Date of Award

Fall 2004

Degree Type

Thesis - Restricted

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Sem, Daniel S.

Abstract

Estrogen Receptors (ERs) are members of the Nuclear Receptor (NR) super family that mediate a diverse range of physiological and developmental processes (1). The ER is a ligand inducible transcription factor that modulates specific gene expression by binding to short DNA sequences, termed estrogen response elements (ERE). The ERE exerts its action irrespective of its orientation and when positioned at a variable distances upstream or down stream from a variety of promoters (2). Therefore, ER represents a modular protein that contains domains (3) important for hormone binding, ERE recognition and activation of transcription. The ER plays an important role in breast cancer by mediating the mitogenic actions of estrogens (4). Hormone Replacement Therapy (HRT) has been the first option in postmenopausal women, who are at high risk for atherosclerosis and osteoporosis, as well as undesirable climacteric effects such as mood swings and hot flushes (5). Though the link has not yet fully substantiated, HRT has been associated with a risk of reproductive cancers such as breast cancer and endometrial cancer. Treatment in these cases would be through medical castration of ovary, in conjunction with use of antiestrogens, otherwise called as selective estrogen receptor modulators, SERMs (Tamoxifen and Raloxifen) (6). The estrogens are proved effective in relieving menopausal symptoms and preventing osteoporosis. But the adverse effects of estrogens have inspired an intense pursuit to develop SERMs, which can be taken for many years without any side effects (7). Estrogens and SERMs produce their action by interacting with two estrogen receptors, ERa and ER~ (8;9). Estrogen initiates transcriptional activation by inducing a conformational change of the ER-LBD (10;11). Steinmetz et al. have reviewed (12) on conformational changes taking place up on interacting with different ligands. The structural transition of transcriptionally inactive and active form of receptor, called "mouse trap" mechanism involves the placement of helix 12 , which is the core of the ligand dependent AF-2 in order to close the ligand binding pocket and exposing the LXXLL motif for co activators. Elucidating the mechanism whereby estrogens and SERMs produce tissuespecific effects is important for designing better drugs to treat conditions associated with estrogen deficiency or excessive estrogen action (13). There are reports suggesting molecular mechanism yet no substantial evidence is available in exploring the abstruse mechanism in homogeneous solution. Present studies were focused on employing Fluorescence polarization (FP) and NMR analysis in exploring the complex mechanism in vitro and in-vivo.

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