Estrogens are a class of hormones that play a role in physiological processes such as development, reproduction, metabolism of liver, fat and bone, and neuronal and cardiovascular function (reviewed in Arnal et al, 2017; Haldosen et al, 2014). Estrogens bind estrogen receptors, members of the nuclear receptor superfamily. Ligand-bound estrogen receptors act as nuclear transcription factors to regulate expression of genes that control cellular proliferation and differentiation, among other processes, but also play a non-genomic role in rapid signaling from the plasma membrane (reviewed in Hah et al, 2014;Schwartz et al, 2016).
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Zhang L, Lukasik SM, Speck NA, Bushweller JH.; ''Structural and functional characterization of Runx1, CBF beta, and CBF beta-SMMHC.''; PubMedEurope PMCScholia
Kong SL, Li G, Loh SL, Sung WK, Liu ET.; ''Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand-inducible growth state.''; PubMedEurope PMCScholia
Lee SH, Kim MY, Kim HY, Lee YM, Kim H, Nam KA, Roh MR, Min do S, Chung KY, Choi KY.; ''The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing.''; PubMedEurope PMCScholia
Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M.; ''Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription.''; PubMedEurope PMCScholia
Chen D, Washbrook E, Sarwar N, Bates GJ, Pace PE, Thirunuvakkarasu V, Taylor J, Epstein RJ, Fuller-Pace FV, Egly JM, Coombes RC, Ali S.; ''Phosphorylation of human estrogen receptor alpha at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera.''; PubMedEurope PMCScholia
Kaushansky A, Gordus A, Budnik BA, Lane WS, Rush J, MacBeath G.; ''System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation that are unusually selective in their recruitment properties.''; PubMedEurope PMCScholia
Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y.; ''Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.''; PubMedEurope PMCScholia
Kim MS, Yoon SK, Bollig F, Kitagaki J, Hur W, Whye NJ, Wu YP, Rivera MN, Park JY, Kim HS, Malik K, Bell DW, Englert C, Perantoni AO, Lee SB.; ''A novel Wilms tumor 1 (WT1) target gene negatively regulates the WNT signaling pathway.''; PubMedEurope PMCScholia
Schmidt D, Schwalie PC, Ross-Innes CS, Hurtado A, Brown GD, Carroll JS, Flicek P, Odom DT.; ''A CTCF-independent role for cohesin in tissue-specific transcription.''; PubMedEurope PMCScholia
Krishnan V, Wang X, Safe S.; ''Estrogen receptor-Sp1 complexes mediate estrogen-induced cathepsin D gene expression in MCF-7 human breast cancer cells.''; PubMedEurope PMCScholia
Wang F, Samudio I, Safe S.; ''Transcriptional activation of cathepsin D gene expression by 17beta-estradiol: mechanism of aryl hydrocarbon receptor-mediated inhibition.''; PubMedEurope PMCScholia
Marfella CG, Imbalzano AN.; ''The Chd family of chromatin remodelers.''; PubMedEurope PMCScholia
Handa RJ, Ogawa S, Wang JM, Herbison AE.; ''Roles for oestrogen receptor β in adult brain function.''; PubMedEurope PMCScholia
Eeckhoute J, Carroll JS, Geistlinger TR, Torres-Arzayus MI, Brown M.; ''A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer.''; PubMedEurope PMCScholia
Losada A.; ''Cohesin in cancer: chromosome segregation and beyond.''; PubMedEurope PMCScholia
Bretschneider N, Kangaspeska S, Seifert M, Reid G, Gannon F, Denger S.; ''E2-mediated cathepsin D (CTSD) activation involves looping of distal enhancer elements.''; PubMedEurope PMCScholia
Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG.; ''Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions.''; PubMedEurope PMCScholia
Mohammed H, D'Santos C, Serandour AA, Ali HR, Brown GD, Atkins A, Rueda OM, Holmes KA, Theodorou V, Robinson JL, Zwart W, Saadi A, Ross-Innes CS, Chin SF, Menon S, Stingl J, Palmieri C, Caldas C, Carroll JS.; ''Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor.''; PubMedEurope PMCScholia
Zeng F, Xu J, Harris RC.; ''Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells.''; PubMedEurope PMCScholia
Hodgkinson KM, Vanderhyden BC.; ''Consideration of GREB1 as a potential therapeutic target for hormone-responsive or endocrine-resistant cancers.''; PubMedEurope PMCScholia
Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D.; ''ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms.''; PubMedEurope PMCScholia
Fliss AE, Benzeno S, Rao J, Caplan AJ.; ''Control of estrogen receptor ligand binding by Hsp90.''; PubMedEurope PMCScholia
Haskins JW, Zhang S, Means RE, Kelleher JK, Cline GW, Canfrán-Duque A, Suárez Y, Stern DF.; ''Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake.''; PubMedEurope PMCScholia
Keita M, Bachvarova M, Morin C, Plante M, Gregoire J, Renaud MC, Sebastianelli A, Trinh XB, Bachvarov D.; ''The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion.''; PubMedEurope PMCScholia
McEwan MV, Eccles MR, Horsfield JA.; ''Cohesin is required for activation of MYC by estradiol.''; PubMedEurope PMCScholia
Wang F, Hoivik D, Pollenz R, Safe S.; ''Functional and physical interactions between the estrogen receptor Sp1 and nuclear aryl hydrocarbon receptor complexes.''; PubMedEurope PMCScholia
Oxelmark E, Roth JM, Brooks PC, Braunstein SE, Schneider RJ, Garabedian MJ.; ''The cochaperone p23 differentially regulates estrogen receptor target genes and promotes tumor cell adhesion and invasion.''; PubMedEurope PMCScholia
Laganière J, Deblois G, Lefebvre C, Bataille AR, Robert F, Giguère V.; ''From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response.''; PubMedEurope PMCScholia
Stender JD, Kim K, Charn TH, Komm B, Chang KC, Kraus WL, Benner C, Glass CK, Katzenellenbogen BS.; ''Genome-wide analysis of estrogen receptor alpha DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation.''; PubMedEurope PMCScholia
Omerovic J, Santangelo L, Puggioni EM, Marrocco J, Dall'Armi C, Palumbo C, Belleudi F, Di Marcotullio L, Frati L, Torrisi MR, Cesareni G, Gulino A, Alimandi M.; ''The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation.''; PubMedEurope PMCScholia
Hall JM, Couse JF, Korach KS.; ''The multifaceted mechanisms of estradiol and estrogen receptor signaling.''; PubMedEurope PMCScholia
Sampayo RG, Toscani AM, Rubashkin MG, Thi K, Masullo LA, Violi IL, Lakins JN, Cáceres A, Hines WC, Coluccio Leskow F, Stefani FD, Chialvo DR, Bissell MJ, Weaver VM, Simian M.; ''Fibronectin rescues estrogen receptor α from lysosomal degradation in breast cancer cells.''; PubMedEurope PMCScholia
Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, Visca P, Marino M.; ''Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol.''; PubMedEurope PMCScholia
Wang X, Blagden C, Fan J, Nowak SJ, Taniuchi I, Littman DR, Burden SJ.; ''Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle.''; PubMedEurope PMCScholia
Berry M, Nunez AM, Chambon P.; ''Estrogen-responsive element of the human pS2 gene is an imperfectly palindromic sequence.''; PubMedEurope PMCScholia
Gilmore-Hebert M, Ramabhadran R, Stern DF.; ''Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways.''; PubMedEurope PMCScholia
Cicatiello L, Addeo R, Sasso A, Altucci L, Petrizzi VB, Borgo R, Cancemi M, Caporali S, Caristi S, Scafoglio C, Teti D, Bresciani F, Perillo B, Weisz A.; ''Estrogens and progesterone promote persistent CCND1 gene activation during G1 by inducing transcriptional derepression via c-Jun/c-Fos/estrogen receptor (progesterone receptor) complex assembly to a distal regulatory element and recruitment of cyclin D1 to its own gene promoter.''; PubMedEurope PMCScholia
Hayes NV, Blackburn E, Smart LV, Boyle MM, Russell GA, Frost TM, Morgan BJ, Baines AJ, Gullick WJ.; ''Identification and characterization of novel spliced variants of neuregulin 4 in prostate cancer.''; PubMedEurope PMCScholia
Jones FE, Welte T, Fu XY, Stern DF.; ''ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation.''; PubMedEurope PMCScholia
Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, Brodsky AS, Keeton EK, Fertuck KC, Hall GF, Wang Q, Bekiranov S, Sementchenko V, Fox EA, Silver PA, Gingeras TR, Liu XS, Brown M.; ''Genome-wide analysis of estrogen receptor binding sites.''; PubMedEurope PMCScholia
Stedman W, Kang H, Lin S, Kissil JL, Bartolomei MS, Lieberman PM.; ''Cohesins localize with CTCF at the KSHV latency control region and at cellular c-myc and H19/Igf2 insulators.''; PubMedEurope PMCScholia
Guérin M, Sheng ZM, Andrieu N, Riou G.; ''Strong association between c-myb and oestrogen-receptor expression in human breast cancer.''; PubMedEurope PMCScholia
Kawazu M, Saso K, Tong KI, McQuire T, Goto K, Son DO, Wakeham A, Miyagishi M, Mak TW, Okada H.; ''Histone demethylase JMJD2B functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development.''; PubMedEurope PMCScholia
Kim HY, Yoon JY, Yun JH, Cho KW, Lee SH, Rhee YM, Jung HS, Lim HJ, Lee H, Choi J, Heo JN, Lee W, No KT, Min D, Choi KY.; ''CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation.''; PubMedEurope PMCScholia
Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM, Jones FE.; ''The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells.''; PubMedEurope PMCScholia
Métivier R, Penot G, Hübner MR, Reid G, Brand H, Kos M, Gannon F.; ''Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter.''; PubMedEurope PMCScholia
Shen Q, Uray IP, Li Y, Krisko TI, Strecker TE, Kim HT, Brown PH.; ''The AP-1 transcription factor regulates breast cancer cell growth via cyclins and E2F factors.''; PubMedEurope PMCScholia
Lin CY, Ström A, Vega VB, Kong SL, Yeo AL, Thomsen JS, Chan WC, Doray B, Bangarusamy DK, Ramasamy A, Vergara LA, Tang S, Chong A, Bajic VB, Miller LD, Gustafsson JA, Liu ET.; ''Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells.''; PubMedEurope PMCScholia
Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR.; ''The E2F transcription factor is a cellular target for the RB protein.''; PubMedEurope PMCScholia
Clarke CL, Graham JD.; ''Non-overlapping progesterone receptor cistromes contribute to cell-specific transcriptional outcomes.''; PubMedEurope PMCScholia
Rio C, Buxbaum JD, Peschon JJ, Corfas G.; ''Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4.''; PubMedEurope PMCScholia
Anbalagan M, Rowan BG.; ''Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer.''; PubMedEurope PMCScholia
Prall OW, Rogan EM, Musgrove EA, Watts CK, Sutherland RL.; ''c-Myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry.''; PubMedEurope PMCScholia
Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, Prébois C, Rochefort H, Vignon F.; ''Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis.''; PubMedEurope PMCScholia
Mangan JK, Speck NA.; ''RUNX1 mutations in clonal myeloid disorders: from conventional cytogenetics to next generation sequencing, a story 40 years in the making.''; PubMedEurope PMCScholia
Wissmann M, Yin N, Müller JM, Greschik H, Fodor BD, Jenuwein T, Vogler C, Schneider R, Günther T, Buettner R, Metzger E, Schüle R.; ''Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression.''; PubMedEurope PMCScholia
Li G, Ruan X, Auerbach RK, Sandhu KS, Zheng M, Wang P, Poh HM, Goh Y, Lim J, Zhang J, Sim HS, Peh SQ, Mulawadi FH, Ong CT, Orlov YL, Hong S, Zhang Z, Landt S, Raha D, Euskirchen G, Wei CL, Ge W, Wang H, Davis C, Fisher-Aylor KI, Mortazavi A, Gerstein M, Gingeras T, Wold B, Sun Y, Fullwood MJ, Cheung E, Liu E, Sung WK, Snyder M, Ruan Y.; ''Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation.''; PubMedEurope PMCScholia
Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto N, Watanabe-Okochi N, Kurokawa M.; ''A role for RUNX1 in hematopoiesis and myeloid leukemia.''; PubMedEurope PMCScholia
Del Pino I, García-Frigola C, Dehorter N, Brotons-Mas JR, Alvarez-Salvado E, Martínez de Lagrán M, Ciceri G, Gabaldón MV, Moratal D, Dierssen M, Canals S, Marín O, Rico B.; ''Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes.''; PubMedEurope PMCScholia
Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K.; ''The retinoblastoma protein binds to a family of E2F transcription factors.''; PubMedEurope PMCScholia
Butt AJ, McNeil CM, Musgrove EA, Sutherland RL.; ''Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E.''; PubMedEurope PMCScholia
Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D.; ''The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase.''; PubMedEurope PMCScholia
White R, Fawell SE, Parker MG.; ''Analysis of oestrogen receptor dimerisation using chimeric proteins.''; PubMedEurope PMCScholia
Kumar V, Chambon P.; ''The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer.''; PubMedEurope PMCScholia
Aumais JP, Lee HS, Lin R, White JH.; ''Selective interaction of hsp90 with an estrogen receptor ligand-binding domain containing a point mutation.''; PubMedEurope PMCScholia
Shann YJ, Cheng C, Chiao CH, Chen DT, Li PH, Hsu MT.; ''Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines.''; PubMedEurope PMCScholia
Rhodes JM, McEwan M, Horsfield JA.; ''Gene regulation by cohesin in cancer: is the ring an unexpected party to proliferation?''; PubMedEurope PMCScholia
Shigesada K, van de Sluis B, Liu PP.; ''Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11.''; PubMedEurope PMCScholia
Pearce ST, Jordan VC.; ''The biological role of estrogen receptors alpha and beta in cancer.''; PubMedEurope PMCScholia
Theodorou V, Stark R, Menon S, Carroll JS.; ''GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility.''; PubMedEurope PMCScholia
Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, Jones FE.; ''The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone.''; PubMedEurope PMCScholia
Amin DN, Perkins AS, Stern DF.; ''Gene expression profiling of ErbB receptor and ligand-dependent transcription.''; PubMedEurope PMCScholia
Gaughan L, Stockley J, Coffey K, O'Neill D, Jones DL, Wade M, Wright J, Moore M, Tse S, Rogerson L, Robson CN.; ''KDM4B is a master regulator of the estrogen receptor signalling cascade.''; PubMedEurope PMCScholia
Kanno T, Kanno Y, Chen LF, Ogawa E, Kim WY, Ito Y.; ''Intrinsic transcriptional activation-inhibition domains of the polyomavirus enhancer binding protein 2/core binding factor alpha subunit revealed in the presence of the beta subunit.''; PubMedEurope PMCScholia
Morris DP, Michelotti GA, Schwinn DA.; ''Evidence that phosphorylation of the RNA polymerase II carboxyl-terminal repeats is similar in yeast and humans.''; PubMedEurope PMCScholia
Su CH, Tzeng TY, Cheng C, Hsu MT.; ''An H2A histone isotype regulates estrogen receptor target genes by mediating enhancer-promoter-3'-UTR interactions in breast cancer cells.''; PubMedEurope PMCScholia
Zheng S, Wyrick JJ, Reese JC.; ''Novel trans-tail regulation of H2B ubiquitylation and H3K4 methylation by the N terminus of histone H2A.''; PubMedEurope PMCScholia
Ballaré C, Uhrig M, Bechtold T, Sancho E, Di Domenico M, Migliaccio A, Auricchio F, Beato M.; ''Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells.''; PubMedEurope PMCScholia
Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, Sudol M, Croce CM.; ''WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function.''; PubMedEurope PMCScholia
Bourdeau V, Deschênes J, Métivier R, Nagai Y, Nguyen D, Bretschneider N, Gannon F, White JH, Mader S.; ''Genome-wide identification of high-affinity estrogen response elements in human and mouse.''; PubMedEurope PMCScholia
Sun Y, Ikrar T, Davis MF, Gong N, Zheng X, Luo ZD, Lai C, Mei L, Holmes TC, Gandhi SP, Xu X.; ''Neuregulin-1/ErbB4 Signaling Regulates Visual Cortical Plasticity.''; PubMedEurope PMCScholia
Panaretou B, Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH.; ''ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo.''; PubMedEurope PMCScholia
Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J, Godowski PJ.; ''Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4.''; PubMedEurope PMCScholia
Guo ZY, Hao XH, Tan FF, Pei X, Shang LM, Jiang XL, Yang F.; ''The elements of human cyclin D1 promoter and regulation involved.''; PubMedEurope PMCScholia
Guan YF, Wu CY, Fang YY, Zeng YN, Luo ZY, Li SJ, Li XW, Zhu XH, Mei L, Gao TM.; ''Neuregulin 1 protects against ischemic brain injury via ErbB4 receptors by increasing GABAergic transmission.''; PubMedEurope PMCScholia
Kainulainen V, Sundvall M, Määttä JA, Santiestevan E, Klagsbrun M, Elenius K.; ''A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis.''; PubMedEurope PMCScholia
Bagchi S, Weinmann R, Raychaudhuri P.; ''The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.''; PubMedEurope PMCScholia
Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, Serandour AA, Birrell SN, Bruna A, Saadi A, Menon S, Hadfield J, Pugh M, Raj GV, Brown GD, D'Santos C, Robinson JL, Silva G, Launchbury R, Perou CM, Stingl J, Caldas C, Tilley WD, Carroll JS.; ''Progesterone receptor modulates ERα action in breast cancer.''; PubMedEurope PMCScholia
Schwabe JW, Chapman L, Finch JT, Rhodes D.; ''The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements.''; PubMedEurope PMCScholia
Hazan R, Margolis B, Dombalagian M, Ullrich A, Zilberstein A, Schlessinger J.; ''Identification of autophosphorylation sites of HER2/neu.''; PubMedEurope PMCScholia
Guan KL, Jenkins CW, Li Y, O'Keefe CL, Noh S, Wu X, Zariwala M, Matera AG, Xiong Y.; ''Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4.''; PubMedEurope PMCScholia
Bender TP, Thompson CB, Kuehl WM.; ''Differential expression of c-myb mRNA in murine B lymphomas by a block to transcription elongation.''; PubMedEurope PMCScholia
Schulze WX, Deng L, Mann M.; ''Phosphotyrosine interactome of the ErbB-receptor kinase family.''; PubMedEurope PMCScholia
Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L, Gulino A, Alimandi M.; ''Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level.''; PubMedEurope PMCScholia
Augello MA, Hickey TE, Knudsen KE.; ''FOXA1: master of steroid receptor function in cancer.''; PubMedEurope PMCScholia
Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M.; ''S-palmitoylation modulates human estrogen receptor-alpha functions.''; PubMedEurope PMCScholia
La Rosa P, Pesiri V, Leclercq G, Marino M, Acconcia F.; ''Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity.''; PubMedEurope PMCScholia
Aras S, Pak O, Sommer N, Finley R, Hüttemann M, Weissmann N, Grossman LI.; ''Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2.''; PubMedEurope PMCScholia
Nguyen VT, Barozzi I, Faronato M, Lombardo Y, Steel JH, Patel N, Darbre P, Castellano L, Győrffy B, Woodley L, Meira A, Patten DK, Vircillo V, Periyasamy M, Ali S, Frige G, Minucci S, Coombes RC, Magnani L.; ''Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion.''; PubMedEurope PMCScholia
Cheng QC, Tikhomirov O, Zhou W, Carpenter G.; ''Ectodomain cleavage of ErbB-4: characterization of the cleavage site and m80 fragment.''; PubMedEurope PMCScholia
Powell E, Wang Y, Shapiro DJ, Xu W.; ''Differential requirements of Hsp90 and DNA for the formation of estrogen receptor homodimers and heterodimers.''; PubMedEurope PMCScholia
Arasada RR, Carpenter G.; ''Secretase-dependent tyrosine phosphorylation of Mdm2 by the ErbB-4 intracellular domain fragment.''; PubMedEurope PMCScholia
Smith DF, Toft DO.; ''Minireview: the intersection of steroid receptors with molecular chaperones: observations and questions.''; PubMedEurope PMCScholia
Lin Z, Reierstad S, Huang CC, Bulun SE.; ''Novel estrogen receptor-alpha binding sites and estradiol target genes identified by chromatin immunoprecipitation cloning in breast cancer.''; PubMedEurope PMCScholia
Liu MH, Cheung E.; ''Estrogen receptor-mediated long-range chromatin interactions and transcription in breast cancer.''; PubMedEurope PMCScholia
Cohen BD, Green JM, Foy L, Fell HP.; ''HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers.''; PubMedEurope PMCScholia
Marino M, Ascenzi P, Acconcia F.; ''S-palmitoylation modulates estrogen receptor alpha localization and functions.''; PubMedEurope PMCScholia
Lukasik SM, Zhang L, Corpora T, Tomanicek S, Li Y, Kundu M, Hartman K, Liu PP, Laue TM, Biltonen RL, Speck NA, Bushweller JH.; ''Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesis.''; PubMedEurope PMCScholia
In addition to its well-characterized role in estrogen-dependent transcription, estrogen (beta-estradiol, also known as E2) also plays a rapid, non-genomic role through interaction with receptors localized at the plasma membrane by virtue of dynamic palmitoylation. Estrogen receptor palmitoylation is a prerequisite for the E2-dependent activation of extra-nuclear signaling both in vitro and in animal models (Acconcia et al, 2004; Acconcia et al, 2005; Marino et al, 2006; Marino and Ascenzi, 2006). Non-genomic signaling through the estrogen receptor ESR1 also depends on receptor arginine methylation by PMRT1 (Pedram et al, 2007; Pedram et al, 2012; Le Romancer et al, 2008; reviewed in Arnal, 2017; Le Romancer et al, 2011 ). E2-evoked extra-nuclear signaling is independent of the transcriptional activity of estrogen receptors and occurs within seconds to minutes following E2 administration to target cells. Extra-nuclear signaling consists of the activation of a plethora of signaling pathways including the RAF/MAP kinase cascade and the PI3K/AKT signaling cascade and governs processes such as apoptosis, cellular proliferation and metastasis (reviewed in Hammes et al, 2007; Handa et al, 2012; Lange et al, 2007; Losel et al, 2003; Arnal et al, 2017; Le Romancer et al, 2011). ESR-mediated signaling also cross-talks with receptor tyrosine kinase, NF- kappa beta and GPCR signaling pathways by modulating the post-translational modification of enzymes and other proteins and regulating second messengers (reviewed in Arnal et al, 2017; Schwartz et al, 2016; Boonyaratanakornkit, 2011; Biswas et al, 2005). In the nervous system, E2 affects neural functions such as cognition, behaviour, stress responses and reproduction in part by inducing such rapid extra-nuclear responses (Farach-Carson and Davis, 2003; Losel et al, 2003), while in endothelial cells, non-genomic ESR-dependent signaling also regulates vasodilation through the eNOS pathway (reviewed in Levin, 2011). Extra-nuclear signaling additionally cross-talks with nuclear estrogen receptor signaling and is required to control ER protein stability (La Rosa et al, 2012) Recent data have demonstrated that the membrane ESR1 can interact with various endocytic proteins to traffic and signal within the cytoplasm. This receptor intracellular trafficking appears to be dependent on the phyical interaction of ESR1 with specific trans-membrane receptors such as IGR-1R and beta 1-integrin (Sampayo et al, 2018)
MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.
During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).
During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.
ERBB4, also known as HER4, belongs to the ERBB family of receptors, which also includes ERBB1 (EGFR/HER1), ERBB2 (HER2/NEU) and ERBB3 (HER3). Similar to EGFR, ERBB4 has an extracellular ligand binding domain, a single transmembrane domain and a cytoplasmic domain which contains an active tyrosine kinase and a C-tail with multiple phosphorylation sites. At least three and possibly four splicing isoforms of ERBB4 exist that differ in their C-tail and/or the extracellular juxtamembrane regions: ERBB4 JM-A CYT1, ERBB4 JM-A CYT2 and ERBB4 JM-B CYT1 (the existence of ERBB4 JM-B CYT2 has not been confirmed).
ERBB4 becomes activated by binding one of its seven ligands, three of which, HB-EGF, epiregulin EPR and betacellulin BTC, are EGF-like (Elenius et al. 1997, Riese et al. 1998), while four, NRG1, NRG2, NRG3 and NRG4, belong to the related neuregulin family (Tzahar et al. 1994, Carraway et al. 1997, Zhang et al. 1997, Hayes et al. 2007). Upon ligand binding, ERBB4 forms homodimers (Sweeney et al. 2000) or it heterodimerizes with ERBB2 (Li et al. 2007). Dimers of ERBB4 undergo trans-autophosphorylation on tyrosine residues in the C-tail (Cohen et al. 1996, Kaushansky et al. 2008, Hazan et al. 1990, Li et al. 2007), triggering downstream signaling cascades. The pathway Signaling by ERBB4 only shows signaling by ERBB4 homodimers. Signaling by heterodimers of ERBB4 and ERBB2 is shown in the pathway Signaling by ERBB2. Ligand-stimulated ERBB4 is also able to form heterodimers with ligand-stimulated EGFR (Cohen et al. 1996) and ligand-stimulated ERBB3 (Riese et al. 1995). Dimers of ERBB4 with EGFR and dimers of ERBB4 with ERBB3 were demonstrated in mouse cell lines in which human ERBB4 and EGFR or ERBB3 were exogenously expressed. These heterodimers undergo trans-autophosphorylation. The promiscuous heteromerization of ERBBs adds combinatorial diversity to ERBB signaling processes. As ERBB4 binds more ligands than other ERBBs, but has restricted expression, ERBB4 expression channels responses to ERBB ligands. The signaling capabilities of the four receptors have been compared (Schulze et al. 2005).
As for other receptor tyrosine kinases, ERBB4 signaling effectors are largely dictated through binding of effector proteins to ERBB4 peptides that are phosphorylated upon ligand binding. All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000).
The CYT1 isoforms of ERBB4 also possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K (Kaushansky et al. 2008, Cohen et al. 1996), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000).
Besides signaling as a conventional transmembrane receptor kinase, ERBB4 differs from other ERBBs in that JM-A isoforms signal through efficient release of a soluble intracellular domain. Ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. For example, in mammary cells, ERBB4 binds SH2 transcription factor STAT5A. ERBB4 s80 shuttles STAT5A to the nucleus, and actsa as a STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Jones et al. 1999, Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 binds activated estrogen receptor in the nucleus and acts as a transcriptional co-factor in promoting transcription of some estrogen-regulated genes, including progesterone receptor gene NR3C3 and CXCL12 (SDF1) (Zhu et al. 2006). In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006).
The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and is a co-regulator of YAP1-mediated transcription in association with TEAD transcription factors (Komuro et al. 2003, Omerovic et al. 2004). Hence, the WW binding motif couples ERBB4 to the major effector arm of the HIPPO signaling pathway. The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005).
WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009).
ERBB4 also binds the E3 ubiquitin ligase MDM2, and inhibitor of p53 (Arasada et al. 2005). Other proteins that bind to ERBB4 intracellular domain have been identified by co-immunoprecipitation and mass spectrometry (Gilmore-Hebert et al., 2010), and include transcriptional co-repressor TRIM28/KAP1, which promotes chromatin compaction. DNA damage signaling through ATM releases TRIM28-associated heterochromatinization. Interactions of ERBB4 with TRIM28 and MDM2 may be important for integration of growth factor responses and DNA damage responses.
In human breast cancer cell lines, ERBB4 activation enhances anchorage-independent colony formation in soft agar but inhibits cell growth in a monolayer culture. Different ERBB4 ligands induce different gene expression changes in breast cancer cell lines. Some of the genes induced in response to ERBB4 signaling in breast cancer cell lines are RAB2, EPS15R and GATA4. It is not known if these gene are direct transcriptional targets of ERBB4 (Amin et al. 2004).
Transcriptome and ChIP-seq comparisons of full-length and intracellular domain isoforms in isogenic MCF10A mammary cell background have revealed the diversification of ERBB4 signaling engendered by alternative splicing and cleavage (Wali et al., 2014). ERBB4 broadly affected protease expression, cholesterol biosynthesis, HIF1-alpha signaling, and HIPPO signaling pathways, and other pathways were differentially activated by CYT1 and CYT2 isoforms. For example, CYT1 promoted expression of transcription factors TWIST1 and SNAIL1 that promote epithelial-mesenchymal transition. HIF1-alpha and HIPPO signaling are mediated, respectively, by binding of ERBB4 to HIF1-alpha and to YAP (Paatero et al., 2012, Komuro et al., 2003). ERBB4 increases activity of the transcription factor SREBF2, resulting in increased expression of SREBF2-target genes involved in cholesterol biosynthesis. The mechanism is not known and may involve facilitation of SREBF2 cleavage through ERBB4-mediated PI3K signaling (Haskins et al. 2016).
In some contexts, ERBB4 promotes growth suppression or apoptosis (Penington et al., 2002). Activation of ERBB4 in breast cancer cell lines leads to JNK dependent increase in BRCA1 mRNA level and mitotic cell cycle delay, but the exact mechanism has not been elucidated (Muraoka Cook et al. 2006). The nature of growth responses may be connected with the spliced isoforms expressed. In comparisons of CYT1 vs CYT2 (full-length and ICD) expression in mammary cells, CYT1 was a weaker growth inducer, associated with attenuated MAPK signaling relative to CYT2 (Wali et al., 2014). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro apoptotic factor (Naresh et al. 2006).
ERBB4 plays important roles in the developing and adult nervous system. Erbb4 deficiency in somatostatin-expressing neurons of the thalamic reticular nucleus alters behaviors dependent on sensory selection (Ahrens et al. 2015). NRG1-activated ERBB4 signaling enhances AMPA receptor responses through PKC-dependent AMPA receptor exocytosis. This results in an increased excitatory input to parvalbumin-expressing inhibitory neurons in the visual cortex and regulates visual cortical plasticity (Sun et al. 2016). NRG1-activated ERBB4 signaling is involved in GABAergic activity in amygdala which mediates fear conditioning (fear memory) (Lu et al. 2014). Conditional Erbb4 deletion from fast-spiking interneurons, chandelier and basket cells of the cerebral cortex leads to synaptic defects associated with increased locomotor activity and abnormal emotional, social and cognitive function that can be linked to some of the schizophrenia features. The level of GAD1 (GAD67) protein is reduced in the cortex of conditional Erbb4 mutants. GAD1 is a GABA synthesizing enzyme. Cortical mRNA levels of GAD67 are consistently decreased in schizophrenia (Del Pino et al. 2014). Erbb4 is expressed in the GABAergic neurons of the bed nucleus stria terminalis, a part of the extended amygdala. Inhibition of NRG1-triggered ERBB4 signaling induces anxiety-like behavior, which depends on GABAergic neurotransmission. NRG1-ERBB4 signaling stimulates presynaptic GABA release, but the exact mechanism is not known (Geng et al. 2016). NRG1 protects cortical interneurons against ischemic brain injury through ERBB4-mediated increase in GABAergic transmission (Guan et al. 2015). NRG2-activated ERBB4 can reduce the duration of GABAergic transmission by binding to GABA receptors at the postsynaptic membrane via their GABRA1 subunit and promoting endocytosis of GABA receptors (Mitchell et al. 2013). NRG1 promotes synchronization of prefrontal cortex interneurons in an ERBB4 dependent manner (Hou et al. 2014). NRG1-ERBB4 signaling protects neurons from the cell death induced by a mutant form of the amyloid precursor protein (APP) (Woo et al. 2012).
Clinical relevance of ERBB4 has been identified in several contexts. In cancer, putative and validated gain-of-function mutations or gene amplification that may be drivers have been identified at modest frequencies, and may also contribute to resistance to EGFR and ERBB2-targeted therapies. This is noteworthy as ERBB4 kinase activity is inhibited by pan-ERBB tyrosine kinase inhibitors, including lapatinib, which is approved by the US FDA. The reduced prevalence relative to EGFR and ERBB2 in cancer may reflect more restricted expression of ERBB4, or differential signaling, as specific ERBB4 isoforms have been linked to growth inhibition or apoptosis in experimental systems. ERBB2/ERBB4 heterodimers protect cardiomyocytes, so reduced activity of ERBB4 in patients treated with the ERBB2-targeted therapeutic antibody trastuzumab may contribute to the cardiotoxicity of this agent when used in combination with (cardiotoxic) anthracyclines.
With the importance of ERBB4 in developing and adult nervous system, NRG1 and/or ERBB4 polymorphisms, splicing aberrations and mutations have been linked to nervous system disorders including schizophrenia and amyotrophic lateral sclerosis, although these findings are not yet definitive.
The RUNX1 (AML1) transcription factor is a master regulator of hematopoiesis (Ichikawa et al. 2004) that is frequently translocated in acute myeloid leukemia (AML), resulting in formation of fusion proteins with altered transactivation profiles (Lam and Zhang 2012, Ichikawa et al. 2013). In addition to RUNX1, its heterodimerization partner CBFB is also frequently mutated in AML (Shigesada et al. 2004, Mangan and Speck 2011). The core domain of CBFB binds to the Runt domain of RUNX1, resulting in formation of the RUNX1:CBFB heterodimer. CBFB does not interact with DNA directly. The Runt domain of RUNX1 mediated both DNA binding and heterodimerization with CBFB (Tahirov et al. 2001), while RUNX1 regions that flank the Runt domain are involved in transactivation (reviewed in Zhang et al. 2003) and negative regulation (autoinhibition). CBFB facilitates RUNX1 binding to DNA by stabilizing Runt domain regions that interact with the major and minor grooves of the DNA (Tahirov et al. 2001, Backstrom et al. 2002, Bartfeld et al. 2002). The transactivation domain of RUNX1 is located C-terminally to the Runt domain and is followed by the negative regulatory domain. Autoinhibiton of RUNX1 is relieved by interaction with CBFB (Kanno et al. 1998). Transcriptional targets of the RUNX1:CBFB complex involve genes that regulate self-renewal of hematopoietic stem cells (HSCs) (Zhao et al. 2014), as well as commitment and differentiation of many hematopoietic progenitors, including myeloid (Friedman 2009) and megakaryocytic progenitors (Goldfarb 2009), regulatory T lymphocytes (Wong et al. 2011) and B lymphocytes (Boller and Grosschedl 2014). RUNX1 binds to promoters of many genes involved in ribosomal biogenesis (Ribi) and is thought to stimulate their transcription. RUNX1 loss-of-function decreases ribosome biogenesis and translation in hematopoietic stem and progenitor cells (HSPCs). RUNX1 loss-of-function is therefore associated with a slow growth, but at the same time it results in reduced apoptosis and increases resistance of cells to genotoxic and endoplasmic reticulum stress, conferring an overall selective advantage to RUNX1 deficient HSPCs (Cai et al. 2015). RUNX1 is implicated as a tumor suppressor in breast cancer. RUNX1 forms a complex with the activated estrogen receptor alpha (ESR1) and regulates expression of estrogen-responsive genes (Chimge and Frenkel 2013). RUNX1 is overexpressed in epithelial ovarian carcinoma where it may contribute to cell proliferation, migration and invasion (Keita et al. 2013). RUNX1 may cooperate with TP53 in transcriptional activation of TP53 target genes upon DNA damage (Wu et al. 2013). RUNX1 is needed for the maintenance of skeletal musculature (Wang et al. 2005). During mouse embryonic development, Runx1 is expressed in most nociceptive sensory neurons, which are involved in the perception of pain. In adult mice, Runx1 is expressed only in nociceptive sensory neurons that express the Ret receptor and is involved in regulation of expression of genes encoding ion channels (sodium-gated, ATP-gated and hydrogen ion-gated) and receptors (thermal receptors, opioid receptor MOR and the Mrgpr class of G protein coupled receptors). Mice lacking Runx1 show defective perception of thermal and neuropathic pain (Chen CL et al. 2006). Runx1 is thought to activate the neuronal differentiation of nociceptive dorsal root ganglion cells during embryonal development possibly through repression of Hes1 expression (Kobayashi et al. 2012). In chick and mouse embryos, Runx1 expression is restricted to the dorso-medial domain of the dorsal root ganglion, to TrkA-positive cutaneous sensory neurons. Runx3 expression in chick and mouse embryos is restricted to ventro-lateral domain of the dorsal root ganglion, to TrkC-positive proprioceptive neurons (Chen AI et al. 2006, Kramer et al. 2006). RUNX1 mediated regulation of neuronally expressed genes will be annotated when mechanistic details become available.
The C-terminal domain (CTD) of POLR2A contains about 52 repeats of the consensus heptad YSPTSPS. Serines-2 and 5 of the heptads are phosphorylated in RNA polymerase II initiating transcription of protein coding genes. The exact repeats that are phosphorylated are not known.
The RUNX1:CBFB complex binds the estrogen receptor alpha (ESR1). The interaction between RUNX1 and ESR1 is significantly enhanced upon ESR1 activation by estrogens (Stender et al. 2010).
GPAM gene expression is cooperatively stimulated by RUNX1 and ESR1, which form a complex and bind the GPAM gene enhancer (Stender et al. 2010). GPAM encodes a glycerol-3-phosphate acyltransferase whose high expression correlates with better overall survival in breast cancer (Brockmoller et al. 2012).
RUNX1 and ESR1 cooperatively bind to the enhancer of the GPAM gene, which contains both estrogen response elements and RUNX1 binding sites (Stender et al. 2010).
RUNX1 and ESR1, which form a complex that binds to the KCTD6 gene enhancer, cooperatively stimulate the expression of the KCTD6 gene (Stender et al. 2010).
RUNX1 and ESR1 cooperatively bind the KCTD6 gene enhancer, which contains both estrogen response elements and RUNX1 response elements (Stender et al. 2010).
Transciption of the AXIN1 gene, which encodes a component of the beta-catenin (CTNNB1) destruction complex, is inhibited by binding of the activated estrogen receptor alpha (ESR1) to estrogen response elements in the second intron of AXIN1 (Chimge et al. 2016). The AXIN1 gene expression is stimulated by cooperative binding of RUNX1 and estrogen receptor alpha (ESR1) to adjacent RUNX1 binding sites and estrogen response elements in the second intron of AXIN1 (Chimge et al. 2016).
RUNX1 and ESR1, which are known to form a complex (Stender et al. 2010), cooperatively bind to adjacent Runx binding sites and estrogen response elements, respectively, in the second intron of the AXIN1 gene (Chimge et al. 2016).
Upon ligand binding, estrogen receptors form homo- or heterodimers mediated by dimerization domains in the DNA-binding and ligand-binding regions (White et al, 1991; Schwabe et al, 1993; Kuntz et al, 1997; Kumar and Chambon, 1998; Powell et al, 2010). Estrogen receptor dimers regulate transcription of estrogen-responsive genes either by direct binding to estrogen response elements (characterized by a palindromic consensus sequence AGGTCA separated by a 3bp spacer) or by interacting with other DNA binding transcriptional regulators (reviewed in Smith and Toft, 2008; Bai and Gust, 2009; Ikeda et al 2015; Liu and Cheung, 2014). Binding of estrogen receptors to the DNA promotes the assembly of higher order transcriptional complexes containing methyltransferases, histone acetyltransferases and other transcriptional activators, which promote transcription by establishing active chromatin marks and by recruiting general transcription factors and RNA polymerase II. ESR1- and estrogen-dependent recruitment of up to hundreds of coregulators has been demonstrated by varied co-immunoprecipitation and proteomic approaches (Kittler et al, 2013; Mohammed et al, 2013; Foulds et al, 2013; Mohammed et al, 2015; Liu et al, 2014; reviewed in Magnani and Lupien, 2014; Arnal, 2017).
Release of the estrogen receptor from the chaperone complex requires requires HSP90-dependent ATP hydrolysis, and occurs at the same rate in the presence and absence of ligand (Smith et al, 1992; Smith et al, 1993; Aumais et al, 1997; Grenert et al, 1997; Obermann et al, 1998; Panaretou et al, 1998; reviewed in Smith and Toft, 2008). In the absence of ligand, released ERs are recaptured by HSP40 through its interaction with the ligand binding domain (LBD), priming reassembly of the chaperone complex. Ligand binding may result in the loss of the HSP40-binding site, allowing the receptor to escape repetitive rounds of chaperone complex assembly, and freeing it for DNA-binding (reviewed in Smith and Toft, 2008).
In the nucleus, estrogens bind to estrogen receptors, members of the nuclear receptor superfamily. Human cells have 2 estrogen receptors, ER alpha and ER beta, encoded by two genes. Expression of the two genes varies by tissue: both are expressed in the central nervous system, the cardiovascular system, the urogenital tract and in the breast and bone; ER alpha expression predominates in the uterus, mammary gland, and liver, and the gastrointestinal tract expresses only ER beta (Pearce and Jordan, 2004; Gustafsson et al, 1999; Pfaffl et al, 2001; reviewed in Bai and Gust, 2009). The receptors show 47% identity overall and share a common organization consisting of 6 domains: an N-terminal A/B domain with ligand-independent activation function, a C domain containing the 2 DNA-binding zinc fingers, a hinge region (D) with a nuclear localization signal, an E domain that contains the ligand binding and dimerization domains as well as a ligand-dependent transactivation function, and a C-terminal F domain of poorly characterized function. The DNA-binding domain is the most highly conserved (97% identity) while the ligand-bindind domain is more variable (47% identity) (reviewed in Ruff et al, 2000; Bai and Gust, 2009). ER alpha and beta can homo- and heterodimerize, and recognize a common estrogen-response element due to their shared DNA-binding domains (reviewed in Bai and Gust, 2009). Functional studies suggest that ER alpha and beta have overlapping but distinct roles in estrogen-responsive transcription (Harrington et al, 2003; Katzenellenbogen and Katzenellenbogen, 2000; Pearce and Jordan, 2004; Pfaffl et al, 2001) In the unliganded state, estrogen receptors are part of a multi-subunit complex containing HSP90, p23 (also known as PTGES3) and other chaperone-associated proteins (Joab et al, 1984; Segnitz et al, 1995; Knoblauch et al, 1999; Bouhouche-Chatelier et al, 2001; Fliss et al, 2000; Oxelmart et al, 2006; reviewed in Smith and Toft, 2008; Bai and Gust, 2009). This complex is part of a chaperone binding and release cycle shared by many nuclear receptors (described in more detail in the pathway "HSP90 chaperone cycle for steroid hormone receptors") that governs receptor folding and activity and may contribute to a high-affinity conformation of the ligand-binding domain (reviewed in Pratt and Toft, 1997; Smith and Toft, 2008). HSP90 release from the receptor complex requires ATP hydrolysis (Smith et al, 1993; Grenert et al, 1997; Panaretou et al, 1998; Obermann et al, 1998; Smith et al, 1992; reviewed in Smith and Toft, 2008).
Extracellular estrogens diffuse freely across the plasma membrane and into the nucleus. In the nucleus, estrogens interact with estrogen receptors and, in conjunction with other transcriptional regulators, promote changes in estrogen-responsive transcription (reviewed in Hall et al, 2001; Deroo and Korach, 2006; Hah and Kraus, 2014). The estrogen receptor binds endogenous estrogens such as 17 beta estradiol (E2, the most potent ligand), estrone (E1), estriol (E3) and estretol (E4), as well as other physiological ligands such as oxysterols derivatives like 27-hydroxycholesterol (reviewed in Arnal, 2017; Nguyen et al, 2015; Nelson et al, 2013). In addition to naturally occurring ligands, there are many other synthetic estrogen ligands in clinical use that bind the estrogen receptor and modulate biological response. These include agonists, which mimic the effect of naturally occurring estrogens, mixed agonist-antagonists (also known as selective estrogen receptor modulators, or SERMs, which show tissue-specific activities) and antagonists (reviewed in Cosman and Lindsay, 1999; Katzenellenbogen et al, 2000; Bai and Gust, 2009; Farooq, 2015).
The complex of ERBB4s80 and activated estrogen receptor ESR1 promotes transcription of the CXCL12 gene, encoding Stromal cell-derived factor 1 (SDF1) (Zhu et al. 2006).
The complex of ERBB4s80 and activated estrogen receptor ESR1 binds estrogen response elements (EREs) in the promoter of the CXCL12 gene, encoding Stromal cell-derived factor 1 (Zhu et al. 2006).
The complex of ERBB4s80 and activated estrogen receptor ESR1 binds estrogen response elements (EREs) in the promoter of the PGR (NR3C3) gene, encoding Progesterone receptor (Zhu et al. 2006).
X-ray crystallography studies illustrated that the ligand-bound ESR1 interacts with LXXLL motif-containing NCOA3 (SRC3) through the ligand-binding domain (LBD) at the C-terminus of ESR1, which also has a ligand-dependent transactivation function (known as AF-2) (Brzozowski et al. 1997). Cryoelectron microscopy (cryo-EM) determined the quaternary structure of an active complex of DNA-bound ESR1, steroid receptor coactivator 3 (SRC3 or NCOA3), and a secondary coactivator (p300/EP300). Structural models suggests the following assembly mechanism for the complex: each of the two ligand-bound ESR1 monomers independently recruits one NCOA3 protein via the transactivation domain of ESR1;the two NCOA3s in turn bind to different regions of one p300 protein through multiple contacts (Yi P et al. 2015).
Hormone-activated estrogen receptor (ER) binds with high affinity to specific DNA sequences, estrogen response elements (EREs), found in the regulatory regions of estrogen-responsive genes (Klinge CM 2001). The majority of known estrogen responsive genes contain imperfect EREs that differ from the consensus ERE sequence, 5′-GGTCAnnnTGACC-3′, by one or more base pairs. The individual ERE sequences were found to differentially induce changes in ER conformation that may influence the recruitment of specific coactivator proteins (Wood JR et al. 2001). The promoter of the TGFA gene has two imperfect EREs between -252 to -200 and an additional upstream sequence between -623 and -549. These elements confer estrogen-responsiveness to the promoter and are bound by ESR1 as assessed by electrophoretic mobility shift assay (Vyhidal et al, 2000).
NCOA1 is a nuclear receptor coactivator that is recruited to the TGFA promoter through direct interaction with ESR1 (Halachmi et al, 1994; Cavaillès et al, 1994; Harnstein et al, 2001). Although NCOA1 has intrinsic histone acetyltransferase activity, it plays a more predominant role in activating gene transcription through its ability to recruit EP300 to the promoter (Harnstein et al, 2001; reviewed in Arnal el al, 2017).
CITED1 and EP300 contribute to the estrogen-dependent expression of the TGFA gene. CITED1 (also known as CBP) interacts directly with ESR1 through the transcriptional activation AF2 domain and enhances its activity. The interaction between ESR1 and exogenous CITED1 also stabilizes the interaction with EP300 (Yahate et al, 2001).
Cryoelectron microscopy (cryo-EM) determined the quaternary structure of an active complex of DNA-bound ESR1, steroid receptor coactivator 3 (SRC3 or NCOA3), and a secondary coactivator (p300/EP300). A structural model suggests the following assembly mechanism for the complex: each of the two ligand-bound ESR1 monomers independently recruits one NCOA3 protein via the transactivation domain of ESR1;the two NCOA3s in turn bind to different regions of one p300 protein through multiple contacts (Yi P et al. 2015).
The TGFA gene encodes the precursor of the transforming growth factor alpha (TGF alpha). Binding of the CITED1 to the promoter of the TGFA gene in the estrogen:ESR1-dependent manner stimulates TGFA transcription in MCF-7 breast cancer cell line (Yahata T et al. 2001).
Estrogen induces cellular proliferation by upregulating expression of critical cell cycle regulators that govern progression through G1, such as Myc and Cyclin D1 (reviewed in Butt et al, 2005). In the absence of estrogen, Cyclin D1 expression is inhibited, at least in part, by the binding of a transcriptional repressor complex YY1:HDAC1 to the promoter (Cicatiello et al, 2004). Estrogen-stimulated induction of target gene expression appears in many cases to be primed by the binding of 'pioneer' transcription factors, such as FOXA and GATA family proteins (Carroll et al, 2005; Laganière et al, 2005; Eeckhoute et al, 2006; Hurtado et al, 2011; Kong et al, 2011; Theodorou et al, 2013; Swinstead et al, 2016; reviewed in Zaret and Carroll, 2011; Augello et al, 2011; Fiorito et al, 2013; Wilson and Giguere, 2008). FOXA factors have a winged helix structure that is thought to bind to closed chromatin structures in a manner analogous to linker histones, displacing linker histones and rendering the DNA more accessible to other transcription factors (reviewed in Zaret and Carroll, 2011). FOXA binding sites tend to be enriched at enhancer elements, characterized by H3K4 mono- and dimethylation, and expression of the histone demethylase KDM1A abrogates FOXA recruitment (Lupien et al, 2008). An enhancer element has been defined downstream of the CCND1 gene that mediates the binding of both the pioneer factor FOXA1 and estrogen-responsive ESR1 (Eeckhoute et al, 2006).
Although there is not a classical estrogen response element (ERE) in the proximal CCND1 promoter, estrogen-responsive transcription is mediated through recruitment of hormone-bound ESR1 by other DNA-binding proteins (reviewed in Guo et al, 2011; Klein and Assoian, 2008). A heterodimer of JUN:FOS binds to an estrogen-responsive G1 element (ERGE) between nucleotides -948 and -925 and is responsible for recruitment of ESR1 and estrogen to this site. OCT1 may facilitate this binding by displacing a YY1:HDAC1 repressive complex that occupies an adjacent site in unstimulated cells (Albanese et al, 1995; Cicatiello et al, 2004; Shen et al, 2007). Binding of ATF2:JUN heterodimers to a cyclic AMP response element (CRE) located 52 nucleotides upstream of the transcriptional start site may also contribute to estrogen-responsive signaling (Sabbah et al, 1999; Castro-Rivera at al, 2001). An ERE has been identified in an enhancer element downstream of the CCND1 gene (enh2). This enhancer binds to FOXA1, and also mediates recruitment of the histone acetyltransferase p300 to the CCND1 promoter (Eeckhoute et al, 2006). Although FOXA1 and GATA3 were initially characterized as 'pioneer' transcription factors that bind to closed chromatin conformations and prime recruitment of sequence-specific DNA binding factors, more recent studies have questioned the order of recruitment of the estrogen receptors, FOXA1 and GATA3 to estrogen-responsive targets (Swinstead et al, 2016).
The proliferative effects of estrogen stimulation arise in part through the estrogen-dependent activation of key cell cycle regulators such as Cyclin D1, encoded by the CCND1 gene. Although there is not a classical estrogen response element (ERE) in the proximal CCND1 promoter, estrogen-responsive transcription is mediated through recruitment of hormone-bound ESR1 by other DNA-binding proteins (reviewed in Guo et al, 2011; Klein and Assoian, 2008). A heterodimer of JUN:FOS binds to an estrogen-responsive G1 element (ERGE) between nucleotides -948 and -925 and is responsible for recruitment of ESR1 and estrogen to this site. OCT1 may facilitate this binding by diplacing a YY1:HDAC1 repressive complex that occupies an adjacent site in unstimulated cells (Albanese et al, 1995; Cicatiello et al, 2004; Shen et al, 2007). Binding of ATF2:JUN heterodimers to a cyclic AMP response element (CRE) located 52 nucleotides upstream of the transcriptional start site may also contribute to estrogen-responsive signaling (Sabbah et al, 1999; Castro-Rivera at al, 2001).
ESR1 and HIST1H2AC contribute to estrogen-responsive transcriptional activation at the BCL and MYC genes by promoting long-range chromatin loops between enhancer elements. This is accompanied by the recruitment of EP300 and RNA polymerase II (Su et al, 2014).
KDM4B (also known as JMJD2B) is an H3 K9 demethylase that is recruited to estrogen-responsive enhancers through interaction with ESR1 (Kawazu et al, 2011; Gaughan et al, 2013). KDM4B promotes target gene activation in the presence of estrogen by removing the repressive H3K9 methylation mark, and KDM4B has been shown to interact with the SWI/SNF-B complex component SMARCA4 and to promote recruitment of RNA polymerase II (Kawazu et al, 2011; Gaughan et al, 2013).
GREB1 is transcribed in response to estrogen stimulation in a manner that depends on NCOA3, ZNF217 and KDM4B (Ghosh et al, 2000; Rae et al, 2005; Sun et al, 2007; Kawazu et al, 2011; Nguyen et al, 2014). Estrogen-responsive transcription is directed by three EREs at -21.2, -9.5 and -1.6kb relative to the transcription start site and may be facilitated by the formation of chromatin loops (Lin et al, 2004; Sun et al, 2007; Deschenes et al, 2007; Lin et al, 2007).
Transcriptional induction of a number of estrogen-responsive genes, including MYC, MYB, GREB1 and KDM4B itself, is dependent on KDM4B-dependent H3K9 promoter/enhancer demethylation. KDM4B interacts with ESR1 and is recruited to estrogen-responsive target gene promoters or enhancers in an estrogen-dependent manner (Kawazu et al, 2011; Gaughan et al, 2013). Depletion of KDM4B in T47D and MCF7 breast cancer cell lines abrogates the proliferative response to estrogen, consistent with its role in driving expression of estrogen-dependent cell cycle regulators like MYC and CCND1 (Kawazu et al, 2011; Yang et al, 2010). KDM4B additionally interacts with the transcriptional activator SMARCA4, and depletion of KDM4B compromises the recruitment of RNA polymerase II to the MYB promoter in T47D cells (Kawazu et al, 2011). KDM4B is highly expressed in ER alpha-positive breast cancer and prostate cancer (Gaughan et al, 2013; Coffey et al, 2013). KDM4B may also promote estrogen-responsive signaling by interacting with GATA3 and binding to the enhancers of ESR1and FOXA1 genes (Gaughan et al, 2013).
Translation of GREB1 mRNA is negatively regulated by mIR-26A and B, which bind directly to the 3'UTR. mIR-26A and B are both downregulated in the presence of estrogen in a manner that depends on estrogen-stimulated MYC gene expression. Of the nine identified estrogen-responsive, mIR-26 regulated genes, GREB1, CHD1 and KPNA2 are the only three that contribute to the proliferative response to estrogen (Tan et al, 2014).
Translation of GREB1 mRNA is negatively regulated by direct binding of mIR-26A and mIR-26B to the 3' UTR. mIR-26 expression is itself negatively regulated in response to estrogen in a manner that depends on estrogen-stimulated MYC gene expression (Tan et al, 2014).
KDM4B regulates its own expression by interacting with the estrogen receptor to promote estrogen-dependent demethylation of its promoter. KDM4B also interacts with the transcriptional activator SMARCA4 to promote recruitment of RNA polymerase II (Kawazu et al, 2011; Gaughan et al, 2013).
MYB is frequently expressed in breast cancer and its expression is correlated with ER positive tumors (Guerin et al, 1990; Kauraniemi et al, 2000). MYB expression is estrogen-responsive, but hormone-dependent control is exerted at the level of transcriptional elongation rather than initiation (Frasor et al, 2003; Carroll et al, 2006; Bender et al, 1987; Watson et al, 1988; Drabsch et al, 2007). In the absence of estrogen, RNA polymerase II stalls at a stem-loop poly-T (SL-dT) tract between within intron 1 (Drabsch et al, 2007). Upon estrogen stimulation, a complex containing estrogen, the estrogen receptor and P-TEFb (an elongation factor consisting of Cyclin T and CDK9) is recruited to an ERE near the SL-dT. P-TEFb phosphorylates serine 2 in the RNA polymerase II CTD, allowing the polymerase to continue elongating (Drabsch et al, 2007; Mitra et al, 2012; reviewed in Gonda et al, 2008; Garriga and Grana, 2004). Although EREs have been identified around the SL-dT and have been shown by ChIP to be bound by ESR1, mutation of the EREs does not abrogate estrogen-responsive MYB expression, suggesting that the estrogen receptor either binds to a non-canonical site or it interacts through another transcription factor in this reaction (Drabsch et al, 2007; Mitra et al, 2012). Transcriptional induction of MYB is also dependent on KDM4B-dependent H3K9 promoter/enhancer demethylation. KDM4B interacts with ESR1 and is recruited to estrogen-responsive target gene promoters or enhancers in an estrogen-dependent manner (Kawazu et al, 2011; Gaughan et al, 2013). Depletion of KDM4B in T47D and MCF7 breast cancer cell lines abrogates the proliferative response to estrogen, consistent with its role in driving expression of estrogen-dependent cell cycle regulators like MYC and CCND1 (Kawazu et al, 2011; Yang et al, 2010). KDM4B additionally interacts with the transcriptional activator SMARCA4, and depletion of KDM4B compromises the recruitment of RNA polymerase II to the MYB promoter in T47D cells (Kawazu et al, 2011). KDM4B is highly expressed in ER alpha-positive breast cancer and prostate cancer (Gaughan et al, 2013; Coffey et al, 2013). KDM4B may also promote estrogen-responsive signaling by interacting with GATA3 and binding to the enhancers of ESR1and FOXA1 genes (Gaughan et al, 2013). How and when (or whether) KDM4B interacts with P-TEFb has not been examined.
MYC gene expression is estrogen-responsive and expression of MYC and CCND1 contribute to the proliferative response stimulated by estrogen treatment (Dubnik et al, 1987; Dubnik et al, 1988; Dubnik and Shu, 1992; Prall et al, 1998). Estrogen-responsive MYC expression appears to depend at least in part on a distal enhancer element 67 kb from the transcriptional start site that contains a half ERE and an AP-1 site (Denardo et al, 2005; Carroll et al, 2006; Wang et al, 2011). Upon estrogen stimulation, these sites are occupied by ESR1 and a JUND:FOSB heterodimer, respectively (Wang et al, 2011). Estrogen-responsive MYC expression also depends on the cohesin complex, as depletion of the RAD21 cohesin subunit abrogates expression (Stedman et al, 2008; Schmidt et al, 2010; McEwan et al, 2011; Antony et al, 2015). Genome-wide studies have shown that RAD21 and ESR1 binding sites overlap in a fraction of estrogen-responsive genes, including MYC (Schmidt et al, 2010). Cohesin may contribute to target gene expression by promoting chromatin looping structures between distal enhancers and the target gene promoters or through other mechanisms that remain to be elucidated (Li et al, 2012; Antony et al, 2015; reviewed Rhodes et al, 2011; Losada, 2014). Overexpression of histone isoform HIST1H2AC in breast cancer has been shown to contribute to MYC gene expression by promoting the formation of activating chromatin loops and facilitating the recruitment of ESR1, EP300 and RNA polymerase II (Su et al, 2014).
ESR1 and HIST1H2AC contribute to estrogen-responsive transcriptional activation at the BCL and MYC genes by promoting long-range chromatin loops between enhancer elements. This is accompanied by the recruitment of EP300 and RNA polymerase II (Su et al, 2014).
HIST1H2AC (also known as H2ac) is a replicative histone H2A isoform that is overexpressed in breast cancer (Shann et al, 2008). HIST1H2AC and HIST1H2AA, unique among HIST1H2 family members, contains a HAR domain that in yeast has been shown mediate interaction with histone H3 and to regulate gene expression (Zheng et al, 2010). Estrogen-dependent recruitment of HIST1H2AC to target genes contributes to the proliferative response to estrogen, and siRNA depletion of HIST1H2AC abrogates expression of genes including MYC, CCND1 and BCL2, among others, and results in cell cycle arrest at G0/G1. By ChIP, both the estrogen receptor and HIST1H2AC are present at distal enhancer elements and in the 3' UTR of target genes upon estrogen stimulation, and the proteins physically interact both in vitro and in vivo. HIST1H2AC and ESR1 contribute to target gene activation by promoting the formation of long distance chromatin loops between disparate regulatory regions (Su et al, 2013). Overexpression of HIST1H2AC additionally decreases the levels of the repressive epigenetic modification H3K9me2 that is associated with estrogen-responsive signaling, and HIST1H2AC contributes to the recruitment of the histone demethylase KDM1A (Perillo et al, 2008; Su et al, 2014).
Histone demethylase KDM1A (also known as LSD1) is recruited to estrogen-responsive promoters and enhancers in a manner that depends on the HAR domain of HIST1H2AC. KDM1A removes the repressive H3K9me2 epigenetic mark, and consistent with this, KDM1A knockdown leads to abrogated expression of BCL2 and MYC genes in response to estrogen stimulation (Perillo et al, 2008; Su et al, 2014; Wang et al, 2009; Wissmann et al, 2007)
KDM1A removes the H3K9me2 repressive epigenetic mark at estrogen-responsive enhancers, allowing transcriptional activation (Wang et al, 2009; Su et al, 2014).
MYC gene expression is estrogen-responsive and expression of MYC and CCND1 contribute to the proliferative response stimulated by estrogen treatment (Dubnik et al, 1987; Dubnik et al, 1988; Dubnik and Shu, 1992; Prall et al, 1998). Estrogen-responsive MYC expression appears to depend at least in part on a distal enhancer element 67 kb from the transcriptional start site that contains a half ERE and an AP-1 site (Denardo et al, 2005; Carroll et al, 2006; Wang et al, 2011). Upon estrogen stimulation, these sites are occupied by ESR1 and a JUND:FOSB heterodimer, respectively (Wang et al, 2011). Estrogen-responsive MYC expression also depends on the cohesin complex, as depletion of the RAD21 cohesin subunit abrogates expression (Stedman et al, 2008; Schmidt et al, 2010; McEwan et al, 2011; Antony et al, 2015). Genome-wide studies have shown that RAD21 and ESR1 binding sites overlap in a fraction of estrogen-responsive genes, including MYC (Schmidt et al, 2010). Cohesin may contribute to target gene expression by promoting chromatin looping structures between distal enhancers and the target gene promoters or through other mechanisms that remain to be elucidated (Li et al, 2012; Antony et al, 2015; reviewed Rhodes et al, 2011; Losada, 2014). Overexpression of histone isoform HIST1H2AC in breast cancer has been shown to contribute to MYC gene expression by promoting the formation of activating chromatin loops and facilitating the recruitment of ESR1, EP300 and RNA polymerase II (Su et al, 2014).
GREB1 (growth regulation by estrogen in breast cancer 1) is an estrogen-responsive gene that contains three EREs located 1.6, 9.5 and 21.2 kb upstream of the transcriptional start site (Ghosh et al 2000; Lin et al, 2004; Rae et al, 2005; Deschenes et al, 2007; Sun et al, 2007). By ChIP, all three EREs are bound by ESR1 and the transcriptional co-activator NCOA3 (also known as SRC3). Although this binding occurs even in the absence of estradiol treatment, binding is enhanced after estrogen stimulation (Sun et al, 2007). Estrogen-dependent GREB1 expression also depends on removal of the repressive H3K9 methlyation mark by KDM4B (Kawazu et al, 2011; Gaughan et al, 2013). Estrogen stimulation increases the occupancy of RNA polymerase II at the GREB1 gene and may promote transcription through the formation of chromatin loops. Estrogen stimulation also increases the level of H4 acetylation at the promoter (Sun et al, 2007; Deschenes et al, 2007). In addition to ESR1 and NCOA3, Kruppel-like finger (KLF) protein ZNF217 has also been shown to bind to ESR1 and enhance recruitment to GREB1 EREs. ZNF217 overexpression is associated with anchorage independent growth in MCF7 cell lines (Nguyen et al, 2014). Although both NCOA3 and ZNF217 have been shown to interact with the GREB1 EREs, no study has examined co-occupancy of the GREB1 enhancer by these two regulators.
Translation of CHD1 is negatively regulated by binding of mIR-26A and mIR-26B to the 3'UTR. Estrogen-and MYC-dependent CHD1 expression contributes to the proliferative response to estrogen stimulation (Tan et al, 2014).
Translation of CHD1 mRNA is negatively regulated by mIR-26A and B, which bind directly to the 3'UTR. mIR-26A and B are both downregulated in the presence of estrogen in a manner that depends on estrogen-stimulated MYC gene expression. Of the nine identified estrogen-responsive, mIR-26 regulated genes, GREB1, CHD1 and KPNA2 are the only three that contribute to the proliferative response to estrogen (Tan et al, 2014).
CHD1 is an ATP-dependent chromatin remodelling factor that is a component of the SAGA complex (Sims et al, 2007; reviewed in Marfella and Imbalzano, 2007). CHD1 expression has been shown to be responsive to estrogen stimulation, and negatively regulated by direct binding of mIR-26A and mIR-26B to the 3' UTR. MYC- and estrogen-dependent down-regulation of mIR-26 expression abrogates the repressive effect on CHD1 expression and promotes the estrogen-responsive proliferative effect (Tan et al, 2014).
Translation of KPNA2 mRNA is negatively regulated by mIR-26A and B, which bind directly to the 3'UTR. mIR-26A and B are both downregulated in the presence of estrogen in a manner that depends on estrogen-stimulated MYC gene expression. Of the nine identified estrogen-responsive, mIR-26 regulated genes, GREB1, CHD1 and KPNA2 are the only three that contribute to the proliferative response to estrogen (Tan et al, 2014). KPNA2 expression has also been demonstrated to be regulated by mIR-26 binding in ovarian cancer (Lin et al 2015).
KPNA2 is a member of the karyopherin alpha family that recognized cargo proteins at the nuclear pore to facilitate their nucleocytoplasmic transport (reviewed in Christiansen and Dyrskjot, 2013). KPNA2 is highly expressed in many cancers and has been shown to be stimulated by estrogen (Tan et al, 2014). KPNA2 expression is negatively regulated by direct binding of mIR-26A and mIR-26B to the 3'UTR (Tan et al, 2014).
MYB is frequently expressed in breast cancer and its expression is correlated with ER positive tumors (Guerin et al, 1990; Kauraniemi et al, 2000). MYB expression is estrogen-responsive, but hormone-dependent control is exerted at the level of transcriptional elongation rather than initiation (Frasor et al, 2003; Carroll et al, 2006; Bender et al, 1987; Watson et al, 1988; Drabsch et al, 2007). In the absence of estrogen, RNA polymerase II stalls at a stem-loop poly-T (SL-dT) tract between within intron 1 (Drabsch et al, 2007). Upon estrogen stimulation, a complex containing estrogen, the estrogen receptor and P-TEFb (an elongation factor consisting of Cyclin T and CDK9) is recruited to an ERE near the SL-dT. P-TEFb phosphorylates serine 2 in the RNA polymerase II CTD, allowing the polymerase to continue elongating (Drabsch et al, 2007; Mitra et al, 2012; reviewed in Gonda et al, 2008; Garriga and Grana, 2004). Although EREs have been identified around the SL-dT and have been shown by ChIP to be bound by ESR1, mutation of the EREs does not abrogate estrogen-responsive MYB expression, suggesting that the estrogen receptor either binds to a non-canonical site or it interacts through another transcription factor in this reaction (Drabsch et al, 2007; Mitra et al, 2012)
Transcriptional pausing at the SL-dT site in the MYB gene is overcome in response to estrogen by the P-TEFb-mediated phosphorylation of serine 2 in the C-terminal domain of RNA polymerase II (Drabsch et al, 2007; Mitra et al, 2012).
ESR1 binds to an ERE at -242 in the promoter of the CXXC5 gene and promotes transcription in an estrogen-dependent fashion. CXXC5 is a member of the zinc finger CXXC family of transcription factors and plays roles in cellular proliferation and differentiation (Nott et al, 2009; YaÅŸar et al, 2016).
CXXC5 expression is estrogen-responsive and depends on the interaction of ligand-bound ESR1 with an ERE at -242 of the promoter (Nott et al, 2009; YaÅŸar et al, 2016). CXXC5 is a transcription factor that plays roles in cellular proliferation and differentiation (Andersson et al, 2009; Kim et al, 2010; Aras et al, 2013; Li et al, 2014; Kim et al, 2016; Kim et al, 2015; Lee et al, 2015; Wang et al, 2013)
Trefoil factor family (TFF) 1 and 3 are secreted in mucous epithelia and the nervous system and have been implicated in oncogenesis and metastasis (reviewed in Busch and Dünker, 2015). TFF1 and 3 are estrogen-responsive genes with ESR1-bound promoters/enhancers that are 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; Kong et al, 2011; Theodorou et al, 2013; reviewed in Zaret and Carroll, 2011; Augello et al, 2011; Fiorito et al, 2013; Wilson and Giguere, 2008). FOXA factors have a winged helix structure that is thought to bind to closed chromatin structures in a manner analogous to linker histones, displacing linker histones and rendering the DNA more accessible to other transcription factors (reviewed in Zaret and Carroll, 2011). FOXA binding sites tend to be enriched at enhancer elements, characterized by H3K4 mono- and dimethylation and H3K27 acetylation, active histone markers (Heintzman et al, 2009; Creyghton et al, 2010; Theodorou et al, 2013).
Estrogen-dependent TFF3 expression is promoted by the formation of FOXA1- and GATA3-dependent chromatin loops. Interaction of ligand-bound ESR1 with the enhancer promotes recruitment of EP300 and other chromatin modifying enzymes, and stimulates the deposition of active chromatin marks like H3K4 methylation and H3K27 acteylation (Laganière et al, 2005; Theodorou et al, 2013; reviewed in Zaret and Carroll, 2011)
TFF3 is an estrogen-responsive gene whose expression is primed prior to estrogen receptor binding by the formation of FOXA1- and GATA3-dependent chromatin loops. Interaction of ligand-bound ESR1 with the enhancer promotes recruitment of EP300 and other chromatin modifiying enzymes, and stimulates the deposition of active chromatin marks like H3K4 methylation and H3K27 acteylation (Laganière et al, 2005; Theodorou et al, 2013; reviewed in Zaret and Carroll, 2011)
EBAG9 is an estrogen-responsive gene with an ill-characterized role in tumorigenesis and is overexpressed in a number of cancers (Jóźwicki et al, 2015; Xu et al, 2014; Giagnis et al, 2013). EBAG9 has been implicated in glycan maturation at the Golgi, and may also play roles in immune response and apoptosis during tumor growth (Wolf et al, 2010; Miyazaki et al, 2014; Tanaka et al, 2014; Mayeama et al, 2011). Estrogen-dependent transcription is mediated by an ERE in the 5'-flanking region which has been shown to bind ESR1 by electrophoretic mobility shift assay (Ikeda et al, 2000).
EBAG9, also known as RCAS1, is an estrogen-responsive gene with an ERE in the 5' flanking region (Ikeda et al, 2000). EBAG9 may play a role in immune response during tumorigenesis, and expression of EBAG9 is often upregulated in malignant tumors (Jóźwicki et al, 2015; Miyazaki et al, 2014; Xu et al, 2014; Tanaka et al, 2014; Wolf et al, 2010; Maeyama et al, 2011)
Estrogen-stimulated expression of CTSD depends on the cyclic recruitment of DNA-binding and other transcriptional activators. Binding sites for the DNA-binding transcriptional activators SP1, USF1 and 2 have been identified in the proximal CTSD promoter (Xing and Archer, 1998; Wang et al, 1998; Krishnan et al, 1994; Wang et al, 2001; reviewed in Safe, 2000). Other early factors that contribute to estrogen-dependent CTSD expression include the co-activator NCOA3, EP300 and MED1, a component of the mediator complex. These factors contribute to the formation of transcriptionally active chromatin and to the recruitment of RNA polymerase II (Shang et al, 2000; Bretschneider et al, 2008). Note that although these factors are shown at the CTSD promoter simultaneously, they have not all been demonstrated to form part of a single complex on an individual CTSD promoter.
Cathepsin D (CTSD) is an estrogen-responsive gene encoding a lysosomal protease with roles in cellular proliferation, apoptosis, cell migration and differentiation, among others (reviewed in Zaidi et al, 2008; Khalkhali-Ellis and Hendrix, 2015). Estrogen-dependence is conferred by the presence of non-canonical EREs in the proximal and distal promoter regions which are bound by ESR1 in a ligand-dependent manner (Augereau et al, 1994; Cavaillès et al, 1993; Wang et al, 1997; Wang et al, 1998; Xing and Archer, 1998; Shang et al, 2000; Wang et al, 2001; Bourdeau et al, 2004). Estrogen-stimulated transcriptional activation is facilitated by the formation of ESR1-dependent loops and by the cyclic recruitment of activators, coactivators, HATs and other components of the general transcriptional machinery (Shang et al, 2000; Bretschneider et al, 2008).
Cathepsin D (CTSD) is a lysosomal aspartyl protease that plays a role in the protein processing and degradation. In addition to its 'housekeeping' roles, CTSD controls the processing of proteins involved in cell cycle progression, differentiation, migration, immunology, neurogenesis, apoptosis and angiogenesis (reviewed in Zaidi et al, 2008; Khalkhali-Ellis and Hendrix, 2015). CTSD is overexpressed in many breast cancers and is implicated in tumor progression and metastasis (Fusek and Vetvicka, 2005). CTSD expression is constitutive in ESR1-negative cells, but estrogen-dependent in ESR1-positive cells (Liaudet-Coopman et al, 2006). Estrogen-responsiveness is conferred by imperfect EREs in both the proximal and the distal promoter and is facilitated by ESR1-dependent looping of the enhancer (Cavaillès et al, 1993; Augereau et al, 1994; Shang et al, 2004; Bourdeau et al, 2004; Bretschneider et al, 2008)
Estrogen-dependent interaction between NCOA1 and EP300 recruits EP300 to the TGFA promoter (Halachmi et al, 1994; Cavaillès et al, 1994; Harnstein et al, 2001). NCOA1 and EP300 contribute to active chromatin structures through their coactivator and histone acetyltransferase activity (reviewed in Xu et al, 2007; Arnal et al, 2017).
ESR1-mediated signaling can be initiated in an estrogen-independent manner downstream of stimuli such as EGF, NRG1, IGF, insulin, dopamine and cAMP (Ignar-Trowbridge et al, 1993, Pietras et al, 1995; Ma et al, 1994; Newton et al, 1994; Smith et al, 1993; Aronica and Katzenellenbogen, 1993). Stimulation with EGF or IFGF-1 promotes the MAPK-dependent phosphorylation of ESR1 at serine 118, which contributes to interaction with CBP/p300 and the p160 family of coactivators (Bunone et al, 1996; Chen et al, 2002; Cheng et al, 2007; reviewed in Anbalagan and Rowan, 2105). Serine 118 is also phosphorylated in response to estrogen stimulation (Chen et al, 2002; reviewed in Anbalagan and Rowan, 2015). The relationship between MAPK-dependent S118 phosphorylation of ESR1 and the release from the cochaperone complex and ESR1 dimerization is not clear. In this reaction, all these events are shown happening simultaneously.
27-hydroxycholesterol binds directly to ESR1 and ESR2 to modulate estrogen signaling in a cell-, tissue-, and gene-specific manner, making it a physiological selective ER modulator (SERM) (Umetani et al, 2007; Nelson et al, 2013; Nguyen et al, 2015). In the context of breast cancer, 27-HC acts as an estrogen agonist, promoting ER-dependent cellular proliferation. The development of resistance to aromatase inhibitors in breast cancer can arise in part through epigenetic reprogramming that activates the cholesterol biosynthetic pathway, elevating 27-HC levels and resulting in constitutive ER alpha activation (Nelson et al, 2013; Nguyen et al, 2015). Note that 27-HC binding to the estrogen receptors likely occurs in the context of a chaperone complex as is the case for estrogens, however this has not been explicitly demonstrated.
In addition to being an estrogen-responsive target, GREB1 also interacts directly with ESR1 and functions as an coactivator at numerous estrogen-responsive promoters, as assessed in MCF7 cell lines, xenograft models and primary tumors (Mohammed et al, 2013). ESR1-binding coincides with ~95% of GREB1 binding events sites as assessed by ChIP-seq, and expression of up to half of ESR1- and estrogen-dependent genes is compromised when GREB1 expression is silenced, without affecting ESR1 binding. GREB1 may function to stabilize interactions with other coactivators such as EP300 and CREBBP (also known as p300 and CBP, respectively), as co-occupancy with these proteins is lost upon GREB1 silencing (Mohammed et al, 2013). GREB1 expression is high in ER+ cancers and is associated with positive prognosis (Mohammed et al, 2013; reviewed in Hodgkinson and Vanderhyden, 2014).
In addition to being a target of estrogen-dependent transcription, the progesterone receptor (PGR) interacts directly with ER alpha after stimulation with progesterone and modulates ESR1:ESTG binding (Ballare et al, 2003; Mohammed et al, 2015). Progesterone stimulation under estrogen-rich conditions promotes the release of PGR from the chaperone complex to facilitate interaction with ESR1 (Mohammed et al, 2015; reviewed in ).
Rapid immunoprecipitation by mass spectrometry of endogenous proteins (RIME) analysis shows that in addition to interacting with PGR after progesterone stimulation, ESR1 also interacts with known co-activators NRIP, GATA3 and TLE3 (Mohammed et al, 2013; Mohammed et al, 2015). Progesterone treatment of breast cancer cell lines under estrogen-rich conditions promotes a redistribution of ER alpha binding to PGR binding sites. This redistribution coincides with co-occupancy of FOXA1 and EP300 at the novel binding sites as well as with the H3K27Ac mark, suggesting that the binding events are functional (Clarke et al, 2012; Mohammed et al, 2015).
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gene:HIST1H2AC
nuclesome:ESR1:ESTG:EP300gene:H3K4me2
nucleosome:FOXA1:GATA3:ESTG:ESR1 dimer:JUN:ATF2:POUF21:ESTG:ESR1 dimer:JUN:FOSgene:H3K4me2
nucleosome:FOXA1:GATA3gene:H3K4me2
nucleosome:YY1:HDAC1dimer:estrogen:TFGA
gene:NCOA1dimer:estrogen:TGFA
gene promoterE2-evoked extra-nuclear signaling is independent of the transcriptional activity of estrogen receptors and occurs within seconds to minutes following E2 administration to target cells. Extra-nuclear signaling consists of the activation of a plethora of signaling pathways including the RAF/MAP kinase cascade and the PI3K/AKT signaling cascade and governs processes such as apoptosis, cellular proliferation and metastasis (reviewed in Hammes et al, 2007; Handa et al, 2012; Lange et al, 2007; Losel et al, 2003; Arnal et al, 2017; Le Romancer et al, 2011). ESR-mediated signaling also cross-talks with receptor tyrosine kinase, NF- kappa beta and GPCR signaling pathways by modulating the post-translational modification of enzymes and other proteins and regulating second messengers (reviewed in Arnal et al, 2017; Schwartz et al, 2016; Boonyaratanakornkit, 2011; Biswas et al, 2005). In the nervous system, E2 affects neural functions such as cognition, behaviour, stress responses and reproduction in part by inducing such rapid extra-nuclear responses (Farach-Carson and Davis, 2003; Losel et al, 2003), while in endothelial cells, non-genomic ESR-dependent signaling also regulates vasodilation through the eNOS pathway (reviewed in Levin, 2011).
Extra-nuclear signaling additionally cross-talks with nuclear estrogen receptor signaling and is required to control ER protein stability (La Rosa et al, 2012)
Recent data have demonstrated that the membrane ESR1 can interact with various endocytic proteins to traffic and signal within the cytoplasm. This receptor intracellular trafficking appears to be dependent on the phyical interaction of ESR1 with specific trans-membrane receptors such as IGR-1R and beta 1-integrin (Sampayo et al, 2018)
genes:H3K9me3
nucleosome:ESR1:ESTG:KDM4Bgenes:H3K9me3
nucleosomegene, BCL2 gene: H3K9me2, HIST1H2AC
nucleosome:ESR1:ESTG:KDM1Agene, BCL2 gene:HIST1H2AC
nucleosome:ESR1:ESTGgene, BCL2 gene:HIST1H2AC
nuclesome:ESR1:ESTG:EP300gene, BLC2 gene:H3K9me2, HIST1H2AC
nucleosome:ESR1:ESTGgene:HIST1H2AC
nucleosome:ESR1:ESTG:EP300:NCOA3During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).
During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.
ERBB4 becomes activated by binding one of its seven ligands, three of which, HB-EGF, epiregulin EPR and betacellulin BTC, are EGF-like (Elenius et al. 1997, Riese et al. 1998), while four, NRG1, NRG2, NRG3 and NRG4, belong to the related neuregulin family (Tzahar et al. 1994, Carraway et al. 1997, Zhang et al. 1997, Hayes et al. 2007). Upon ligand binding, ERBB4 forms homodimers (Sweeney et al. 2000) or it heterodimerizes with ERBB2 (Li et al. 2007). Dimers of ERBB4 undergo trans-autophosphorylation on tyrosine residues in the C-tail (Cohen et al. 1996, Kaushansky et al. 2008, Hazan et al. 1990, Li et al. 2007), triggering downstream signaling cascades. The pathway Signaling by ERBB4 only shows signaling by ERBB4 homodimers. Signaling by heterodimers of ERBB4 and ERBB2 is shown in the pathway Signaling by ERBB2. Ligand-stimulated ERBB4 is also able to form heterodimers with ligand-stimulated EGFR (Cohen et al. 1996) and ligand-stimulated ERBB3 (Riese et al. 1995). Dimers of ERBB4 with EGFR and dimers of ERBB4 with ERBB3 were demonstrated in mouse cell lines in which human ERBB4 and EGFR or ERBB3 were exogenously expressed. These heterodimers undergo trans-autophosphorylation. The promiscuous heteromerization of ERBBs adds combinatorial diversity to ERBB signaling processes. As ERBB4 binds more ligands than other ERBBs, but has restricted expression, ERBB4 expression channels responses to ERBB ligands. The signaling capabilities of the four receptors have been compared (Schulze et al. 2005).
As for other receptor tyrosine kinases, ERBB4 signaling effectors are largely dictated through binding of effector proteins to ERBB4 peptides that are phosphorylated upon ligand binding. All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000).
The CYT1 isoforms of ERBB4 also possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K (Kaushansky et al. 2008, Cohen et al. 1996), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000).
Besides signaling as a conventional transmembrane receptor kinase, ERBB4 differs from other ERBBs in that JM-A isoforms signal through efficient release of a soluble intracellular domain. Ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. For example, in mammary cells, ERBB4 binds SH2 transcription factor STAT5A. ERBB4 s80 shuttles STAT5A to the nucleus, and actsa as a STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Jones et al. 1999, Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 binds activated estrogen receptor in the nucleus and acts as a transcriptional co-factor in promoting transcription of some estrogen-regulated genes, including progesterone receptor gene NR3C3 and CXCL12 (SDF1) (Zhu et al. 2006). In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006).
The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and is a co-regulator of YAP1-mediated transcription in association with TEAD transcription factors (Komuro et al. 2003, Omerovic et al. 2004). Hence, the WW binding motif couples ERBB4 to the major effector arm of the HIPPO signaling pathway. The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005).
WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009).
ERBB4 also binds the E3 ubiquitin ligase MDM2, and inhibitor of p53 (Arasada et al. 2005). Other proteins that bind to ERBB4 intracellular domain have been identified by co-immunoprecipitation and mass spectrometry (Gilmore-Hebert et al., 2010), and include transcriptional co-repressor TRIM28/KAP1, which promotes chromatin compaction. DNA damage signaling through ATM releases TRIM28-associated heterochromatinization. Interactions of ERBB4 with TRIM28 and MDM2 may be important for integration of growth factor responses and DNA damage responses.
In human breast cancer cell lines, ERBB4 activation enhances anchorage-independent colony formation in soft agar but inhibits cell growth in a monolayer culture. Different ERBB4 ligands induce different gene expression changes in breast cancer cell lines. Some of the genes induced in response to ERBB4 signaling in breast cancer cell lines are RAB2, EPS15R and GATA4. It is not known if these gene are direct transcriptional targets of ERBB4 (Amin et al. 2004).
Transcriptome and ChIP-seq comparisons of full-length and intracellular domain isoforms in isogenic MCF10A mammary cell background have revealed the diversification of ERBB4 signaling engendered by alternative splicing and cleavage (Wali et al., 2014). ERBB4 broadly affected protease expression, cholesterol biosynthesis, HIF1-alpha signaling, and HIPPO signaling pathways, and other pathways were differentially activated by CYT1 and CYT2 isoforms. For example, CYT1 promoted expression of transcription factors TWIST1 and SNAIL1 that promote epithelial-mesenchymal transition. HIF1-alpha and HIPPO signaling are mediated, respectively, by binding of ERBB4 to HIF1-alpha and to YAP (Paatero et al., 2012, Komuro et al., 2003). ERBB4 increases activity of the transcription factor SREBF2, resulting in increased expression of SREBF2-target genes involved in cholesterol biosynthesis. The mechanism is not known and may involve facilitation of SREBF2 cleavage through ERBB4-mediated PI3K signaling (Haskins et al. 2016).
In some contexts, ERBB4 promotes growth suppression or apoptosis (Penington et al., 2002). Activation of ERBB4 in breast cancer cell lines leads to JNK dependent increase in BRCA1 mRNA level and mitotic cell cycle delay, but the exact mechanism has not been elucidated (Muraoka Cook et al. 2006). The nature of growth responses may be connected with the spliced isoforms expressed. In comparisons of CYT1 vs CYT2 (full-length and ICD) expression in mammary cells, CYT1 was a weaker growth inducer, associated with attenuated MAPK signaling relative to CYT2 (Wali et al., 2014). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro apoptotic factor (Naresh et al. 2006).
ERBB4 plays important roles in the developing and adult nervous system. Erbb4 deficiency in somatostatin-expressing neurons of the thalamic reticular nucleus alters behaviors dependent on sensory selection (Ahrens et al. 2015). NRG1-activated ERBB4 signaling enhances AMPA receptor responses through PKC-dependent AMPA receptor exocytosis. This results in an increased excitatory input to parvalbumin-expressing inhibitory neurons in the visual cortex and regulates visual cortical plasticity (Sun et al. 2016). NRG1-activated ERBB4 signaling is involved in GABAergic activity in amygdala which mediates fear conditioning (fear memory) (Lu et al. 2014). Conditional Erbb4 deletion from fast-spiking interneurons, chandelier and basket cells of the cerebral cortex leads to synaptic defects associated with increased locomotor activity and abnormal emotional, social and cognitive function that can be linked to some of the schizophrenia features. The level of GAD1 (GAD67) protein is reduced in the cortex of conditional Erbb4 mutants. GAD1 is a GABA synthesizing enzyme. Cortical mRNA levels of GAD67 are consistently decreased in schizophrenia (Del Pino et al. 2014). Erbb4 is expressed in the GABAergic neurons of the bed nucleus stria terminalis, a part of the extended amygdala. Inhibition of NRG1-triggered ERBB4 signaling induces anxiety-like behavior, which depends on GABAergic neurotransmission. NRG1-ERBB4 signaling stimulates presynaptic GABA release, but the exact mechanism is not known (Geng et al. 2016). NRG1 protects cortical interneurons against ischemic brain injury through ERBB4-mediated increase in GABAergic transmission (Guan et al. 2015). NRG2-activated ERBB4 can reduce the duration of GABAergic transmission by binding to GABA receptors at the postsynaptic membrane via their GABRA1 subunit and promoting endocytosis of GABA receptors (Mitchell et al. 2013). NRG1 promotes synchronization of prefrontal cortex interneurons in an ERBB4 dependent manner (Hou et al. 2014). NRG1-ERBB4 signaling protects neurons from the cell death induced by a mutant form of the amyloid precursor protein (APP) (Woo et al. 2012).
Clinical relevance of ERBB4 has been identified in several contexts. In cancer, putative and validated gain-of-function mutations or gene amplification that may be drivers have been identified at modest frequencies, and may also contribute to resistance to EGFR and ERBB2-targeted therapies. This is noteworthy as ERBB4 kinase activity is inhibited by pan-ERBB tyrosine kinase inhibitors, including lapatinib, which is approved by the US FDA. The reduced prevalence relative to EGFR and ERBB2 in cancer may reflect more restricted expression of ERBB4, or differential signaling, as specific ERBB4 isoforms have been linked to growth inhibition or apoptosis in experimental systems. ERBB2/ERBB4 heterodimers protect cardiomyocytes, so reduced activity of ERBB4 in patients treated with the ERBB2-targeted therapeutic antibody trastuzumab may contribute to the cardiotoxicity of this agent when used in combination with (cardiotoxic) anthracyclines.
With the importance of ERBB4 in developing and adult nervous system, NRG1 and/or ERBB4 polymorphisms, splicing aberrations and mutations have been linked to nervous system disorders including schizophrenia and amyotrophic lateral sclerosis, although these findings are not yet definitive.
The core domain of CBFB binds to the Runt domain of RUNX1, resulting in formation of the RUNX1:CBFB heterodimer. CBFB does not interact with DNA directly. The Runt domain of RUNX1 mediated both DNA binding and heterodimerization with CBFB (Tahirov et al. 2001), while RUNX1 regions that flank the Runt domain are involved in transactivation (reviewed in Zhang et al. 2003) and negative regulation (autoinhibition). CBFB facilitates RUNX1 binding to DNA by stabilizing Runt domain regions that interact with the major and minor grooves of the DNA (Tahirov et al. 2001, Backstrom et al. 2002, Bartfeld et al. 2002). The transactivation domain of RUNX1 is located C-terminally to the Runt domain and is followed by the negative regulatory domain. Autoinhibiton of RUNX1 is relieved by interaction with CBFB (Kanno et al. 1998).
Transcriptional targets of the RUNX1:CBFB complex involve genes that regulate self-renewal of hematopoietic stem cells (HSCs) (Zhao et al. 2014), as well as commitment and differentiation of many hematopoietic progenitors, including myeloid (Friedman 2009) and megakaryocytic progenitors (Goldfarb 2009), regulatory T lymphocytes (Wong et al. 2011) and B lymphocytes (Boller and Grosschedl 2014).
RUNX1 binds to promoters of many genes involved in ribosomal biogenesis (Ribi) and is thought to stimulate their transcription. RUNX1 loss-of-function decreases ribosome biogenesis and translation in hematopoietic stem and progenitor cells (HSPCs). RUNX1 loss-of-function is therefore associated with a slow growth, but at the same time it results in reduced apoptosis and increases resistance of cells to genotoxic and endoplasmic reticulum stress, conferring an overall selective advantage to RUNX1 deficient HSPCs (Cai et al. 2015).
RUNX1 is implicated as a tumor suppressor in breast cancer. RUNX1 forms a complex with the activated estrogen receptor alpha (ESR1) and regulates expression of estrogen-responsive genes (Chimge and Frenkel 2013).
RUNX1 is overexpressed in epithelial ovarian carcinoma where it may contribute to cell proliferation, migration and invasion (Keita et al. 2013).
RUNX1 may cooperate with TP53 in transcriptional activation of TP53 target genes upon DNA damage (Wu et al. 2013).
RUNX1 is needed for the maintenance of skeletal musculature (Wang et al. 2005).
During mouse embryonic development, Runx1 is expressed in most nociceptive sensory neurons, which are involved in the perception of pain. In adult mice, Runx1 is expressed only in nociceptive sensory neurons that express the Ret receptor and is involved in regulation of expression of genes encoding ion channels (sodium-gated, ATP-gated and hydrogen ion-gated) and receptors (thermal receptors, opioid receptor MOR and the Mrgpr class of G protein coupled receptors). Mice lacking Runx1 show defective perception of thermal and neuropathic pain (Chen CL et al. 2006). Runx1 is thought to activate the neuronal differentiation of nociceptive dorsal root ganglion cells during embryonal development possibly through repression of Hes1 expression (Kobayashi et al. 2012). In chick and mouse embryos, Runx1 expression is restricted to the dorso-medial domain of the dorsal root ganglion, to TrkA-positive cutaneous sensory neurons. Runx3 expression in chick and mouse embryos is restricted to ventro-lateral domain of the dorsal root ganglion, to TrkC-positive proprioceptive neurons (Chen AI et al. 2006, Kramer et al. 2006). RUNX1 mediated regulation of neuronally expressed genes will be annotated when mechanistic details become available.
Annotated Interactions
gene:HIST1H2AC
nuclesome:ESR1:ESTG:EP300gene:H3K4me2
nucleosome:FOXA1:GATA3:ESTG:ESR1 dimer:JUN:ATF2:POUF21:ESTG:ESR1 dimer:JUN:FOSgene:H3K4me2
nucleosome:FOXA1:GATA3:ESTG:ESR1 dimer:JUN:ATF2:POUF21:ESTG:ESR1 dimer:JUN:FOSgene:H3K4me2
nucleosome:FOXA1:GATA3gene:H3K4me2
nucleosome:FOXA1:GATA3gene:H3K4me2
nucleosome:YY1:HDAC1dimer:estrogen:TFGA
gene:NCOA1dimer:estrogen:TFGA
gene:NCOA1dimer:estrogen:TGFA
gene promoterdimer:estrogen:TGFA
gene promoterdimer:estrogen:TGFA
gene promoterdimer:estrogen:TGFA
gene promotergenes:H3K9me3
nucleosome:ESR1:ESTG:KDM4Bgenes:H3K9me3
nucleosome:ESR1:ESTG:KDM4Bgenes:H3K9me3
nucleosome:ESR1:ESTG:KDM4Bgenes:H3K9me3
nucleosomegene, BCL2 gene: H3K9me2, HIST1H2AC
nucleosome:ESR1:ESTG:KDM1Agene, BCL2 gene: H3K9me2, HIST1H2AC
nucleosome:ESR1:ESTG:KDM1Agene, BCL2 gene: H3K9me2, HIST1H2AC
nucleosome:ESR1:ESTG:KDM1Agene, BCL2 gene:HIST1H2AC
nucleosome:ESR1:ESTGgene, BCL2 gene:HIST1H2AC
nucleosome:ESR1:ESTGgene, BCL2 gene:HIST1H2AC
nuclesome:ESR1:ESTG:EP300gene, BLC2 gene:H3K9me2, HIST1H2AC
nucleosome:ESR1:ESTGgene, BLC2 gene:H3K9me2, HIST1H2AC
nucleosome:ESR1:ESTGgene:HIST1H2AC
nucleosome:ESR1:ESTG:EP300:NCOA3The AXIN1 gene expression is stimulated by cooperative binding of RUNX1 and estrogen receptor alpha (ESR1) to adjacent RUNX1 binding sites and estrogen response elements in the second intron of AXIN1 (Chimge et al. 2016).
In the unliganded state, estrogen receptors are part of a multi-subunit complex containing HSP90, p23 (also known as PTGES3) and other chaperone-associated proteins (Joab et al, 1984; Segnitz et al, 1995; Knoblauch et al, 1999; Bouhouche-Chatelier et al, 2001; Fliss et al, 2000; Oxelmart et al, 2006; reviewed in Smith and Toft, 2008; Bai and Gust, 2009). This complex is part of a chaperone binding and release cycle shared by many nuclear receptors (described in more detail in the pathway "HSP90 chaperone cycle for steroid hormone receptors") that governs receptor folding and activity and may contribute to a high-affinity conformation of the ligand-binding domain (reviewed in Pratt and Toft, 1997; Smith and Toft, 2008). HSP90 release from the receptor complex requires ATP hydrolysis (Smith et al, 1993; Grenert et al, 1997; Panaretou et al, 1998; Obermann et al, 1998; Smith et al, 1992; reviewed in Smith and Toft, 2008).
Although FOXA1 and GATA3 were initially characterized as 'pioneer' transcription factors that bind to closed chromatin conformations and prime recruitment of sequence-specific DNA binding factors, more recent studies have questioned the order of recruitment of the estrogen receptors, FOXA1 and GATA3 to estrogen-responsive targets (Swinstead et al, 2016).
Transcriptional induction of MYB is also dependent on KDM4B-dependent H3K9 promoter/enhancer demethylation. KDM4B interacts with ESR1 and is recruited to estrogen-responsive target gene promoters or enhancers in an estrogen-dependent manner (Kawazu et al, 2011; Gaughan et al, 2013). Depletion of KDM4B in T47D and MCF7 breast cancer cell lines abrogates the proliferative response to estrogen, consistent with its role in driving expression of estrogen-dependent cell cycle regulators like MYC and CCND1 (Kawazu et al, 2011; Yang et al, 2010). KDM4B additionally interacts with the transcriptional activator SMARCA4, and depletion of KDM4B compromises the recruitment of RNA polymerase II to the MYB promoter in T47D cells (Kawazu et al, 2011). KDM4B is highly expressed in ER alpha-positive breast cancer and prostate cancer (Gaughan et al, 2013; Coffey et al, 2013). KDM4B may also promote estrogen-responsive signaling by interacting with GATA3 and binding to the enhancers of ESR1and FOXA1 genes (Gaughan et al, 2013). How and when (or whether) KDM4B interacts with P-TEFb has not been examined.
The relationship between MAPK-dependent S118 phosphorylation of ESR1 and the release from the cochaperone complex and ESR1 dimerization is not clear. In this reaction, all these events are shown happening simultaneously.