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      Molecular mechanism of estrogen–estrogen receptor signaling


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          17β‐Estradiol (E2), as the main circulating estrogen hormone, regulates many tissue and organ functions in physiology. The effects of E2 on cells are mediated by the transcription factors and estrogen receptor ( ER)α and ERβ that are encoded by distinct genes. Localized at the peri‐membrane, mitochondria, and the nucleus of cells that are dependent on estrogen target tissues, the ERs share similar, as well as distinct, regulatory potentials. Different intracellular localizations of the ERs result in dynamically integrated and finely tuned E2 signaling cascades that orchestrate cellular growth, differentiation, and death. The deregulation of E2– ER signaling plays a critical role in the initiation and progression of target tissue malignancies. A better understanding of the complex regulatory mechanisms that underlie ER actions in response to E2 therefore holds a critical trajectory for the development of novel prognostic and therapeutic approaches with substantial impacts on the systemic management of target tissue diseases.

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          The steroid and thyroid hormone receptor superfamily.

          Analyses of steroid receptors are important for understanding molecular details of transcriptional control, as well as providing insight as to how an individual transacting factor contributes to cell identity and function. These studies have led to the identification of a superfamily of regulatory proteins that include receptors for thyroid hormone and the vertebrate morphogen retinoic acid. Although animals employ complex and often distinct ways to control their physiology and development, the discovery of receptor-related molecules in a wide range of species suggests that mechanisms underlying morphogenesis and homeostasis may be more ubiquitous than previously expected.
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            AP-1 function and regulation.

            AP-1 (activating protein-1) is a collective term referring to dimeric transcription factors composed of Jun, Fos or ATF (activating transcription factor) subunits that bind to a common DNA site, the AP-1-binding site. As the complexity of our knowledge of AP-1 factors has increased, our understanding of their physiological function has decreased. This trend, however, is beginning to be reversed due to the recent studies of gene-knockout mice and cell lines deficient in specific AP-1 components. Such studies suggest that different AP-1 factors may regulate different target genes and thus execute distinct biological functions. Also, the involvement of AP-1 factors in functions such as cell proliferation and survival has been made somewhat clearer as a result of such studies. In addition, there has been considerable progress in understanding some of the mechanisms and signaling pathways involved in the regulation of AP-1 activity. In addition to regulation by heterodimerization between Jun, Fos and ATF proteins, AP-1 activity is regulated through interactions with specific protein kinases and a variety of transcriptional coactivators.
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              Estrogen receptors: how do they signal and what are their targets.

              During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ER alpha and ER beta) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.

                Author and article information

                Reprod Med Biol
                Reprod. Med. Biol
                Reproductive Medicine and Biology
                John Wiley and Sons Inc. (Hoboken )
                05 December 2016
                January 2017
                : 16
                : 1 ( doiID: 10.1111/rmb2.2017.16.issue-1 )
                : 4-20
                [ 1 ] Department of Biological Sciences Middle East Technical University Ankara Turkey
                [ 2 ]Present address: Cell and Molecular Biology Program Duke University Durham North Carolina USA
                Author notes
                [*] [* ] Correspondence

                Mesut Muyan, Department of Biological Sciences, Middle East Technical University, Ankara, Turkey.

                Email: mmuyan@ 123456metu.edu.tr


                Contributed equally and should be considered as the first author.

                © 2016 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                : 15 March 2016
                : 16 May 2016
                Page count
                Figures: 5, Tables: 0, Pages: 17, Words: 15616
                Funded by: Scientific and Technological Research Council of Turkey
                Award ID: TUBITAK‐KBAG 212T031
                Award ID: 114Z243
                Funded by: Middle East Technical University
                Award ID: METU‐BAP‐08‐11‐2015‐019
                Review Article
                Review Articles
                Custom metadata
                January 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.7 mode:remove_FC converted:04.12.2017

                estrogen,estrogen receptor,molecular mechanism,signaling,structure


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