Estrogen Receptors ERa and ER

The functions of some domains of the ER have been defined using deletion mutants and site-directed mutagenesis as well as structural analyses [13]. 

The physiological functions of the ER subtypes have been characterised in mice lacking the ERa, the ER/1, or both receptors [11]. Disruption of the ERo resulted in infertility of both male and female mice and inhibited the outgrowth of the mammary duct during puberty, whereas disruption of the ER/1 had no effect on fertihty and mammary gland development [ 17]. A number of ERo and ER/1 isoforms have also been described, many of which alter estrogen-mediated gene expression [18]. 

The LEDs of the ERa and the ER/1 share a similar overall architecture. Two separate transactivation domains (AF) mediate the transactivation of the ER an N-terminal hgand-independent activation fimction (AF-1) and a C-terminal ligand-dependent activation function (AF-2), which is located within the LED (Fig. 3). The surface of the AF-1 is composed of amino acids in helices 3,4, 5 and 12, and the binding of ligands alters the position of heHx 

The AF-1 domain in ERa is very active on a variety of estrogen responsive promoters, whereas the AF-1 is only minimally active in ER/3 [19]. 

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Paech K, Webb P, Kuiper GGJM, Nilsson S, Gustafsson JA, Kushner PJ, et al. (1997) Differential ligand activation of estrogen receptors ERa and ER/S at API sites. Science 77 1508-1510... 

Pure antiestrogens are distinguishable form other SERMs in terms of their mechanism of action, although both classes of agent mediate their effects through the two types of estrogen receptors (ERa and ER/J). 

The anti-estrogen, tamoxifen, is the most commonly used hormonal therapy for breast cancer and has demonstrated positive effects on the cardiovascular and skeletal systems of postmenopausal women but is associated with an increased risk of uterine cancer. Tamoxifen is described as a SERM, a selective estrogen receptor modulator with a tissue selective profile that is caused by the different distribution of the a- and /3-subtypes of the estrogen receptor (ERa and ER/3) that activate and inhibit transcription respectively (77). These selective effects have been ascribed to differential interactions with gene promotor elements and coregulatory proteins depending on whether the ERa interacts directly, or in a tethered manner with DNA (78). In uterine tissue, tamoxifen interacts with a specific coactivator, SRCl, that is abundant in uterine tissue. 

Circosta et al. 2006 Dixon-Shanies and Shaikh 1999 Lau et al. 2005), a human study of dong quai in menopausal women demonstrated no estrogenic activity (Hirata et al. 1997), and a binding and transcription study showed no activity of dong quai in estrogen receptors ERa or ER 5 (Amato et al. 2002). 

This chapter reviews the main characteristics of two of the better known members of the nuclear hormone receptor family estrogen receptors a and ft (ERa and ER/i). First, the different functional regions harbored by the molecule of the receptor are described. These properties will be used to describe the cellular, molecular, and other consequences that derive from the interactions of receptors with their own hormone, other proteins, or DNA. 

Estrogen receptor comprises several structural domains with specific and overlapping functions. A number of monoclonal and polyclonal antibodies are available, some of which show affinity for specific domains of the ER molecule. The antibodies discussed below are efficient tools for ER immunohistochemistry on sections of formalin-fixed, paraffin-embedded tissues and facilitate the cellular site expression of ERa and ER 3 receptors in human and rat tissues. Most of these antibodies are used for labeling ERs in breast tissue in conjunction with pretreatment with antigen retrieval methods. 

The low homology between ERa and ER(3 in the N-terminal A/B domain indicates different patterns of gene activation between these two receptors. Construction of ER(3 chimeras with ERa A/B domain exhibited an improved transcriptional response to estrogens and antiestrogens and indicated that differences in the N-terminal and contribute to cell- and promotor-specific differences in transcriptional activity of ERa and ER(3 (M14). 

Selective ERa and ER(3 receptor modulators consisting of triphenylethylenes, (n), and naphthyl benzoxazole derivatives, (III), were prepared by Kaltenbach (3) and Malamas (4), respectively, and used in treating estrogen-stimulated diseases such as breast, uterine, and ovarian cancers. 

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