BioPAX pathway converted from "ESR1 binds to TFF1 gene promoter" in the Reactome database.ESR1 binds to TFF1 gene promoterESR1 binds to TFF1 gene promoterTFF1 is an estrogen-responsive gene with an ESR1-bound promoter/enhancer that is primed for ligand-dependent expression by the binding of 'pioneer' transcription factors, such as FOXA1 and GATA3 (Berry et al, 1989; Shang et al, 2000; Carroll et al, 2005; Laganière et al, 2005; Eeckhoute et al, 2006; Hurtado et al, 2011; Theodorou et al, 2013; reviewed in Klinge, 2001; Zaret and Carroll, 2011; Fiorito et al, 2013). Ligand-bound estrogen receptor binds to a functional ERE between -405 and -393 and to a region 10.5 kb upstream of the TFF1 transcription start site (Berry et al, 1989; Sewack and Hansen, 1997; Métivier et al, 2003; Carroll et al, 2005). Detailed ChIP studies of the TFF1 promoter in synchronized cells after estrogen stimulation reveal an ordered and cyclical recruitment of co-activators, chromatin remodellers and general transcriptional machinery that modify the epigenetic and chromatin environment to regulate transcriptional activity (Metivier et al, 2003; Metivier et al, 2008; Kangaspeska et al, 2008). Three phases are observed after estrogen stimulation of blocked cells, including an initial unproductive cycle followed by two transcriptionally productive cycles. These are marked by the combinatorial recruitment of different subsets of proteins and cyclical alterations to the methylation and acetylation status of the promoter (Metivier et al, 2003; Metivier et al, 2008; Kangaspeska et al, 2008; reviewed in Reid et al, 2009).Authored: Shamovsky, Veronica, 2017-06-20Reviewed: Magnani, Luca, 2018-02-23Edited: Rothfels, Karen, 2017-11-13Reactome DB_ID: 90238201nucleoplasmGO0005654TFF1 gene:FOXA1:GATA3 [nucleoplasm]TFF1 gene:FOXA1:GATA3Reactome DB_ID: 4530741UniProt:P55317 FOXA1FOXA1FOXA1HNF3ATCF3AFUNCTION Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5'-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3' (By similarity). Proposed to play a role in translating the epigenetic signatures into cell type-specific enhancer-driven transcriptional programs. Its differential recruitment to chromatin is dependent on distribution of histone H3 methylated at 'Lys-5' (H3K4me2) in estrogen-regulated genes. Involved in the development of multiple endoderm-derived organ systems such as liver, pancreas, lung and prostate; FOXA1 and FOXA2 seem to have at least in part redundant roles (By similarity). Modulates the transcriptional activity of nuclear hormone receptors. Is involved in ESR1-mediated transcription; required for ESR1 binding to the NKX2-1 promoter in breast cancer cells; binds to the RPRM promoter and is required for the estrogen-induced repression of RPRM. Involved in regulation of apoptosis by inhibiting the expression of BCL2. Involved in cell cycle regulation by activating expression of CDKN1B, alone or in conjunction with BRCA1. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis.SUBUNIT Binds DNA as a monomer (By similarity). Interacts with FOXA2. Interacts with NKX2-1. Interacts with HDAC7. Interacts with the histone H3-H4 heterodimer. Associates with nucleosomes containing histone H2A. Interacts with AR. Interacts with NR0B2 (By similarity).TISSUE SPECIFICITY Highly expressed in prostate and ESR1-positive breast tumors. Overexpressed in esophageal and lung adenocarcinomas.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtP55317Chain Coordinates1EQUAL472EQUALReactome DB_ID: 9967681UniProt:P23771 GATA3GATA3GATA3FUNCTION Transcriptional activator which binds to the enhancer of the T-cell receptor alpha and delta genes. Binds to the consensus sequence 5'-AGATAG-3'. Required for the T-helper 2 (Th2) differentiation process following immune and inflammatory responses.SUBUNIT Interacts with TBX21 ('Tyr-530' phosphorylated form).TISSUE SPECIFICITY T-cells and endothelial cells.DOMAIN Binds DNA via the 2 GATA-type zinc fingers. Each zinc finger may bind either adjacent sites in a palindromic motif, or a different DNA molecule allowing looping and long-range gene regulation.DOMAIN The YxKxHxxxRP motif is critical for DNA-binding and function.UniProtP237711EQUAL443EQUALReactome DB_ID: 90095371ENSEMBL:ENSG00000160182 TFF1TFF1BCEIPS2ENSEMBLENSG00000160182Reactome Database ID Release 719023820Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9023820ReactomeR-HSA-90238201Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9023820.1Reactome DB_ID: 90082841ESR1 dimer:estrogen [nucleoplasm]ESR1 dimer:estrogenConverted from EntitySet in ReactomeReactome DB_ID: 90082572E1, EST17b, estriol, estetrol [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityEST17b [nucleoplasm]estriol [nucleoplasm]estetrol [nucleoplasm]E1 [nucleoplasm]ChEBI16469ChEBI27974ChEBI142773ChEBI17263Reactome DB_ID: 4461682UniProt:P03372 ESR1ESR1ESRESR1NR3A1FUNCTION Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full-length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.SUBUNIT Binds DNA as a homodimer. Can form a heterodimer with ESR2. Isoform 3 can probably homodimerize or heterodimerize with isoform 1 and ESR2. Interacts with FOXC2, MAP1S, SLC30A9, UBE1C and NCOA3 coactivator (By similarity). Interacts with EP300; the interaction is estrogen-dependent and enhanced by CITED1. Interacts with CITED1; the interaction is estrogen-dependent. Interacts with NCOA5 and NCOA6 coactivators. Interacts with NCOA7; the interaction is a ligand-inducible. Interacts with PHB2, PELP1 and UBE1C. Interacts with AKAP13. Interacts with CUEDC2. Interacts with KDM5A. Interacts with SMARD1. Interacts with HEXIM1. Interacts with PBXIP1. Interaction with MUC1 is stimulated by 7 beta-estradiol (E2) and enhances ERS1-mediated transcription. Interacts with DNTTIP2, FAM120B and UIMC1. Interacts with isoform 4 of TXNRD1. Interacts with KMT2D/MLL2. Interacts with ATAD2 and this interaction is enhanced by estradiol. Interacts with KIF18A and LDB1. Interacts with RLIM (via C-terminus). Interacts with MACROD1. Interacts with SH2D4A and PLCG. Interaction with SH2D4A blocks binding to PLCG and inhibits estrogen-induced cell proliferation. Interacts with DYNLL1. Interacts with CCDC62 in the presence of estradiol/E2; this interaction seems to enhance the transcription of target genes. Interacts with NR2C1; the interaction prevents homodimerization of ESR1 and suppresses its transcriptional activity and cell growth. Interacts with DNAAF4. Interacts with PRMT2. Interacts with PI3KR1 or PI3KR2, SRC and PTK2/FAK1. Interacts with RBFOX2. Interacts with STK3/MST2 only in the presence of SAV1 and vice-versa. Binds to CSNK1D. Interacts with NCOA2; NCOA2 can interact with ESR1 AF-1 and AF-2 domains simultaneously and mediate their transcriptional synergy. Interacts with DDX5. Interacts with NCOA1; the interaction seems to require a self-association of N-terminal and C-terminal regions. Interacts with ZNF366, DDX17, NFKB1, RELA, SP1 and SP3. Interacts with NRIP1 (By similarity). Interacts with GPER1; the interaction occurs in an estrogen-dependent manner. Interacts with CLOCK and the interaction is stimulated by estrogen. Interacts with BCAS3. Interacts with TRIP4 (ufmylated); estrogen dependent. Interacts with LMTK3; the interaction phosphorylates ESR1 (in vitro) and protects it against proteasomal degradation. Interacts with CCAR2 (via N-terminus) in a ligand-independent manner. Interacts with ZFHX3. Interacts with SFR1 in a ligand-dependent and -independent manner (PubMed:23874500). Interacts with DCAF13, LATS1 and DCAF1; regulates ESR1 ubiquitination and ubiquitin-mediated proteasomal degradation (PubMed:28068668). Interacts (via DNA-binding domain) with POU4F2 (C-terminus); this interaction increases the estrogen receptor ESR1 transcriptional activity in a DNA- and ligand 17-beta-estradiol-independent manner (By similarity). Interacts with ESRRB isoform 1 (PubMed:19755138). Interacts with UBE3A and WBP2 (PubMed:16772533). Interacts with GTF2B (PubMed:1517211). Interacts with RBM39 (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863).TISSUE SPECIFICITY Widely expressed. Isoform 3 is not expressed in the pituitary gland.DOMAIN Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. The modulating domain, also known as A/B or AF-1 domain has a ligand-independent transactivation function. The C-terminus contains a ligand-dependent transactivation domain, also known as E/F or AF-2 domain which overlaps with the ligand binding domain. AF-1 and AF-2 activate transcription independently and synergistically and act in a promoter- and cell-specific manner. AF-1 seems to provide the major transactivation function in differentiated cells.PTM Phosphorylated by cyclin A/CDK2 and CK1. Phosphorylation probably enhances transcriptional activity. Self-association induces phosphorylation. Dephosphorylation at Ser-118 by PPP5C inhibits its transactivation activity. Phosphorylated by LMTK3 in vitro.PTM Glycosylated; contains N-acetylglucosamine, probably O-linked.PTM Ubiquitinated; regulated by LATS1 via DCAF1 it leads to ESR1 proteasomal degradation (PubMed:21602804, PubMed:28068668). Deubiquitinated by OTUB1 (PubMed:19383985).PTM Dimethylated by PRMT1 at Arg-260. The methylation may favor cytoplasmic localization (PubMed:18657504, PubMed:24498420). Demethylated by JMJD6 at Arg-260 (PubMed:24498420).PTM Palmitoylated (isoform 3). Not biotinylated (isoform 3).PTM Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation, but not for signaling mediated by the nuclear hormone receptor.POLYMORPHISM Genetic variations in ESR1 are correlated with bone mineral density (BMD). Low BMD is a risk factor for osteoporotic fracture. Osteoporosis is characterized by reduced bone mineral density, disruption of bone microarchitecture, and the alteration of the amount and variety of non-collagenous proteins in bone. Osteoporotic bones are more at risk of fracture.MISCELLANEOUS Selective estrogen receptor modulators (SERMs), such as tamoxifen, raloxifene, toremifene, lasofoxifene, clomifene, femarelle and ormeloxifene, have tissue selective agonistic and antagonistic effects on the estrogen receptor (ER). They interfere with the ER association with coactivators or corepressors, mainly involving the AF-2 domain.SIMILARITY Belongs to the nuclear hormone receptor family. NR3 subfamily.UniProtP033721EQUAL595EQUALReactome Database ID Release 719008284Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9008284ReactomeR-HSA-90082841Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9008284.1Reactome DB_ID: 90095311ESR1:estrogen:TFF1 gene:FOXA1:GATA3 [nucleoplasm]ESR1:estrogen:TFF1 gene:FOXA1:GATA3Reactome DB_ID: 90238201Reactome DB_ID: 90082841Reactome Database ID Release 719009531Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9009531ReactomeR-HSA-90095311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9009531.1Reactome Database ID Release 719009541Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9009541ReactomeR-HSA-90095411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9009541.117013392Pubmed2006Genome-wide analysis of estrogen receptor binding sitesCarroll, Jason SMeyer, Clifford ASong, JunLi, WeiGeistlinger, Timothy REeckhoute, JérômeBrodsky, Alexander SKeeton, Erika KrasnickasFertuck, Kirsten CHall, Giles FWang, QianbenBekiranov, StefanSementchenko, VictorFox, Edward ASilver, PAGingeras, Thomas RLiu, X ShirleyBrown, MylesNat. Genet. 38:1289-972919170Pubmed1989Estrogen-responsive element of the human pS2 gene is an imperfectly palindromic sequenceBerry, MeeraNunez, Anne-MarieChambon, PierreProc. Natl. Acad. Sci. U.S.A. 86:1218-2216980581Pubmed2006A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancerEeckhoute, JérômeCarroll, Jason SGeistlinger, Timothy RTorres-Arzayus, Maria IBrown, MylesGenes Dev. 20:2513-2614675539Pubmed2003Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoterMétivier, RaphaëlPenot, GraziellaHübner, Michael RReid, GeorgeBrand, HeikeKos, MartinGannon, FrankCell 115:751-6311452016Pubmed2001Estrogen receptor interaction with estrogen response elementsKlinge, C MNucleic Acids Res. 29:2905-1923172872Pubmed2013GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibilityTheodorou, VasilikiStark, RoryMenon, SurajCarroll, Jason SGenome Res. 23:12-2218805503Pubmed2009Marking time: the dynamic role of chromatin and covalent modification in transcriptionReid, GeorgeGallais, RozennMétivier, RaphaëlInt. J. Biochem. Cell Biol. 41:155-6316087863Pubmed2005From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen responseLaganière, JoséeDeblois, GenevièveLefebvre, CélineBataille, Alain RRobert, FrançoisGiguère, VincentProc. Natl. Acad. Sci. U.S.A. 102:11651-611136970Pubmed2000Cofactor dynamics and sufficiency in estrogen receptor-regulated transcriptionShang, YongfengHu, XiaoDiRenzo, JamesLazar, Mitchell ABrown, MylesCell 103:843-5222056668Pubmed2011Pioneer transcription factors: establishing competence for gene expressionZaret, KSCarroll, Jason SGenes Dev. 25:2227-419388265Pubmed1997Nucleosome positioning and transcription-associated chromatin alterations on the human estrogen-responsive pS2 promoterSewack, Gerald FHansen, UllaJ. Biol. Chem. 272:31118-2923192763Pubmed2013Cooperating transcription factors mediate the function of estrogen receptorFiorito, ElisaKatika, Madhumohan RHurtado, AntoniChromosoma 122:1-1218322535Pubmed2008Transient cyclical methylation of promoter DNAKangaspeska, SaraStride, BrendaMétivier, RaphaëlPolycarpou-Schwarz, MariaIbberson, DavidCarmouche, Richard PaulBenes, VladimirGannon, FrankReid, GeorgeNature 452:112-5