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FLASH GENE
Symbol ESR1 contributors: mct - updated : 17-04-2014
HGNC name estrogen receptor 1
HGNC id 3467
Location 6q25.1      Physical location : 152.011.630 - 152.424.406
Synonym name
  • estrogen receptor alpha
  • nuclear receptor subfamily 3 group A member 1
  • estrogen receptor alpha delta 4*,5,6,7*/633 isoform
  • Synonym symbol(s) ER, NR3A1, ERA, ESRA, DKFZp686N23123, ER-alpha
    DNA
    TYPE functioning gene
    STRUCTURE 412.78 kb     10 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter (TATA box)
    alternative promoter
    cytosine-phosphate-guanine/HTF
    Binding site
    text structure
  • ligand binding domain
  • promoter, approximately 16 kb upstream of the first coding exon with TATA box,predominantly active only in testis and epididymal tissues
  • MAPPING cloned Y linked N status confirmed
    Physical map
    LRP11 6q24.3 low density lipoprotein receptor-related protein 11 RAET1E 6q25 retinoic acid early transcript 1E ULBP2 6q25 UL16 binding protein 2 ULBP1 6q25 UL16 binding protein 1 LOC345829 6q24.3 similar to Transcription factor BTF3 (RNA polymerase B transcription factor 3) LOC391980 6 similar to UL16 binding protein 1; alcan-beta RAET1L 6q25 retinoic acid early transcript 1L PHBP1 6q25 prohibitin pseudogene 1 ULBP3 6q25 UL16 binding protein 3 PPP1R14C 6q24.3-q25.3 protein phosphatase 1, regulatory (inhibitor) subunit 14C RNU4P1 6q25.1 RNA, U4 small nuclear pseudogene 1 (U4/7) LOC389434 6 similar to iodotyrosine dehalogenase protein PLEKHG1 6q25.1 pleckstrin homology domain containing, family G (with RhoGef domain) member 1 FTHFSDC1 6q25.1 formyltetrahydrofolate synthetase domain containing 1 LOC391982 6 similar to ribosomal protein S12 AKAP12 6q24-q25 a kinase (PRKA) anchor protein (gravin) 12 ZBTB2 6q25.1 zinc finger and BTB domain containing 2 C6orf96 6q25.1 chromosome 6 open reading frame 96 C6orf211 6q25.1 chromosome 6 open reading frame 211 C6orf97 6q25.1 chromosome 6 open reading frame 97 ESR1 6q25.1 estrogen receptor 1 SYNE1 6q25 spectrin repeat containing, nuclear envelope 1 MYCT1 6q25.1 myc target 1 VIP 6q24-q27 vasoactive intestinal peptide LOC391983 6 similar to Tubulin beta-2 chain FBXO5 6q25-q26 F-box only protein 5 MTRF1L 6q25-q26 mitochondrial translational release factor 1-like RGS17 6q25-q26 regulator of G-protein signalling 17 LOC389435 6 similar to 60S ribosomal protein L27a
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    - - - - - only in the human breast adenocarcinoma cell line, MCF7 2013 23032375
    untranslated exons, N1
    8 - 6330 66 595 - 2006 16636675
    9 - 6357 66 595 - 2006 16636675
    9 - 6314 66 595 - 2006 16636675
    10 - 6466 66 595 - 2006 16636675
    - - - - - expressed in the adult liver and MCF7 cells 2013 23032375
    untranslated exons, N2
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Reproductivefemale systembreast  highly Homo sapiens
     female systemovary  highly Homo sapiens
     male systemprostate  highly
    Urinarykidney   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadiposebrown highly Homo sapiensFetal
    Muscularstriatumskeletal highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
     adipocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal modulator domain
  • a central bipartite zinc finger DNA binding domain
  • a nuclear localization signal (NLS)
  • a DNA binding domain required for high-affinity nuclear interaction induced by estradiol (Weinberg 2007)
  • a C terminal ligand binding domain, including a transactivation and dimerization domain, translocation of ESR1 from cell membrane to nucleus is mediated by MAP kinase and ligand independent
  • conjugated GlycoP , PhosphoP
    mono polymer homomer , heteromer , dimer
    HOMOLOGY
    interspecies homolog to murine Esr1 (89.6pc)
    homolog to rattus Esr1 (88.9pc)
    Homologene
    FAMILY
  • nuclear hormone receptor family
  • NR3 subfamily
  • CATEGORY transcription factor , receptor nuclear
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,nucleus,nucleoplasm
    text
  • translocation of ESR1 from all membrane to nucleus is mediated by MAP kinase and ligand independent
  • under an unstimulated condition, resides in the cytoplasm; upon binding to its hormone ligands, such as 17beta-estradiol, ESR1 dimerize and translocates into the nucleus
  • basic FUNCTION
  • ligand-activated transcription factor involved in hormone-mediated inhibition of gene expression, by binding estrogen responsive element (ERE) or interacting with other transcription factors (like FOXA1)
  • playing an important role in mediating estrogen signaling and having an effect on menarcheal age
  • involved in the regulation of gene expression and affects cellular proliferation and differentiation
  • BARX2 and ESR1 may coordinately regulate cell growth, survival and invasion pathways that are critical to breast cancer progression
  • ESR1 is co-expressed with C6ORF211, spanning a breast cancer susceptibility locus
  • cross-talk of distinct modifications in the hinge region of ESR1 plays an important role in fine tuning the functions of ESR1 at chromatin in hormone response
  • potential role for ESR1, ESR2 in fetal brown adipose tissue development, primarily via ESR1
  • possible role of both ESR1, ESR2 in mitochondriogenesis
  • CELLULAR PROCESS nucleotide, transcription, initiation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling hormonal
    estrogen
    a component
  • heterodimerizing with ESR2
  • INTERACTION
    DNA binding to estrogen responsive element (ERE)
    RNA
    small molecule
    protein
  • PI3K
  • SMAD1, SMAD2, SMAD3, SMAD4
  • NCOA3, NCOA5, NCOA6, NCOA7
  • PHB2, PECP1, UBE1C, AKAP13, CUEDC2, KDM5A, HEXIM1, MAP1S, PBXIP1
  • MUC1, DNTTIP2, FAM120B, UIMC1, TXNRD1, MLL2, ATAD2, KIF18A
  • LDB1, RLIM, MACROD1, FOXL2, SH2D4A, PLCG, SLC30A9
  • BARX2 and ESR1 proteins bind to different ESR1 gene promoters and regulate the expression of alternatively spliced mRNAs that encode 66 and 46 kDa ESR1 protein isoforms
  • NCOA2 interacts with ESR1, ESR2 and PGR in a subtype-specific manner, which may contribute to the functional differences of these steroid receptor subtypes in brain
  • interacts with corepressor complexes, which normally consist of histone deacetylases (HDACs), to remove acetylation on histones, leading to gene repression
  • estrogen induces the binding of the ESR1 onto the promoter of ZFHX3 and ZFHX3 is an ESR1 target gene
  • ESR1, ESR2 coordinate with MLL and MLL3 in E2-mediated transcriptional regulation of HOXB9
  • association of ESR1 and CRKL directly enhances the tumorigenic potential of CRKL, thus pointing to its role in cell proliferation
  • cooperation of KAT5 with ESR1 and other chromatin-remodeling enzymes is required for estrogen-induced transcription
  • KDM1A functions as a transcription coactivator of ESR1 and androgen receptor (AR)
  • by destabilizing ESR1, RUNX3 acts as a novel tumor suppressor in breast cancer
  • in breast cancer cells, NR5A2 promotes cell proliferation by enhancing ESR1 mediated transcription of target genes such as GREB1)
  • ESR1 interacts with both SAFB1 and SAFB2 in the presence of E2
  • TP53 is a target gene of ESR1 (feedback loop between ESR1 and TP53 and a biological role of TP53 in the DNA damage response in ER-positive breast cancers)
  • rapid, non-genomic changes in cardiac myofilament function following acute ESR1 stimulation mediated by the MAPK14 pathway
  • ESR1 regulation of its own mRNA expression is facilitated by RBCK1 recruitment, suggesting an ESR1 coactivator function of RBCK1
  • CACUL1 associated with histone demethylase KDM1A and suppressed KDM1A-enhanced ESR1 activity
  • LATS2 modulates ESR1-regulated gene transcription, through direct and/or indirect interactions with ESR1
  • HDAC3 is necessary for ESR1 mRNA stability, and is involved in the estrogen-dependent proliferation of ESR1-positive tumors
  • GRB1 is a chromatin-bound ESR1 coactivator and is essential for ESR1-mediated transcription, because it stabilizes interactions between ESR1 and additional cofactors
  • PDZK1 expression was indirectly regulated by ESR1 stimulation, requiring IGF1R expression and function
  • plays a crucial role in decreasing HIF1A protein levels in osteoclasts, even in hypoxic conditions (
  • PRL promotes pubertal ESR1-dependent mammary ductal elongation and gene expression in the absence of estrogen, which are abrogated by the antiestrogen
  • role for HOXA7 in modulating breast cancer cell proliferation via regulation of ESR1 expression
  • SMYD2 directly methylates estrogen receptor alpha (ESR1) protein at lysine 266 and represses ESR1 transactivation activity
  • SMYD2 attenuates ESR1 chromatin recruitment
  • KDM1A cooperates with EP300 to facilitate ESR1 protein acetylation and target gene activation upon estrogen stimulation
  • ESR1 stimulates likely IBSP gene transcription in a ligand-independent manner by targeting the CRE and AP1/GRE elements in the IBSP gene promoter
  • cell & other
    REGULATION
    activated by Ser164 phosphorylation through the RPS6KB1 and RPS6KA1 signaling pathways and may be a cuase of resistance to anti-estrogen therapy in breast cancer (Yamnick 2010)
    inhibited by BRCA1 (modulated by EP300)
    repressed by ZNF398
    actions of estrogen receptor alpha and SIN3A at the proximal promoter (Ellison-Zelski 2009)
    MAPK7/MAP2K5 signaling that suppresses ESR1 expression and promotes hormone-independent tumorigenesis
    Other coactivated by PPARBP
    coactivated by HRMT1L1
    direct binding to chromatin required the presence of Forkhead factor (FOXA1) binding in close proximity
    phosphorylated by cyclin A/CDK2, enhancing transcriptional activity
    deubiquitinated by OTUB1
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral fusion      
    with TNFRSF6 in several cancer cell lines (prostate, breast, cervical bladder)
    tumoral     --low  
    by hypermethylation, methylation being both age-dependent and tumor differentiation-dependent, in late- stage prostate carcinoma
    tumoral   amplification    
    in proliferative breast disease and breast cancer
    constitutional       loss of function
    inactivation through methylation of TUSC3 and ESR1 associated with ulcerative colitis, but not with colrectal carcinoma
    tumoral   amplification    
    may be an early event in endometrial carcinoma development
    Susceptibility
  • several cancer cell lines (prostate, breast, cervical bladder)
  • to reduced hip bone mass density and to risk of femoral neck bone loss in postmenopausal women
  • to low lumbar bone mass density in postmenopausal women
  • to estrogenic effects of environmental endocrine disruptors in cryptorchidism
  • to risk of hypospadias
  • to type 2 diabetes patients with nephropathy
  • to idiopathic male infertility
  • to breast cancer
  • Variant & Polymorphism SNP , repeat , other
  • (TA)n repeat variant (short alleles)
  • haplotype px associated with reduced hip bone mass density and risk of femoral neck bone loss in postmenopausal women
  • G allele containing variants of ESR1 XbaI may decrease the risk of hypospadias, whereas the ESR1 C-A haplotype may increase its risk
  • homozygosity for the specific ESR1 haplotype in the development of cryptorchidism
  • SNP increasing the risk of type 2 diabetes patients with nephropathy
  • variant associated with idiopathic male infertility
  • SNP rs2046210 at 6q25.1, located upstream of ESR1, showed strong and consistent association with breast cancer across all three stages (Zheng 2009)
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativealzheimer
    role for therapeutic selective ESR1 modulation in the attenuation or prevention of toxic oligomeric Abeta species formation in ALzheimer and related disorders
    ANIMAL & CELL MODELS
  • osteoporotic phenotype of Esr1(-/NERKI) mice may involve the suppression of Lef1-mediated Wnt signaling through both the stimulation of secreted Wnt inhibitors and/or disruption of normal CTNNB function