Differential Effects of Xenoestrogens on Coactivator Recruitment by Estrogen Receptor (ER) α and ERβ

Abstract

It has been proposed that tissue-specific estrogenic and/or antiestrogenic actions of certain xenoestrogens may be associated with alterations in the tertiary structure of estrogen receptor (ER) ␣ and/or ER␤ following ligand binding; changes which are sensed by cellular factors (coactivators) required for normal gene expression. However, it is still unclear whether xenoestrogens affect the normal behavior of ER␣ and/or ER␤ subsequent to receptor binding. In view of the wide range of structural forms now recognized to mimic the actions of the natural estrogens, we have assessed the ability of ER␣ and ER␤ to recruit TIF2 and SRC-1a in the presence of 17␤-estradiol, genistein, diethylstilbestrol, 4-tert-octylphenol, 2,3,4,5-tetrachlorobiphenyl-ol, and bisphenol A. We show that ligand-dependent differences exist in the ability of ER␣ and ER␤ to bind coactivator proteins in vitro, despite the similarity in binding affinity of the various ligands for both ER subtypes. The enhanced ability of ER␤ (over ER␣) to recruit coactivators in the presence of xenoestrogens was consistent with a greater ability of ER␤ to potentiate reporter gene activity in transiently transfected HeLa cells expressing SRC-1e and TIF2. We conclude that ligand-dependent differences in the ability of ER␣ and ER␤ to recruit coactivator proteins may contribute to the complex tissue-dependent agonistic/antagonistic responses observed with certain xenoestrogens.One of the greatest challenges in understanding the mechanisms of estrogen action has been to determine how different estrogen receptor (ER) 1 ligands (steroidal estrogens, antiestrogens, xenoestrogens) produce such diverse biological effects. The recent discovery of a second subtype of the estrogen receptor, named estrogen receptor-␤ (ER␤) to distinguish it from the classical ER (now renamed ER␣), adds another level of complexity to the mechanism of estrogen action and has opened new possibilities by which estrogens might exert tissue-and cell-specific effects (1). Indeed, it has been shown that ⌭R␣ and ER␤ differ in terms of their ability to activate gene expression from either the consensus estrogen response element (ERE) from the VTG gene or the divergent ERE from the luteinizing hormone ␤ gene in transiently transfected Cos-1 cells (2). Moreover, ⌭R␣ and ER␤ activate and inhibit, respectively, transcription from an AP1 enhancer site when complexed to 17␤-estradiol (E2), whereas ER␤ was a transcriptional activator on AP1 sites when complexed to antiestrogens (3). Studies in rodents have revealed that the distribution and relative levels of ⌭R␣ and ER␤ expression differ among tissues. For example, ⌭R␣ is predominantly expressed in the pituitary, uterus, ovary (oviduct and germinal epithelium), mammary gland, testis, epididymis, and kidney, whereas ER␤ is the predominant form in regions of the hypothalamus, ovary (granulosa cells), prostate gland, lung, and bladder (4 -8). The coexpression of ⌭R␣ and ER␤ in certain tissues and cells, and the ability of ⌭R␣ and ER␤ to form heterodimers and bind...

Nutritional flavonoids impact on nuclear and extranuclear estrogen receptor activities

“…Consistent with this data, genistein-bound ERα recruits the steroid receptor coactivator (SRC)-3 nuclear receptor (NR) box I of the p160 transcriptional coactivator family with less than half of the efficacy of E2-bound ERα, and SRC-3 NR box II is not recruited at all (Routledge et al, 2000;Bramlett et al, 2001). On the other hand, the crystal structure of ERβ with genistein indicates that H12 is positioned on the surface of the LBD and the binding of SRC-3 NR box I showed a 3-fold amount in the presence of genistein greater than E2-bound receptor (Routledge et al, 2000;Bramlett et al, 2001). Thus, selective coactivator recruitment may be an underlying mechanism for tissue/cell (anti) estrogenicity of genistein.…”

Expression of oestrogen receptor beta (ERβ1) protein in human breast cancer biopsies

“…Barkhem et al (1998) have used cell lines stabily transfected with either ERa or ERb to test the affinity and potency of widely used anti-oestrogens including tamoxifen, raloxifine and ICI 164,384 and concluded that the ligand binding cavity of ERb is more different to that of ERa than can be anticipated from the primary sequence. Recently novel non-steroidal ligands that show subtype specific binding affinity and transcriptional potency have been identified (Sun et al, 1999) and ligand-dependent differences in the ability of ERa and ERb to recruit co-activators following exposure to xenoestrogens described (Routledge et al, 2000). ERdriven gene activation can be determined by the formation of homo-or hetero-dimers, the cell type, and whether the ligand-activated receptors bind to a promotor containing ERE or an AP-1 site (Watanabe et al, 1997;Jones et al, 1999).…”

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

“…Perhaps the binding of these compounds triggers the recruitment of other coactivators to counteract the Tip60-mediated inhibition (7). For example, GEN can recruit SRC1 isoforms to ER␤1 (64,65). Moreover, all estrogenic chemicals except apigenin significantly inhibited the enhancement by Tip60 at the AP-1 site.…”