Review summarizing transfection and reporter coexpression studies

    PMID:14993442

    Open questions at the time
    • Review-level synthesis, not new primary data
    • Structural detail of heterodimer not addressed
  6. 2004 High

    Revealed a chaperone-like function whereby ERβ facilitates ERα nuclear re-entry after E2-induced export, restoring estrogen responsiveness.

    Evidence BrdU labeling, subtype-specific immunohistochemistry, and ERβ-knockout mice with hormonal challenge

    PMID:14762170

    Open questions at the time
    • Molecular machinery of ERα re-import unknown
    • Whether ERβ acts directly on ERα trafficking untested
  7. 2006 High

    Defined the dimerization rules of ERβ isoforms, establishing ERβ1 as the obligatory partner and showing helix-12-deficient isoforms modulate rather than independently activate.

    Evidence Molecular modeling with reporter and co-immunoprecipitation dimerization assays across isoforms

    PMID:16938840

    Open questions at the time
    • In vivo relevance of isoform heterodimers not established
    • Tissue-specific isoform stoichiometry unknown
  8. 2005 High

    Distinguished ERβ from ERα non-genomically, showing E2–ERβ activates p38/MAPK to drive apoptosis rather than engaging survival ERK/PI3K-AKT pathways.

    Evidence Kinase activation, caspase-3, and PARP cleavage assays across HepG2, DLD1, and HeLa cells

    PMID:15389627

    Open questions at the time
    • Membrane receptor pool/scaffold mediating signaling unidentified
    • Link to genomic ERβ outputs unclear
  9. 2008 High

    Mechanistically dissected ERβ repression of ERα-driven BRCA2 transcription via competition at Sp1 sites and reduced histone acetylation.

    Evidence Reciprocal Co-IP, ChIP, reporter assays, and Sp1-site mutagenesis

    PMID:18765668

    Open questions at the time
    • Generalizability beyond BRCA2 promoter untested here
    • Coactivator quantitation indirect
  10. 2008 High

    Showed ERβ directly suppresses ERα gene expression by binding non-classical AP-1/Sp1 and classic ERE motifs in ERα promoters, creating a feedback loop controlling estrogen sensitivity.

    Evidence siRNA knockdown, overexpression, ChIP, and promoter analysis in endometriotic stromal cells

    PMID:19001520

    Open questions at the time
    • Cofactors at AP-1/Sp1 sites not identified
    • Restricted to endometriotic stromal context
  11. 2008 Medium

    Extended ERβ function to behavior and neuroimmune regulation, implicating it in anxiolysis and in non-hematopoietic control of autoimmune neuroinflammation.

    Evidence ERβ-knockout/heterozygous mice in anxiety tests and EAE with reciprocal bone marrow chimeras and cytokine assays

    PMID:15161628 PMID:18996135

    Open questions at the time
    • Anxiolytic effect partial and dose-restricted, single lab
    • Non-hematopoietic cell type mediating EAE heterosis unresolved
  12. 2009 Medium

    Identified an anti-inflammatory mechanism whereby ERβ agonism suppresses macrophage iNOS by blocking NF-κB p65 nuclear translocation independent of ERK.

    Evidence ERB-041 and U0126 treatment with immunoblotting in endometriosis peritoneal macrophages

    PMID:19447495

    Open questions at the time
    • Direct ERβ–NF-κB interaction not demonstrated
    • Single lab, pharmacological only
  13. 2013 High

    Demonstrated cell-autonomous ERβ requirement in oligodendrocytes for agonist-driven remyelination via PI3K/Akt/mTOR.

    Evidence Oligodendrocyte-specific conditional ERβ knockout in EAE with electrophysiology, immunostaining, and pathway Western blots

    PMID:24191028

    Open questions at the time
    • Direct transcriptional targets in oligodendrocytes not defined
    • Whether effect is genomic or non-genomic unclear
  14. 2014 Medium

    Separated ERβ-specific circadian effects from ERα, showing ERβ activation reshapes locomotor activity distribution and phase responses.

    Evidence Selective agonists (PPT vs DPN) in ovariectomized mice with wheel-running and phase-response analysis

    PMID:24735329

    Open questions at the time
    • Brain locus and target genes unidentified
    • Single lab pharmacological dissection
  15. 2016 High

    Provided human genetic proof that ERβ loss causes unopposed ERα signaling and tumorigenic proliferation, including de-repression of the RET promoter.

    Evidence Exome sequencing of a c.948delT frameshift with ERE/RET reporter, proliferation assays, and tumor immunostaining

    PMID:26945007

    Open questions at the time
    • Single patient/mutation
    • Full spectrum of de-repressed targets not catalogued
  16. 2018 High

    Established ERβ's DNA-binding transcriptional activity as indispensable for ovulation and identified Kiss1 as a direct granulosa-cell target activated via promoter/enhancer EREs and gonadotropin-driven ERK phosphorylation.

    Evidence Esr2-null and DBD-mutant rats, granulosa-cell RNA-seq, ChIP, ERE-mutagenesis reporter assays, and kinase assays

    PMID:29580824 PMID:30277501

    Open questions at the time
    • Functional hierarchy among the 1,696 DEGs unresolved
    • Role of ERβ phosphorylation site mutants not directly tested
  17. 2017 High

    Defined cardioprotective mechanisms by which E2/ERβ limits hypertrophy through Ca²⁺-calcineurin inhibition and limits apoptosis via PI3K/Akt/MDM2-mediated calcineurin degradation.

    Evidence ERβ overexpression in H9c2 cardiomyoblasts with pharmacological epistasis (CsA, BAPTA) and Western blots

    PMID:28441761 PMID:28863192

    Open questions at the time
    • Genomic vs non-genomic contribution not separated
    • In vivo cardiac validation absent
    • Apoptosis arm single lab/single method
  18. 2020 High

    Defined ERβ as a transcription-dependent gatekeeper of the primordial follicle reserve, suppressing AKT/ERK/mTOR follicle activation, an effect specific to ERβ and not ERα.

    Evidence Esr2-null and DBD-mutant rats, ERβ agonist/antagonist (DPN/PHTPP), follicle counting, hormone measurement, and pathway Western blots; CRISPR full-gene-deletion mouse confirming sex-specific reproductive requirement

    PMID:32141511 PMID:32703416

    Open questions at the time
    • Direct intrafollicular target genes controlling activation unconfirmed
    • Cell-of-origin (granulosa vs oocyte) of the signal unresolved
  19. 2024 Medium

    Extended ERβ as a transcriptional regulator into neural and joint contexts, repressing miR-10a to control BDNF/synaptic plasticity and acting via an LXA4/ESR2/LPAR3/Nrf2 axis to inhibit ferroptosis.

    Evidence Postpartum depression mouse models, primary neurons, luciferase reporters; KOA rat models with LPAR3 gain/loss and PHTPP antagonism

    PMID:38754271 PMID:39588356

    Open questions at the time
    • Direct ERβ binding to miR-10a and LPAR3 loci not shown
    • Single lab for each axis
    • Causal hierarchy within multi-node pathways inferred

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ERβ's genomic (ERE/Sp1/AP-1 binding) and non-genomic (p38, PI3K/Akt) activities are integrated within a given cell to specify antiproliferative, pro-apoptotic, or protective outcomes remains unresolved.
  • No unified model linking conformation, dimer composition, and signaling output
  • Tissue-specific coregulator complements largely uncatalogued
  • Endogenous direct target gene atlas incomplete outside ovary

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1474165 Reproduction 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2
Partners
CBP/P300ESR1

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 ESR2 (ERβ) was cloned as a novel estrogen receptor with high conservation in the DNA-binding domain (96%) and ligand-binding domain (58%) relative to ERα. Transient transfection of ESR2 with an ERE-based reporter in CHO cells demonstrated 17β-estradiol-induced transactivation, and ICI-164384 (an ERα antagonist) also acts as a potent antagonist for ESR2. ESR2 shows lower transactivation levels than ERα under equivalent conditions. Degenerate PCR cloning, sequence homology analysis, transient transfection reporter assay, pharmacological antagonism FEBS letters High 8769313
1999 ERβ and ERα adopt distinct ligand-dependent conformational changes when bound to estradiol versus 4-OH tamoxifen, as revealed by differential peptide binding surfaces on each receptor complex. These conformation-specific peptides can discriminate between ERα and ERβ ligand complexes, providing a structural basis for isoform- and ligand-specific biological activities. Affinity selection of peptides to probe receptor conformation (peptide phage display / affinity selection) on apo-ER and ligand-bound ER complexes Proceedings of the National Academy of Sciences of the United States of America High 10097152
2000 ERβ (ESR2) modulates ERα activity in the uterus: BERKO (ERβ knockout) mice exhibit elevated progesterone receptor, increased Ki-67, and exaggerated E2 responses (uterine enlargement, elevated C3, IL-1β, VEGF, IGF-1), demonstrating that ERβ has an antiproliferative, modulatory function opposing ERα-mediated actions. ERβ knockout mouse model (BERKO), immunohistochemistry, protein quantification, hormonal challenge experiments Proceedings of the National Academy of Sciences of the United States of America High 10823946
2001 ERβ (ESR2), when 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, induces pS2, TGFα, and p21 expression, inhibits cell proliferation in a ligand-independent manner, and decreases cell motility and invasion. Unlike ERα, ERβ does not regulate c-myc expression. Adenoviral vector-mediated expression, RT-PCR, Western blot, immunocytochemistry, ERE-reporter transactivation assay, proliferation assay, invasion/motility assay Endocrinology High 11517191
2003 ERα and ERβ form functional heterodimers when coexpressed; ERβ exhibits inhibitory action on ERα-mediated gene expression in multiple cell-type and promoter contexts, opposing ERα transcriptional activity. Transient transfection, reporter gene assays, coexpression studies (review summarizing experimental evidence) Molecular interventions Medium 14993442
2004 Both ERα and ERβ can independently mediate E2-induced proliferation in mammary gland epithelial cells. ERβ facilitates the return of ERα to the nucleus after E2-induced nuclear export, thereby restoring E2 responsiveness. After E2 treatment, ERα is lost from nuclei of epithelial cells within 4 h; in ERβ-knockout mice, re-entry of ERα is delayed by an additional 24 h. Tamoxifen treatment retains ERα but loses ERβ from the nucleus. BrdUrd incorporation assay, immunohistochemistry with subtype-specific antibodies, ERβ-knockout (ERβ−/−) mouse model, hormonal challenge Proceedings of the National Academy of Sciences of the United States of America High 14762170
2005 The E2-ERβ complex rapidly and persistently activates p38/MAPK, leading to caspase-3 activation and PARP cleavage, driving cells into apoptosis. In contrast to E2-ERα, the E2-ERβ complex does not activate ERK/MAPK or PI3K/AKT survival pathways. These non-genomic signaling differences were demonstrated in cells containing endogenous (HepG2, DLD1) or transfected (HeLa) ERβ or ERα. Transient transfection, kinase activation assays (ERK/MAPK, p38/MAPK, PI3K/AKT), caspase-3 activity assay, PARP cleavage, cell growth/apoptosis measurements in multiple cell lines Journal of cellular physiology High 15389627
2006 ESR2 isoforms β2, β4, and β5 lack a functional helix 12 (required for coactivator binding); they cannot form homodimers and have no intrinsic transactivation activity. However, they heterodimerize with ERβ1 and enhance its transactivation in a ligand-dependent manner. ERβ1 is the obligatory partner in ERβ dimers; a single functional helix 12 per dimer is sufficient for gene transactivation. ERβ1 preferentially forms heterodimers with other isoforms under estrogen but not phytoestrogen stimulation. Molecular modeling, transient transfection reporter assays, dimerization assays (co-immunoprecipitation), isoform-specific expression from prostate cell line Proceedings of the National Academy of Sciences of the United States of America High 16938840
2008 ERβ (ESR2) suppresses ERα gene expression in endometriotic stromal cells by binding to non-classical AP-1 and Sp1 motifs in ERα promoters A and C, and to a classic ERE in promoter B (shown by ChIP). ERβ knockdown increases ERα mRNA and protein; ERβ overexpression decreases ERα mRNA and protein. ERβ also regulates cell cycle progression in endometriotic stromal cells. siRNA knockdown, overexpression, RT-PCR, Western blot, chromatin immunoprecipitation (ChIP), promoter analysis The Journal of clinical endocrinology and metabolism High 19001520
2008 ERβ (ESR2) mediates anxiety-regulation: lower-dose E2 treatment exerts anxiolytic effects partially through ERβ in female mice, as ERβ-knockout (betaERKO) mice show attenuated anxiolytic responses in the social investigation test compared to wild-type, while high-dose E2 anxiogenic effects are ERβ-independent. ERβ-knockout mouse model, light-dark transition test, elevated plus-maze test, social investigation test, estradiol dose-response Physiology & behavior Medium 18996135
2008 ESR2 loss-of-function in male mice (Esr2−/−) does not alter EAE disease severity, while heterozygosity (Esr2+/−) increases disease severity with earlier onset (heterotic effect). Bone marrow chimera experiments established that the heterotic effect at Esr2 in regulating EAE severity is a function of the non-hematopoietic compartment. ESR2 genotype-dependently regulates IL-6 and TNF-α cytokine secretion. ERβ-knockout and heterozygous mouse models, EAE immunization, reciprocal bone marrow chimeras, cytokine assays (proliferation, IL-2, IFN-γ, IL-6, TNF-α, MCP-1) The American journal of pathology High 15161628
2008 ERβ (ESR2) attenuates ERα-mediated transcriptional activation of the BRCA2 promoter: ERβ interacts with ERα and CBP/p300, forming a weak activating complex that competes with the ERα-CBP/p300-p68/p72-MyoD complex for Sp1 binding sites on the BRCA2 promoter, reducing histone acetylation and BRCA2 transcription. Co-immunoprecipitation, ChIP, reporter gene assay, site-directed mutagenesis of Sp1 sites, Western blot for histone acetylation The Journal of biological chemistry High 18765668
2013 ERβ (ESR2) expression specifically in oligodendrocytes (OLs) is required for the neuroprotective and pro-myelination effects of the ERβ agonist DPN in EAE mice. Conditional deletion of ERβ in OLs prevented DPN-induced decrease in EAE clinical disease, blocked DPN-induced attenuation of demyelination, impaired axon conduction recovery, and abolished PI3K/Akt/mTOR pathway activation in OLs, while BDNF upregulation by DPN was preserved. Conditional Cre-loxP knockout of ESR2 in oligodendrocytes, EAE model, electrophysiology (axon conduction), immunostaining, Western blot (PI3K/Akt/mTOR), ELISA (BDNF) Proceedings of the National Academy of Sciences of the United States of America High 24191028
2014 ESR2 activation (using the selective agonist diarylpropionitrile, DPN) modifies the distribution of daily locomotor activity, delays acrophase of wheel running, and advances the time of activity onset in ovariectomized female mice; DPN also attenuates photic phase-shifting in the early subjective night. These effects are distinct from ESR1-mediated effects on total activity and amplitude. Ovariectomy, selective ESR1/ESR2 agonist administration (PPT vs. DPN), wheel-running activity measurement, free-running period analysis, light-pulse phase-response curve Endocrinology Medium 24735329
2016 A germline ESR2 frameshift mutation (c.948delT) causes loss of ERβ expression and results in unopposed ERα-mediated transcriptional activation. In vitro, this ESR2 mutation leads to increased cellular proliferation, activation of ERE-containing reporters, and increased RET promoter-driven expression (the RET promoter contains three EREs). ERβ normally represses ERα-mediated activation of the RET promoter. Exome resequencing, in vitro reporter assay (ERE and RET promoter), cell proliferation assay, immunostaining for RET protein in tumor tissue Human molecular genetics High 26945007
2017 E2/ERβ suppresses isoproterenol (ISO)-induced cardiomyocyte hypertrophy by inhibiting Ca2+-calcineurin signaling: ERβ overexpression and/or E2 treatment blocked ISO-induced upregulation of ANP, BNP, p-CaMKII, calcineurin, p-GATA4, and NFATc3, and inhibited NFATc3 nuclear translocation. The calcineurin inhibitor CsA confirmed calcineurin as the key mediator; calcium chelation (BAPTA) blocked the anti-hypertrophic effect, establishing that ERβ acts by reducing Ca2+ influx and thereby inhibiting calcineurin to activate I-1 protein, suppress PP1, and enhance PLB phosphorylation to restore SR Ca2+ cycling. ERβ overexpression in H9c2 cardiomyoblasts, Western blot, immunofluorescence (NFATc3 translocation), pharmacological inhibitors (CsA, BAPTA), ISO-induced hypertrophy model PloS one High 28863192
2017 E2/ERβ inhibits isoproterenol-induced myocardial cell apoptosis by promoting calcineurin protein degradation through activation of the PI3K/Akt/MDM2 signaling pathway, suppressing cytochrome c release and downstream apoptotic markers. ERβ overexpression in H9c2 cells, ISO-induced apoptosis model, Western blot (calcineurin, PI3K/Akt/MDM2, cytochrome c, apoptosis markers) International journal of molecular sciences Medium 28441761
2018 ESR2 regulates granulosa cell genes essential for follicle maturation and ovulation. Both null and DNA-binding domain (DBD) mutant ESR2 rats fail to ovulate, demonstrating that ESR2 transcriptional activity (via DNA binding) is indispensable for ovulation. RNA-seq identified 1,696 differentially expressed genes in Esr2-mutant granulosa cells including steroidogenesis, follicle maturation, and ovulation pathways; Kiss1 was identified as an ESR2-regulated gene in granulosa cells. Esr2-null and DBD-mutant rat models, exogenous gonadotropin stimulation, granulosa cell isolation, RNA-sequencing, molecular pathway analysis Molecular and cellular endocrinology High 29580824
2018 ESR2 is required for gonadotropin-induced Kiss1 expression in granulosa cells. ESR2 binds directly to estrogen response elements (EREs) in the Kiss1 promoter and both upstream and downstream enhancers (shown by ChIP). ESR2 overexpression induces Kiss1 promoter activity, and ERE mutation abolishes this induction. Gonadotropins induce ERK2-mediated ESR2 phosphorylation, upregulate AP-1 factors (FOSL2, JUNB), which synergistically activate the Kiss1 promoter together with ESR2. ChIP, reporter gene/luciferase assay, ERE site-directed mutagenesis, ESR2 overexpression, kinase phosphorylation assays, Esr2-null rat model Endocrinology High 30277501
2020 ESR2 acts as a gatekeeper to maintain the primordial follicle reserve by suppressing follicle activation. Esr2-null (Esr2−/−) rats show increased activation of primordial follicles (not increased total follicle number), premature ovarian senescence, reduced serum AMH and estradiol. ESR2-specific antagonist (PHTPP) increases activated follicle counts; ESR2 agonist (DPN) decreases activation. ESR1 loss does not increase primordial follicle activation (ESR2-specific effect). ESR2 loss augments AKT, ERK, and mTOR pathway activation in both granulosa cells and oocytes, suggesting a direct intrafollicular regulatory mechanism via canonical transcriptional function (DNA-binding domain mutant also shows increased activation). Esr2-null and DBD-mutant rat models, selective agonist/antagonist treatment, follicle counting, hormone measurement (AMH, estradiol), Western blot (AKT, ERK, mTOR phosphorylation) Endocrinology High 32141511
2020 ESR2 (ERβ) generates an all-exon deleted mouse (Esr2ΔE1-10). Female Esr2ΔE1-10 mice are subfertile at young age and become infertile/severely subfertile by ~6 months. Ovaries are smaller with very few corpora lutea (defect in ovulation), and estradiol levels are reduced at diestrus. Male Esr2ΔE1-10 mice are fertile, establishing that ERβ is required for female but not male reproductive function. CRISPR/Cas9 full-gene deletion, fertility tracking (litter number, litter size), ovarian histomorphology, hormone measurement (serum estradiol) Biochemical and biophysical research communications High 32703416
2009 ERβ agonist ERB-041 inhibits LPS-induced iNOS production in peritoneal macrophages of endometriosis by suppressing NF-κB nuclear translocation (preventing p65 nuclear accumulation), but does not act through the ERK pathway (ERK activity is not repressed by ER activation). Peritoneal macrophages from endometriosis patients express higher levels of ERβ relative to ERα. RT-PCR, immunoblot (ERα/ERβ expression, iNOS, p65, ERKs), pharmacological treatment with ERB-041 (ERβ agonist) and U0126 (ERK inhibitor), LPS stimulation Molecular immunology Medium 19447495
2019 ERβ (ER-β) regulates FATP1/SLC27A1 expression in breast cancer cells: treatment with estradiol plus the ERβ antagonist PHTPP blocked estradiol-induced FATP1/SLC27A1 upregulation, fatty acid uptake, and cell viability in four breast cancer cell lines, establishing ERβ as the receptor mediating these estrogen effects on fatty acid transport. Pharmacological ERβ antagonism (PHTPP), estradiol treatment, RT-qPCR/protein expression, fatty acid uptake assay, cell viability assay in 4 breast cancer cell lines Scientific reports Medium 31575907
2024 ESR2 acts as a negative transcription factor to down-regulate miR-10a transcription in the prefrontal cortex; miR-10a-5p in turn suppresses BDNF expression. This ESR2→miR-10a-5p→BDNF axis affects synaptic plasticity (synapse-related proteins SYP, SYN, PSD95 and glutamate receptor expression) and contributes to postpartum depressive-like behavior. Bioinformatics, in vivo mouse models, cell transfection, and primary neuron cultures were used to validate the pathway. Bioinformatics, in vivo behavioral studies (postpartum depression mouse model), cell transfection, primary neuron culture, stereotactic/intranasal antagomir delivery, Western blot (synaptic proteins), luciferase reporter Research (Washington, D.C.) Medium 39588356
2024 ESR2 activation by LXA4 inhibits ferroptosis in fibroblast-like synoviocytes (FLSs) through the ESR2/LPAR3/Nrf2 axis: LXA4 upregulates ESR2, LPAR3, and GPX4 in FLSs. LPAR3 overexpression upregulates GPX4, Nrf2, and SOD1 while downregulating MMP13 and MMP3; LPAR3 knockdown reverses these changes. The ESR2 antagonist PHTPP partially reversed the beneficial effects of exercise on synovial and cartilage pathology in a rat KOA model. GSE29746 dataset analysis, synovial tissue sampling from KOA patients, LPAR3 overexpression/knockdown in vitro, rat MIA-induced KOA model, ESR2 antagonist (PHTPP) treatment, Western blot (GPX4, Nrf2, SOD1, MMPs) Redox biology Medium 38754271

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1986 Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 2086 3754034
1996 ER beta: identification and characterization of a novel human estrogen receptor. FEBS letters 1839 8769313
1986 Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature 1254 3003577
2012 Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 878 22460952
2012 Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 684 22460951
2003 Estrogen signaling: a subtle balance between ER alpha and ER beta. Molecular interventions 572 14993442
2014 REV-ERB and ROR nuclear receptors as drug targets. Nature reviews. Drug discovery 473 24577401
2000 Estrogen receptor (ER) beta, a modulator of ERalpha in the uterus. Proceedings of the National Academy of Sciences of the United States of America 397 10823946
1999 Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. Proceedings of the National Academy of Sciences of the United States of America 366 10097152
2001 ER beta inhibits proliferation and invasion of breast cancer cells. Endocrinology 340 11517191
2006 Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Proceedings of the National Academy of Sciences of the United States of America 313 16938840
1997 Expression of oestrogen receptor beta (ER beta) in multiple rat tissues visualised by immunohistochemistry. The Journal of endocrinology 270 9379111
2001 Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. British journal of cancer 257 11355950
1999 HER-2/neu (c-erb-B2) gene and protein in breast cancer. American journal of clinical pathology 231 10396301
2005 Survival versus apoptotic 17beta-estradiol effect: role of ER alpha and ER beta activated non-genomic signaling. Journal of cellular physiology 176 15389627
2009 Rev-erb-alpha: an integrator of circadian rhythms and metabolism. Journal of applied physiology (Bethesda, Md. : 1985) 144 19696364
2019 SR9009 has REV-ERB-independent effects on cell proliferation and metabolism. Proceedings of the National Academy of Sciences of the United States of America 141 31127047
1999 Oestrogen receptor (ER)-alpha and ER-beta isoforms in normal endometrial and endometriosis-derived stromal cells. Molecular human reproduction 141 10381820
2011 The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology. The International journal of developmental biology 136 22161825
2004 Estrogen receptor beta (ER beta) level but not its ER beta cx variant helps to predict tamoxifen resistance in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 134 15355905
2002 Ionizing radiation activates Erb-B receptor dependent Akt and p70 S6 kinase signaling in carcinoma cells. Oncogene 134 12037685
2011 Direct regulation of CLOCK expression by REV-ERB. PloS one 130 21479263
2005 Estrogen and the brain: beyond ER-alpha, ER-beta, and 17beta-estradiol. Annals of the New York Academy of Sciences 129 16024756
2008 Estrogen receptor (ER) beta regulates ERalpha expression in stromal cells derived from ovarian endometriosis. The Journal of clinical endocrinology and metabolism 114 19001520
2004 Estrogen receptors ER alpha and ER beta in proliferation in the rodent mammary gland. Proceedings of the National Academy of Sciences of the United States of America 114 14762170
2010 Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology 111 20427485
2005 Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle. American journal of physiology. Heart and circulatory physiology 106 15863464
2021 Estrogen and Glycemic Homeostasis: The Fundamental Role of Nuclear Estrogen Receptors ESR1/ESR2 in Glucose Transporter GLUT4 Regulation. Cells 85 33430527
2007 Rev-erb alpha gives a time cue to metabolism. FEBS letters 83 17765229
2004 Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer. British journal of cancer 83 15477868
1998 Oestrogen receptor beta (ER beta). Reviews of reproduction 81 9829551
2017 Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism. PloS one 79 29232411
2022 Myocardial Rev-erb-Mediated Diurnal Metabolic Rhythm and Obesity Paradox. Circulation 78 35034472
2004 Estrogen and the brain: beyond ER-alpha and ER-beta. Experimental gerontology 72 15582272
2018 ESR2 regulates granulosa cell genes essential for follicle maturation and ovulation. Molecular and cellular endocrinology 71 29580824
2021 REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity. Nature 68 33762728
2013 Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand. Proceedings of the National Academy of Sciences of the United States of America 67 24191028
2002 Human oestrogen receptors: differential expression of ER alpha and beta and the identification of ER beta variants. Steroids 67 12398995
2008 Effect of ER-beta gene disruption on estrogenic regulation of anxiety in female mice. Physiology & behavior 61 18996135
2022 Clinical associations of ESR2 (estrogen receptor beta) expression across thousands of primary breast tumors. Scientific reports 59 35304506
2001 Expression of the c-erb-B2 and p53 protein in gallbladder carcinomas. Oncology reports 58 11496329
2005 Estrogen receptor beta (ESR2) polymorphisms in familial and sporadic breast cancer. Breast cancer research and treatment 57 16261413
2002 Expression of ER-alpha and ER-beta in the hamster ovary: differential regulation by gonadotropins and ovarian steroid hormones. Endocrinology 56 12021204
2014 Sex-specific Esr2 mRNA expression in the rat hypothalamus and amygdala is altered by neonatal bisphenol A exposure. Reproduction (Cambridge, England) 50 24352099
2024 Deciphering and Targeting the ESR2-miR-10a-5p-BDNF Axis in the Prefrontal Cortex: Advancing Postpartum Depression Understanding and Therapeutics. Research (Washington, D.C.) 49 39588356
2017 Rev-erb-α regulates atrophy-related genes to control skeletal muscle mass. Scientific reports 47 29085009
2008 Genetic polymorphisms of ESR1 and ESR2 that may influence estrogen activity and the risk of hypospadias. Human reproduction (Oxford, England) 45 18375409
2014 ESR1 and ESR2 differentially regulate daily and circadian activity rhythms in female mice. Endocrinology 44 24735329
2004 The expression of oestrogen receptor (ER)-beta and its variants, but not ERalpha, in adult human mammary fibroblasts. Journal of molecular endocrinology 44 15291741
2008 ER-beta expression in large bowel adenomas: implications in colon carcinogenesis. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 43 18093886
1988 Hypomethylation of ornithine decarboxylase gene and erb-A1 oncogene in human chronic lymphatic leukemia. Blood 42 2904292
2002 Gene amplification and protein overexpression of c-erb-b2 in Barrett carcinoma and its precursor lesions. American journal of clinical pathology 41 12109857
1998 c-myc, c-erb-B2, nm23 and p53 expression in human endometriosis. Oncology reports 40 9458291
2024 Lipoxin A4 ameliorates knee osteoarthritis progression in rats by antagonizing ferroptosis through activation of the ESR2/LPAR3/Nrf2 axis in synovial fibroblast-like synoviocytes. Redox biology 39 38754271
2020 Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication. Scientific reports 39 32764708
2011 A systematic review of the relationship between polymorphic sites in the estrogen receptor-beta (ESR2) gene and breast cancer risk. Breast cancer research and treatment 39 20390341
2020 A Gatekeeping Role of ESR2 to Maintain the Primordial Follicle Reserve. Endocrinology 38 32141511
2018 REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 38 29401617
2017 Pharmacological inhibition of REV-ERB stimulates differentiation, inhibits turnover and reduces fibrosis in dystrophic muscle. Scientific reports 37 29215066
2013 REV-ERB-ALPHA circadian gene variant associates with obesity in two independent populations: Mediterranean and North American. Molecular nutrition & food research 37 24173768
2001 Expression of estrogen receptor (ER-alpha and ER-beta) mRNA in human prostate cancer. European urology 37 11752866
1986 Amplification of RNA and DNA specific for erb B in unbalanced 1;7 chromosomal translocation associated with myelodysplastic syndrome. Journal of cellular biochemistry 36 3464613
2014 ESR1 and ESR2 gene polymorphisms are associated with human reproduction outcomes in Brazilian women. Journal of ovarian research 34 25526766
2012 ESR1, ESR2 and FSH receptor gene polymorphisms in combination: a useful genetic tool for the prediction of poor responders. Current pharmaceutical biotechnology 33 21658000
2004 Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice. The American journal of pathology 32 15161628
2022 Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB. Nature communications 30 36414641
2008 Estrogen receptors alpha (ESR1) and beta (ESR2) are expressed in circulating human lymphocytes. Journal of receptor and signal transduction research 30 18569528
2008 Estrogen receptor (ER) beta or p53 attenuates ERalpha-mediated transcriptional activation on the BRCA2 promoter. The Journal of biological chemistry 30 18765668
2017 Rev-erb regulation of cholesterologenesis. Biochemical pharmacology 29 28213272
2017 Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome. Molecular metabolism 29 28702326
2004 Estrogen receptor beta (ESR2 ) polymorphisms and endometrial cancer (United States). Cancer causes & control : CCC 28 15280642
2016 Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression. Human molecular genetics 27 26945007
2020 The transcriptional repressor REV-ERB as a novel target for disease. Bioorganic & medicinal chemistry letters 26 32738989
2019 Unraveling FATP1, regulated by ER-β, as a targeted breast cancer innovative therapy. Scientific reports 26 31575907
2018 ESR2 Is Essential for Gonadotropin-Induced Kiss1 Expression in Granulosa Cells. Endocrinology 25 30277501
2011 The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide. Pharmacogenomics 24 21174621
2009 ERB-041, a selective ER beta agonist, inhibits iNOS production in LPS-activated peritoneal macrophages of endometriosis via suppression of NF-kappaB activation. Molecular immunology 24 19447495
2008 Development of ER-alpha and ER-beta expression in the developing ovine brain and pituitary. Gene expression patterns : GEP 24 18424193
2016 Rev-erb agonist and TGF-β similarly affect autophagy but differentially regulate hepatic stellate cell fibrogenic phenotype. The international journal of biochemistry & cell biology 23 27840152
2014 Association of polymorphisms in estrogen receptors (ESR1 and ESR2) with male infertility: a meta-analysis and systematic review. Journal of assisted reproduction and genetics 22 24647635
2020 Association of estrogen receptor gene variants (ESR1 and ESR2) with polycystic ovary syndrome in Tunisia. Gene 21 32169631
2018 HSD3B2, HSD17B1, HSD17B2, ESR1, ESR2 and AR expression in infertile women with endometriosis. Ginekologia polska 21 29664547
2014 The influence of ESR1 rs9340799 and ESR2 rs1256049 polymorphisms on prostate cancer risk. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 21 24859835
1995 Expression of c-erb B-2 protein and DNA ploidy in breast carcinogenesis. Archives of pathology & laboratory medicine 21 7668939
2018 Genetic association between HER2 and ESR2 polymorphisms and ovarian cancer: a meta-analysis. OncoTargets and therapy 20 29535531
2011 Investigation on association and expression of ESR2 as a candidate gene for boar sperm quality and fertility. Reproduction in domestic animals = Zuchthygiene 20 22212297
2020 Methylation of estrogen receptor 2 (ESR2) in deep paravertebral muscles and its association with idiopathic scoliosis. Scientific reports 19 33339862
2010 ER-β mediates 17β-estradiol attenuation of HIV-1 Tat-induced apoptotic signaling. Synapse (New York, N.Y.) 19 20340172
2021 Altered Expression of ESR1, ESR2, PELP1 and c-SRC Genes Is Associated with Ovarian Cancer Manifestation. International journal of molecular sciences 18 34207568
2017 E2/ER β Enhances Calcineurin Protein Degradation and PI3K/Akt/MDM2 Signal Transduction to Inhibit ISO-Induced Myocardial Cell Apoptosis. International journal of molecular sciences 18 28441761
2017 E2/ER β inhibit ISO-induced cardiac cellular hypertrophy by suppressing Ca2+-calcineurin signaling. PloS one 18 28863192
2020 Estrogen receptor (ESR1 and ESR2)-mediated activation of eNOS-NO-cGMP pathway facilitates high altitude acclimatization. Nitric oxide : biology and chemistry 17 32544536
2019 Depressive behavior induced by nonylphenol and its effect on the expression of ER-α and ER-β in nerve cells of rats. Journal of affective disorders 17 31969267
2009 Association between ESR1 and ESR2 gene polymorphisms and hyperlipidemia in Chinese Han postmenopausal women. Journal of human genetics 17 19927160
2000 The normal and malignant mammary gland: a fresh look with ER beta onboard. Journal of mammary gland biology and neoplasia 17 14973391
2020 Interaction of Coumarin Phytoestrogens with ERα and ERβ: A Molecular Dynamics Simulation Study. Molecules (Basel, Switzerland) 16 32150902
2020 Generation of an all-exon Esr2 deleted mouse line: Effects on fertility. Biochemical and biophysical research communications 16 32703416
2015 Changes in Estrogen Receptor ERβ (ESR2) Expression without Changes in the Estradiol Levels in the Prostate of Aging Rats. PloS one 16 26147849
2009 Rev-erb beta regulates the Srebp-1c promoter and mRNA expression in skeletal muscle cells. Biochemical and biophysical research communications 16 19682428
2021 Transcriptional regulation of CYP19A1 expression in chickens: ESR1, ESR2 and NR5A2 form a functional network. General and comparative endocrinology 15 34710471

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