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Binding to estrogen receptor (ER)-α leads to Induction of GATA3 expression
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding to estrogen receptor (ER)-α in immune cells leading to exacerbation of systemic lupus erythematosus (SLE)||adjacent||Moderate||Moderate||Yasuharu Otsubo (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
The hormone binding domain (HBD) of the ERα is required not only for binding ligand but also to form stable homodimers of the protein and mediate transcriptional activation by the receptor. There are two ligand-dependent signaling pathway. One is “classical” and the other is “tethered” pathway. A direct genomic interaction occurs between the ER ligand complex and specific sequences of DNA known as estrogen response elements (ERE) (Parker MG. 1993, Goldstein RA. 1993, Sasson S. 1991, Brandt ME. 1997). Transcriptional activation by ERα is mediated by two distinct activation functions: the constitutively active AF-1 domain, located in the N-terminal domain of the receptor protein, and the ligand-dependent AF-2 domain, located in the C-terminal domain of the receptor protein (Delaunay F. 2000). This is called “classical” signaling pathway. In addition to above classical mechanism, ligand-activated ERα interact with other transcription factor complexes and bind to non-EREs by attaching to other transcription factors and not with ERE directly. (Carolyn MK. 2001). This is also called “tethered” signaling pathway. The transcription factors GATA3 and STAT6 are essential for the establishment and/or maintenance of these interactions (Spilianakis and Flavell, 2004). In the tethered pathway, STAT6-ER fusion protein induce GATA-3 mRNA expression. Furthermore, in mammary gland but not in immune cells, GATA3 and ERα regulate each other and, along with FOXA1, can nucleate a remodeling complex at heterochromatic enhancer regions of ERα target genes, leading to the opening and epigenetic marking of sites for active transcription (Eeckhoute J. 2007, Kong SL. 2011). Alone, FOXA1 or ERα are not sufficient to fully open the chromatin, supporting a bona fide pioneer activity for GATA3 (Eeckhoute J. 2007, Kong SL. 2011).
Evidence Supporting this KER
STAT6-ER fusion protein (STAT6:ER) induce expression of GATA-3 mRNAs in presence of 4-Hydroxytamoxifen (4-HT), estrogen analogue (Kurata H. 1999, Zhu J. 2001). Furthermore, A constitutively active form of Stat6 (STAT6VT) introduced GATA3 expression and resulted in both Th2 differentiation and enhanced cell expansion without IL-4 (Zhu J. 2001, Horiuchi S. 2011). CD4 T cells from Stat6-knockout mice are not able to drive Th2 differentiation and cell expansion under ThN conditions with added IL-4 (Zhu J. 2001). Therefore, it is considered that activated STAT6 after ligand-biniding to ERα induce GATA3 expression in immune cells.
Uncertainties and Inconsistencies
The “tethered” pathway is confirmed indirectly using artificial STAT6-ER fusion protein but not endogenous STAT6. It remains unknown whether the “classical” pathway is utilized after binding to ERα in immune cells.
Known modulating factors
The Th1/Th2 shift is one of the most important immunologic changes during the menstrual cycle and gestation. Immune activity shifts across the menstrual cycle, with higher follicular-phase Th1 cell activity and higher luteal-phase Th2 cell activity (Tierney KL. 2015). This is due to the progressive increase of estrogens, which reach peak level in the third trimester of pregnancy. At these high levels, estrogens suppress the Th1-mediated responses and stimulate Th2-mediated immunologic responses (Doria A. 2006). The effects of ERα signaling on T cells appear to be estrogen-dose dependent, i.e., low doses of estrogen stimulate a Th1 response, but higher doses promote a Th2 response (Priyanka HP. 2013).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Parker MG, Arbuckle N, Dauvois S, Danielian P, White R. Structure and function of the estrogen receptor. Ann N Y Acad Sci. 1993. 684:119-26.
- Goldstein RA, Katzenellenbogen JA, Wolynes PG, et al. Three-dimensional model for the hormone binding domains of steroid receptors. Proc Natl Acad Sci. 1993;90 (21):9949-53.
- Sasson S. Equilibrium binding analysis of estrogen agonists and antagonists: relation to the activation of the estrogen receptor. Pathol Biol (Paris). 1991;39(1):59-69.
- Brandt ME, Vickery LE. Cooperativity and dimerization of recombinant human estrogen receptor hormone-binding domain. J Biol Chem. 1997;272(8):4843-9.
- Delaunay, F., Pettersson, K., Tujague, M., and Gustafsson, J. A. (2000). Functional Differences between the Amino-Terminal Domains of Estrogen Receptors α and β. Molecular Pharmacology 58: 584-590.
- Carolyn MK. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res. 2001 Jul 15; 29(14): 2905-2919.
- Spilianakis CG & Flavell RA, Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nature Immunology. 2004; 5: 1017-1027.
- Eeckhoute J, Positive Cross-Regulatory Loop Ties GATA-3 to Estrogen Receptor α Expression in Breast Cancer. Cancer Res. 2007; 67(13):6477-83.
- Kong SL, Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand‐inducible growth state. Mol Syst Biol (2011)7:526
- Kurata, H., Lee, H. J., O’Garra, A. and Arai, N. (1999). Ectopic expression of activated STAT6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. Immunity 11: 677-688.
- Zhu, J., Guo, L., Watson, C. J., Hu-Li, J. and Paul, W. E. (2001). STAT6 is necessary and sufficient for IL-4's role in Th2 differentiation and cell expansion. The Journal of Immunology 166(12): 7276-7281.
- Horiuchi S, Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3. (2011) J Immunol. 1;186(11):6378-89.
- Lambert KC, Curran EM, et al. Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol. 2005; 175(9): 5716-23.
- Kamogawa, Y., Lee, H.J., Johnston, J.A., McMahon, M., O’Garra, A., and Arai, N. (1998). Cutting Edge: A conditionally active form of STAT6 can mimic certain effects of IL-4. J. Immunol. 161, 1074-1077.
- Tierney, K. L., Julia, R. H. and Gregory, E. D. (2015). Sexual activity modulates shifts in Th1/Th2 cytokine profile across the menstrual cycle: An observational study. Fertility and Sterility 104 (6): 1513-1521.
- Doria, A., Iaccarino, L., Sarzi-Puttini, P., Ghirardello, A., Zampieri, S., Arienti, S., Cutolo, M. and Todesco, S. (2006). Estrogens in pregnancy and systemic lupus erythematosus. Annals of the New York Academy of Sciences 1069: 247-256.
- Priyanka HP, Krishnan HC, Singh RV, Hima L, Thyagarajan S. Estrogen modulates in vitro T cell responses in a concentration- and receptor-dependent manner: effects on intracellular molecular targets and antioxidant enzymes. Mol Immunol. 2013;56(4):328-39.