Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:APRD00345 (ICI)
 5,388 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cloning of a novel estrogen receptor beta (denoted ERbeta) has recently been described (Kuiper, G. G. J. M., Enmark, E., Pelto-Huikko, M., Nilsson, S., and Gustafsson, J-A. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 5925-5930 and Mosselman, S., Polman, J. , and Dijkema, R. (1996) FEBS Lett. 392, 49-53). ERbeta is highly homologous to the "classical" estrogen receptor alpha (here referred to as ERalpha), has been shown to bind estrogens with an affinity similar to that of ERalpha, and activates expression of reporter genes containing estrogen response elements in an estrogen-dependent manner. Here we describe functional studies comparing the DNA binding abilities of human ERalpha and beta in gel shift assays. We show that DNA binding by ERalpha and beta are similarly affected by elevated temperature in the absence of ligand or in the presence of 17beta-estradiol and the partial estrogen agonist 4-hydroxy-tamoxifen. In the absence of ligand, DNA binding by ERalpha and beta is rapidly lost at 37 degrees C, while in the presence of 17beta-estradiol and 4-hydroxy-tamoxifen, the loss in DNA binding at elevated temperature is much more gradual. We show that the loss in DNA binding is not due to degradation of the receptor proteins. However, while the complete antagonist ICI 182, 780 does not "protect" human ERalpha (hERalpha) from loss of DNA binding at elevated temperature in vitro, it does appear to protect human ERbeta (hERbeta), suggestive of differences in the way ICI 182, 780 acts on hERalpha and beta. We further report that ERalpha and beta can dimerize with each other, the DNA binding domain of hERalpha being sufficient for dimerization with hERbeta. Cell and promoter-specific transcription activation by ERalpha has been shown to be dependent on the differential action of the N- and C-terminal transcription activation functions AF-1 and AF-2, respectively. The existence of a second estrogen receptor gene and the dimerization of ERalpha and beta add greater levels of complexity to transcription activation in response to estrogens.
 ...
PMID:Human estrogen receptor beta binds DNA in a manner similar to and dimerizes with estrogen receptor alpha. 932 13

Phosphorylation of Ser118 of human estrogen receptor alpha (ER) enhances ER-mediated transcription and is induced by hormone binding and by activation of the mitogen-activated protein kinase (MAPK) pathway. We discovered that phosphorylation of Ser118 reduces the electrophoretic mobility of the ER. Using this mobility shift as an assay, we determined the in vivo stoichiometry and kinetics of Ser118 phosphorylation in response to estradiol, ICI 182,780, epidermal growth factor (EGF), and phorbol 12-myristate 13-acetate (PMA). In human breast cancer MCF-7 cells, estradiol induced a steady state phosphorylation of Ser118 within 20 min with a stoichiometry of 0.67 mol of phosphate/mol of ER. Estradiol did not activate p42/p44 MAPK, and basal p42/p44 MAPK activity was not sufficient to account for phosphorylation of Ser118 in response to estradiol. In contrast, both EGF and PMA induced a rapid, transient phosphorylation of Ser118 with a stoichiometry of approximately 0. 25, and the onset of Ser118 phosphorylation correlated with the onset of p42/p44 MAPK activation by these agents. Either the EGF- or PMA-induced Ser118 phosphorylation could be inhibited without influencing estradiol-induced Ser118 phosphorylation. The data suggest that a kinase other than p42/p44 MAPK is involved in the estradiol-induced Ser118 phosphorylation. We propose that the hormone-induced change in ER conformation exposes Ser118 for phosphorylation by a constitutively active kinase.
 ...
PMID:Estradiol-induced phosphorylation of serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase. 958 78

The existence of two rather than one estrogen receptor, today characterized as estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), indicates that the mechanism of action of 17beta-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ERbeta is high compared with those amino acid residues in ERalpha LBD, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both receptor subtypes. We report that 17alpha-ethynyl, 17beta-estradiol, for example, has an ERalpha-selective agonist potency and that 16beta,17alpha-epiestriol has an ERbeta-selective agonist potency. We also report that genistein has an ERbeta-selective affinity and potency but an ERalpha-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ERalpha-selective partial agonist/antagonist function but a pure antagonist effect through ERbeta. In addition, raloxifene displayed an ERalpha-selective antagonist potency, in agreement with its ERalpha-selective affinity. However, although ICI 164,384 showed an ERbeta-selective affinity, it had a similar potency to antagonize the effect of 17beta-estradiol in the ERalpha- and ERbeta-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ERbeta is probably more different from that of ERalpha than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop receptor-specific ligands that may form the basis of novel pharmaceuticals with better in vivo efficacy and side effect profile than current available drugs.
 ...
PMID:Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. 965 95

We investigated the interaction of bisphenol A (BPA, an estrogenic environmental contaminant used in the manufacture of plastics) with the estrogen receptor alpha (ERalpha) transfected into the human HepG2 hepatoma cell line and expanded the study in vivo to examine the effect of BPA on the immature rat uterus. Bisphenol A was 26-fold less potent in activating ER-WT and was a partial agonist with the ERalpha compared to E2. The use of ERalpha mutants in which the AF1 or AF2 regions were inactivated has permitted the classification of ER ligands into mechanistically distinct groups. The pattern of activity of BPA with the ERalpha mutants differed from the activity observed with weak estrogens (estrone and estriol), partial ERalpha agonists (raloxifene or 4-OH-tamoxifen), or a pure antagonist (ICI 182, 780). Intact immature female Sprague-Dawley rats were exposed to BPA alone or with E2 for 3 days. Unlike E2, BPA had no effect on uterine weight; however, like E2, both peroxidase activity and PR levels were elevated, though not to the level induced by E2. Following simultaneous administration, BPA antagonized the E2 stimulatory effects on both peroxidase activity and PR levels but did not inhibit E2-induced increases of uterine weight. These results demonstrate that BPA is not merely a weak estrogen mimic but exhibits a distinct mechanism of action at the ERalpha.
 ...
PMID:Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol. 978 16

The human estrogen receptor alpha (ER alpha) has been tagged at its amino terminus with the S65T variant of the green fluorescent protein (GFP), allowing subcellular trafficking and localization to be observed in living cells by fluorescence microscopy. The tagged receptor, GFP-ER, is functional as a ligand-dependent transcription factor, responds to both agonist and antagonist ligands, and can associate with the nuclear matrix. Its cellular localization was analyzed in four human breast cancer epithelial cell lines, two ER+ (MCF7 and T47D) and two ER- (MDA-MB-231 and MDA-MB-435A), under a variety of ligand conditions. In all cell lines, GFP-ER is observed only in the nucleus in the absence of ligand. Upon the addition of agonist or antagonist ligand, a dramatic redistribution of GFP-ER from a reticular to punctate pattern occurs within the nucleus. In addition, the full antagonist ICI 182780 alters the nucleocytoplasmic compartmentalization of the receptor and causes partial accumulation in the cytoplasm in a process requiring continued protein synthesis. GFP-ER localization varies between cells, despite being cultured and treated in a similar manner. Analysis of the nuclear fluorescence intensity for variation in its frequency distribution helped establish localization patterns characteristic of cell line and ligand. During the course of this study, localization of GFP-ER to the nucleolar region is observed for ER- but not ER+ human breast cancer epithelial cell lines. Finally, our work provides a visual description of the "unoccupied" and ligand-bound receptor and is discussed in the context of the role of ligand in modulating receptor activity.
 ...
PMID:Direct visualization of the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor. 995 Jun 89

A low estrogen status in postmenopausal women is associated with elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1). In this study, the ability of estrogen compounds to regulate PAI-1 expression was determined in a hepatocyte HepG2 cell line made to stably express estrogen receptor alpha (ERalpha). In both the wild type and ER expressing HepG2 cells, estrogen had no effect on basal PAI-1 expression. However, in the ER expressing cells the ability of IL-1beta to increase PAI-1 mRNA and protein levels was attenuated by 17beta-estradiol, tamoxifen and twelve estrogen components of Premarin. In contrast, the mixed agonist/antagonist raloxifene had weak agonist activity and like the pure antagonist ICI 182780, it dose dependently blocked the effect of 17beta-estradiol on IL-1beta stimulated PAI-1 levels. These results suggest that estrogen agonists may lower PAI-1 levels in vivo by inhibiting cytokine activated PAI-1 expression by an ER dependent mechanism.
 ...
PMID:The activation of plasminogen activator inhibitor-1 expression by IL-1beta is attenuated by estrogen in hepatoblastoma HepG2 cells expressing estrogen receptor alpha. 1010 72

Induction of apoptosis of mononucleated cells is a physiological process for regulating the intensity of the immune response. The female steroid hormones estrogen (E2) and progesterone (Prog) are known to modulate the reactivity of the immune system; recently it has been demonstrated that they can regulate induction of apoptosis of endothelial cells and osteoblasts. TNF-alpha-mediated induction of apoptosis has been well characterized in myeloid cells. We investigated whether E2 and Prog could interfere with TNF-alpha-induced apoptosis of the monoblastoid U937 cell line. Treatment with E2 or Prog increased survival and prevented apoptosis induced by TNF-alpha in both undifferentiated and macrophage-like PMA-differentiated U937 cells, as assessed by trypan blue exclusion cell counting, thymidine incorporation, AnnexinV labeling, followed by flow cytometry and DNA fragmentation studies. This effect can be associated with the activation of specific hormone receptors, since we observed the expression of the estrogen receptor alpha (ER-alpha), ER-beta, and progesterone receptor (PR) mRNAs; the ER-alpha protein expression was confirmed by immunocytochemical analysis. In addition, hormone-mediated survival against apoptosis was concentration dependent, reaching the half-maximal effect at 10 nM and blocked by the ER antagonist ICI 182,780 in undifferentiated cells, further supporting a receptor-mediated mechanism of cell survival. Other steroid receptor drugs such as Raloxifene, RU486, or the ICI 182,780 in PMA-differentiated cells displayed agonist activity by preventing TNF-alpha-induced apoptosis as efficiently as the hormones alone, providing further evidence to the notion that steroid receptor drugs may manifest agonist or antagonist activities depending on the cellular context in which they are studied. Treatment with E2 was also associated with a time-dependent decrease in the mRNA level of the proapoptotic Nip-2 protein, supporting the hypothesis that hormone responsiveness of U937 cells is mediated by target gene transcription. Together, these results demonstrate that ER and PR can be activated by endogenous or exogenous ligands to induce a genetic response that impairs TNF-alpha-induced apoptosis in U937 cells. The data presented here suggest that the female steroid receptors play a role in regulation of the immune response by preventing apoptosis of monoblastoid cells; this effect might have important consequences in the clinical use of steroid receptor drugs. --Vegeto, E., Pollio, G., Pellicciari, C., Maggi, A. Estrogen and progesterone induction of survival of monoblastoid cells undergoing TNF-alpha-inuced apoptosis.
 ...
PMID:Estrogen and progesterone induction of survival of monoblastoid cells undergoing TNF-alpha-induced apoptosis. 1022 23

ECC-1 endometrial cancer cells express estrogen receptor alpha (ER(alpha)), and 17beta-estradiol (E2) induces cell proliferation, cathepsin D mRNA levels, and reporter gene activity in cells transiently transfected with constructs derived from the human cathepsin D and creatine kinase B (pCD and pCKB, respectively) gene promoters. The comparative antiestrogenic activity of aryl hydrocarbon receptor (AhR) agonists and ER(alpha) antagonists were also determined in these endometrial cancer cells. A functional AhR was expressed in ECC-1 cells and AhR agonists including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibited E2-induced cell proliferation and transactivation. This was comparable to inhibitory AhR-ER crosstalk in breast cancer cell lines. The pure ER antagonist ICI 182,780 also exhibited antiestrogenic activity in ECC-1 cells; however, the results obtained for 4'-hydroxytamoxifen were response-specific. 4'-Hydroxytamoxifen alone did not induce ECC-1 cell proliferation but completely inhibited E2-induced cell proliferation. 4'-Hydroxytamoxifen primarily exhibited ER antagonist activities in transactivation assays and this contrasted to the predominant ER agonist responses observed in other endometrial cancer cell lines. The unique cellular context of ECC-1 cells was confirmed using pCKB and constructs expressing wild-type ER or ER variants expressing activation function 1 (AF1) or AF2 (ER-AF1 and ER-AF2, respectively). 4'-Hydroxytamoxifen did not induce reporter gene activity in cells cotransfected with pCKB and ER-AF1 or ER-AF2; however, in cotreatment studies (4'-hydroxytamoxifen plus E2), 4'-hydroxytamoxifen inhibited E2-induced transcriptional activation by ER-AF1 or ER-AF2. Thus, the primarily antiestrogenic activity observed for 4'-hydroxytamoxifen in ECC-1 cells may be related to the inability to activate gene expression through AF1-dependent pathways.
 ...
PMID:Estrogen and aryl hydrocarbon responsiveness of ECC-1 endometrial cancer cells. 1041 Dec 95

Acute administration of 17beta-estradiol (E(2)) exerts antiatherosclerotic effects in healthy postmenopausal women. The vasoprotective action of E(2) may be partly accounted for by a rapid increase in nitric oxide (NO) levels in endothelial cells (ECs). However, the signaling mechanisms producing this rise are unknown. In an attempt to address the short-term effect of E(2) on endothelial NO production, confluent bovine aortic endothelial cells (BAECs) were incubated in the absence or presence of E(2), and NO production was measured. Significant increases in NO levels were detected after only 5 min of E(2) exposure without a change in the protein levels of endothelial NO synthase (eNOS). This short-term effect of estrogen was significantly blunted by various ligands which decrease intracellular Ca(2+) concentration. Furthermore, plasma membrane-impermeable BSA-conjugated E(2) (E(2)BSA) stimulated endothelial NO release, indicating that in the current system the site of action of E(2) is on the plasma membrane rather than the classical nuclear receptor. The partial antagonist tamoxifen did not block E(2)-induced NO production; however, a pure estrogen receptor alpha (ERalpha) antagonist ICI 182,780 completely inhibited E(2)-stimulated NO release. The binding of E(2) to the membrane was confirmed using FITC-labeled E(2)BSA (E(2)BSA-FITC). Western blot analysis showed that plasmalemmal caveolae possess ERalpha in addition to well-known caveolae-associated proteins eNOS and caveolin. This study demonstrates that the nongenomic and short-term effect of E(2) on endothelial NO release is Ca(2+)-dependent and occurs via ERalpha localized in plasmalemmal caveolae.
 ...
PMID:Nongenomic stimulation of nitric oxide release by estrogen is mediated by estrogen receptor alpha localized in caveolae. 1048 86

The present studies evaluated the suitability of using cultured dispersed testicular cells from neonatal rats as a source for fetal Leydig cells and the use of these cells to examine direct toxic effects of environmental/occupational chemicals on androgen biosynthesis. For the current studies, the direct actions of octylphenol (OP), a surfactant additive widely used in the manufacture of various detergents, on testosterone biosynthesis by cultured rat neonatal Leydig cells were examined. Octylphenol is considered a xenoestrogen and has been reported to mimic the actions of estrogen in many cellular systems. Following exposure of cultured cells for 24 h to varying concentrations of OP (1 to 2000 nM) together with 10 mlU/mL human chorionic gonadotropin (hCG), the lower concentrations of OP (1 and 10 nM) consistently enhanced testosterone levels (approximately 10 to 70% above control), whereas higher OP concentrations (100 to 2000 nM) progressively decreased testosterone from peak levels to approximately 40 to 80% below control at the highest OP concentration. Interestingly, increasing concentrations of 17beta-estradiol (1 to 1000 nM) were without effect on testosterone biosynthesis under the same conditions, and the biphasic pattern of testosterone biosynthesis elicited by increasing OP concentrations was unaffected by concomitant treatment with 10 or 100 nM ICI 182,780, which is considered a pure estrogen antagonist. Therefore, the actions of OP on testosterone biosynthesis by cultured neonatal Leydig cells do not appear to be mediated through the classic estrogen receptor alpha or beta pathway. Although the increase in testosterone levels after exposure to lower OP concentrations and to 0.1 and 1.0 mM 8-Br-cAMP was attenuated, suggesting that lower OP concentrations may alter cellular cAMP levels, because hCG-stimulated cAMP levels were unaffected by any of the OP concentrations evaluated, it appears that its main site(s) of action occurs after the generation of cAMP. In addition, because pretreatment of cells with increasing OP concentrations and hCG had no effect on the conversion of steroid precursors (22(R)-hydroxycholesterol, pregnenolone, progesterone, or androstenedione) to testosterone, it seems that the main actions of OP under the present conditions occur before the mitochondrial cholesterol side-chain cleavage step. Furthermore, because concomitant treatment of cells with various antioxidants (alpha-tocopherol, butylated hydroxyanisole, or ascorbic acid) did not alter the biphasic pattern of testosterone response to increasing concentrations of OP and hCG, it seems that OP is not acting as an anti- or pro-oxidant in producing these effects. It will be important to determine whether this dose-sensitive response to OP is observed in vivo, and whether the maturational status of Leydig cells influences their pattern of response to OP and similar chemicals.
 ...
PMID:Biphasic effects of octylphenol on testosterone biosynthesis by cultured Leydig cells from neonatal rats. 1061 93


1 2 3 4 5 6 7 8 9 10 Next >>