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Anatclinar.com.arAction of estrogen receptors Rev Arg de Anat Clin; 2012, 4 (2): 65-69__________________________________________________________________________________________ Review
UPDATE ON THE MECHANISM OF ACTION OF ESTROGEN
Ieda Millas, Bianca M. Liquidato, Mirna D. Barros
Department of Morphology. Santa Casa School of Medical Sciences – São Paulo, SP. Brazil and tissues, either or not directly related to reproduction. As in other regulatory processes, the Los mecanismos de acción de los receptores mechanisms of receptor-ligand binding are crucial to estrogénicos (ER) han sido estudiados debido a sus enable the action of the estrogen hormone that will importantes funciones en el crecimiento celular y la ultimately produce effects in the cellular metabolism.
diferenciación de varios órganos y tejidos, relacio- Although extensively studied, the mechanisms of nados o no con la reproducción. Como en otros action of estrogen receptors are not completely procesos regulatorios, los mecanismos de ligados a unraveled. The present study is a literature review on receptor son cruciales para permitir la acción de los the mechanism of action of the ER-α and ER-β in the estrógenos que finalmente producirían efectos en el human body. The knowledge of the location and metabolismo celular. Aunque muy estudiados, los concentrations of the ER in different tissues is mecanismos de acción de los receptores estrogénicos essential to determine specific treatments for different no han sido completamente desentrañados. El pathologies, such as breast cancer. Moreover, in non- presente estudio es una revisión de la literatura sobre reproductive tissues, such as the nasal conchae el mecanismo de acción de ER-α y ER-β en el cuerpo mucosa, the presence of ER-α and ER-β may explain humano. El conocimiento de la localización y the variations in secretory activity of the nasal mucosa concentraciones de ER en diferentes tejidos es according to hormonal variability. ER neuro-protective esencial para determinar tratamientos específicos para and anti-inflammatory actions in the central nervous diferentes patologías, tales como cáncer de mama. system, as well as its allergic-response function in the Más aún, en tejidos no reproductivos, tales como la epithelium of the conjunctiva are also considered and mucosa de los cornetes nasales, la presencia de ER-α may apply to other studies concerning the diagnosis, y ER-β podría explicar las variaciones en la actividad drugs development and clinical treatments of different secretora acorde con la variación hormonal. También diseases, related to hormonal actions.
se consideran las acciones ER neuro-productivas y antinflamatorias en el sistema nervioso central al igual Keywords: estrogen, hormones, estrogen receptor,
que su función de respuesta alérgica en el epitelio de la conjuntiva y podrían aplicarse a otros estudios referidos al diagnóstico, desarrollo de drogas y el tratamiento de diferentes enfermedades asociados a acciones hormonales.
Palabras clave: estrógenos, hormonas, receptores
estrogénicos, fisiología, mecanismo
* Correspondence to: Ieda Millas, Rua Dr. Diogo de Faria,
1087 – 1009, São Paulo, SP. Brazil. email@example.com
The action mechanisms of estrogen receptors (ER) Received: 28 May, 2012. Revised: 27 June, 2012.
have been studied due to their important functions in Accepted: 2 July, 2012.
cellular growth and differentiation in several organs Todos los derechos reservados. Reg. Nº: 5024555 www.anatclinar.com.ar Action of estrogen receptors Rev Arg de Anat Clin; 2012, 4 (2): 65-69__________________________________________________________________________________________ INTRODUCTION
following key words were used in the survey of the literature: estrogen, hormones, estrogen Estrogen is a hormone related to cell growth and receptor, physiology, and mechanism. Papers differentiation in many organs and tissues.
were selected for this review regarding as It acts mainly in the regulation of cellular inclusion criteria, those in English language and human researches. And as exclusion criteria intranuclear specific protein receptors (Enmark papers related to cancer or any proliferative and Gustafsson, 1999; Green et al, 1986; Katzenellenbogen et al, 2000; Kuiper et al, 1996).
Estrogen receptors (ER) are homodimeric nuclear receptor protein belonging to the super family of nuclear receptors that bind to liposoluble hormones and interact with specific response elements of DNA. In the absence of hormones, Estrogen receptors molecular structure and
inhibitory proteins, but when attached to their Estrogen receptor α and ER-β are formed by ligands may be taken to the nucleus and activate amino acid sequences where the N-terminal transcription of target genes. There are two region contains one or more transcriptional estrogen receptor isoforms, designated as alpha activation domains, the central region has binding and beta, which have homologous amino acid domains with the "zinc fingers" DNA and the C- sequences, particularly differing in the N-terminal region (Enmark and Gustafsson, 1999; Green et chromosome 14 q 22-24 region and the ER-α Mosselman, 1996; Paech et al, 1997).
The classical estrogen receptor, which is called chromosome 6 (Green et al, 1986; Gruber et al, alpha, was described in 1962 by Jensen. In 1986 2004; Kuiper et al, 1996; Paech et al, 1997).
its genetic structure was cloned and defined by When estrogen binds to ER, these monomers Green et al. In 1994, the report of a patient become dimers, and are coupled to specific having a genetic mutation with absence of the regions of DNA called estrogen and AP-1 sites receptor alpha (ER-α), and showed changes responsive elements, in which may or may not such as osteoporosis and decreased fertility, occur the gene transcription. Both types of annulled the hypothesis that the lack of estrogen receptors can act in different ways in the DNA receptor alpha could be lethal .This fact led to the (Katzenellenbogen et al, 2000; Kuiper et al, 1996; discovery of a second type of receptor, called Paech et al, 1997). Studies have shown that beta (ER-β) by Kuiper et al in 1996. Thus, changes in the structures of the receptors and several studies have followed regarding the their affinity for certain co-activators (enzymes of existence of these two isoforms, with high specific actions) are directly related to their specificity and affinity in humans, a phenomenon functions. Depending on the dimer formed which allows the selective action of the hormone (receptor + co-activator) the response in the in different tissues (Fchsjauger-mayrl et al, 2002; target gene will be different (Amstead et al, 1997; Gruber et al, 2004; Katzenellenbogen et al, 2000; Bernheimer and Soskin, 1942; Jensen, 1962; Kian et al, 2004; Millas et al, 2010; Mosselman, 1996; Soskin and Bernheimer, 1939 ; Taylor and The action of the receptors depends on a Azzawi, 2000; Tiwari-Woodruff et al, 2007).
combination of the receptor, its binding factors In this article we will discuss the mechanisms of and the co-activating or modulating proteins action of estrogen receptors, due to its (Katzenellenbogen et al, 2000; Kuiper et al, 1996; importance in tissue growth, differentiation and Paech et al, 1997). These modulators may have metabolism in reproductive organs and in other activity that can be agonist and antagonist in the DNA, so the same receptor can express different actions in different cells (Amstead et al, 1997). The activities related to these modulators among different receptor ligans α and β show distinct MATERIAL AND METHOD
pharmacological actions on their target genes. For example, drugs such as tamoxifen, This study consisted of a review of the literature tetrahidrocriseno 2-fenilbenzofuram have an over the last sixteen years, indexed in Pubmed, agonist activity to α-type receptors, but Medline and Scielo, covering papers relating to antagonist to the β, this is due to differences in estrogen receptors and steroid hormones. The Todos los derechos reservados. Reg. Nº: 5024555 www.anatclinar.com.ar Action of estrogen receptors Rev Arg de Anat Clin; 2012, 4 (2): 65-69__________________________________________________________________________________________ contributing to distinct and specific transcriptional Katzenellenbogen et al, 2000 exemplify the activities (Amstead et al, 1997; Bhagu et al, contrary action of the receptors, where tamoxifen 2008; Kian et al, 2004; McDonnell, 2004).
has both an agonistic activity with the ER-α and antagonistic activity with ER-β, depending on the Estrogen receptors expression
receptor. The differences in the amino-terminal Literature describes a difference of expression of regions of ER-α and ER-β contribute to distinct ER in various tissues. They are present and and specific transcriptional activities, as long as playing important roles in the reproductive organs both receptors have different distributions and concentrations in the tissues. The respective Fchsjauger-Mayrl et al, 2002; Ishunina et al, interactions or activities between these two 2000; Millas et al, 2010; Tiwari-Woodruff et al, receptors can generate significant differences in 2007) . For example, the ER-β has a higher biological tissue responses (Kian et al, 2004).
expression in organs such as brain and adrenal, A repressor protein of estrogen receptor activity and ER-α in the uterus and breast. Both are (REA) competes with the co-activator of these abundantly expressed in reproductive system, receptors. REA represents an example of a while the ER-β is found in high concentrations in protein which increases the potency of two tissues that do not produce or are not estrogen- inhibitors of ER. For example, the protein dependent, suggesting that different receptors quinone reductase (QR), present in the ER, participate in biochemical processes in different which undergoes an "up-regulation" in the organs. The expression of ER-α is not related to the β and vice versa indicating that they are antagonist action to estrogen), suffers a involved in independent mechanisms of action suppression of its activity when bound to (Katzenellenbogen et al, 2000; Paech et al, 1997; estrogen (Amstead et al, 1997; Bhagu et al, 2008). The anti-estrogens have a higher stimulus The specificity of the receptors’ cellular action is through QR by ER-β than ER-α. Most genes associated with different concentrations in these under the regulation of estrogen receptors seem tissues and with different genetic sites related to to suffer an "up-regulation" by estrogen (Bhagu et them in the cells of these tissues (Amstead et al, 1997; Katzenellenbogen et al, 2000; Kian et al, Thus, the balance in the performance of ER’s 2004). The actions of these two subtypes and tissular functions depends on a complex network their ligands depend on a ligand-induced of factors; co-activators, co-repressors, estrogen conformation for ER-α and ER-β. For example, and anti-estrogen concentration and the affinity of when estrogen binds to a greater amount of ER- each direct transcriptional receptor and the β, the activity of ER-α is inhibited (Bhagu et al, indirect genetic action, repressing or activating 2008). Moreover, the behavior of each subtype of response elements in DNA. The knowledge of ER varies within the same tissue. Ishunina et al ER-α and ER-β regarding their location and their (2000) observed "up-regulation" of the ER-β and concentration in different tissues becomes "down-regulation" of α in the same cell group essential for certain medical treatments as in the subjected to estrogen, ie, ER have different and case of breast cancer, where, depending on the specific transcriptional activities, in addition to predominant receptor, selective modulators of ER several tissue responses, due its peculiar such as tamoxifen (Kian et al, 2004; McDonnell, concentration and distribution in each tissue. Gruber et al (2004) and Yang et al (2004) also observed Estrogen receptors in non reproductive
transcriptional affinity, that is affinity in binding to In organs not associated with reproduction, as in the mucosa of inferior nasal conchae the The selective modulators of estrogen receptors presence of both receptors, ER-α and ER-β was such as tamoxifen and raloxifene show both the observed in the nucleus and cytoplasm of cells of the glandular epithelium of the lamina propria and depending on the type of tissue, and show tissue respiratory epithelium (Millas et al, 2010; Millas et selectivity. The ER-α has a more effective al 2011; Shirasaki et al 2004). This may explain response to estradiol than the ER-β in activation the hormonal action on the nasal secretory with the estrogen response element present in activity and possibly the future use of drugs with the DNA. Thus, the ER-β is more effective in the hormones to stimulate the nasal secretion in activation of element AP-1 with these modulators, cases of atrophic rhinitis, as it was originally compared to the alpha (Katzenellenbogen et al, proposed in 1942 by Bernheimer and Soskin, 2000; Kian et al, 2004; McDonnell, 2004).
who examined the local effect of estrogen on nasal mucosa for the treatment of patients with Todos los derechos reservados. Reg. Nº: 5024555 www.anatclinar.com.ar Action of estrogen receptors Rev Arg de Anat Clin; 2012, 4 (2): 65-69__________________________________________________________________________________________ atrophic rhinitis and observed an increase of Fchsjauger-Mayrl G, Nepp J, Schneeberger C, vascularization and gland secretion of the coated Sator M, Dietrich W, Wedrich A, Huber J, nasal epithelium in the studied cases. In the Tschuffuel W. 2002. Identification of estrogen same line, Caruso et al, 2003, observed better and progesterone receptor mRNA expression features of the nasal epithelium in women treated in the conjunctiva of premenopausal women. with hormones, through the cytology index of Green S, Walter P, Kumar V, Krust A, Bonert JM, Similarly, ERs participate in other organs’ Argos P, Chambon P. 1986.Human oestrogen functions. ERs’ different actions in the central nervous system are described by observation homology to v-erb-A. Nature 320: 134-139.
that the ER-α has anti-inflammatory activity and Gruber JC, Gruber DM, Gruber IML, Wieser F, beta has neuroprotective activity through Huber JC. 2004. Anatomy of the estrogen reduction of demyelination and axons preserving response element. Trends Endocrinol Metab (Tiwari-Woodruff et al, 2007). In the conjunctival epithelium, the ERs influence the allergic Ishunina TA, Kruijver FPM, Balesar R, Swaab response, since they act in the maturation of DF. 2000. Differential expression of estrogen goblet cells and cells from the respiratory receptor and immunoreactivity in the epithelium as well as influencing the balance of human supraoptic nucleus in relation to sex secretion and absorption of aqueous humor, with and aging. J Clin Endocrinol Metab 85: 3283- an important role in the development of glaucoma Jensen EV. 1962. On the mechanism of estrogen This way, as final considerations, we remark the action. Perspectives in Biology and Medicine 6: importance of studying the mechanism of action of estrogen receptors in different organs and Katzenellenbogen BG, Choi I, Delage-Mourrow R, Ediger TR, Martini PG, Montana M, Sun J, depending on the expression and the predomin- Weis K, Katzenellenbogen JA. 2000. Molecular ance of one or another subtype. As above mentioned, the study of their functions can Ligands and Receptor Pharmacology. J Steroid contribute significantly to the understanding of the pathophysiology of certain diseases and for Kian Tee M, Rogatsky I, Tzagarakis-Foster C, future advances in treating others, like atrophic Cvoro A, An J, Christy RJ, Yamamoto KR, Leitman DC. 2004. Estradiol and Selective Estrogen Receptor Modulators Differentially Regulate Receptors alpha e beta. ASBOC 15: 1262-72. REFERENCES
Kuiper GGJM, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. 1996. Cloning of a Amstead GM; Calson KE; Katzenellenbogen JA. novel estrogen receptor expressed in rat 1997. The estradiol pharmacophore: ligand prostate and ovary. Proc Natl Acad Sci USA structure-estrogen receptor binding affinity relationships and a model for the receptor Bernheimer LB, Soskin S. 1942. Mechanism of pharmacology. Maturitas 48 Suppl. 1 (S7-S12).
effect of estrogen on nasal mucosa in atrophic Millas I, Liquidato BM, Dolci JEL, Macea JR, rhinitis. Arch Otolaryngol 32: 57-9.
Fregnani JHT, Meceles LR. 2010. Immuno- Bhagu BR, Shui-Pang T, Xiao FL. 2008.Structure histochemical evaluation of estrogen receptors alpha and beta in normal inferior turbinate interactions and functional activity of various Millas I, Liquidato BM, Buck HS, Barros MD, Paes RAP, Dolci JEL. 2011. Evaluation of estrogen receptors in the nasal mucosa of Caruso S, Roccassalva C, Di Fazio E, Sapienza G, Agnello C, Ficarra S, Di Mari L, Serra A. 2003. Cytology aspects of the nasal respiratory Mosselman S, Polman J, Dijkema R. 1996. ER epithelium in post-menopausal women treated beta: identification and characterization of a with hormone therapy. Fertil Steril 79: 543-49. novel human estrogen receptor. FEBS Lett Enmark E, Gustafsson JA. 1999. Oestrogen receptors - an overview. J Intern Med; 246: Paech K, Webb P, Kuiper GGJM, Nilsson S, Gustafsson JA, Kushner PJ, Scanlan T. 1997. Todos los derechos reservados. Reg. Nº: 5024555 www.anatclinar.com.ar Action of estrogen receptors Rev Arg de Anat Clin; 2012, 4 (2): 65-69__________________________________________________________________________________________ Differential ligand activation of estrogen Proceeding of the Society for Experimental receptors ER and ER at AP1 Sites. Science Shirasaki H, Watanabe K, Kanaizumi E. 2004. Immunolocalization of estrogen receptor beta in Expression and localization of steroid receptors human tissues. J Mol Endocrinol 24: 145-55.
in human nasal mucosa. Acta Otolaryngol 124: Tiwari-Woodruff S, Morales LBJ, Lee R, Voskuhi RR. 2007. Differential neuroprotective and anti- Soskin S, Bernheimer CB. 1939. Mechanism of inflammatory effects of estrogen receptor (ER) Estrogen Effect on Nasal Mucosa in Atrophic and ER ligand treatment. PNAS 104: Rhinitis, successful treatment with Prostigmin. Todos los derechos reservados. Reg. Nº: 5024555 www.anatclinar.com.ar
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