Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silymarin is a widely used standardized mixture of flavonolignans and its major component Silybinin binds to cytosolic estrogen receptors. Here, we demonstrate that this binding is exclusive to the estrogen receptor beta (ERbeta). Treatment of ovariectomized (ovx) rats with silymarin or estradiol (E2) may allow differentiation of biological effects mediated by the ERalpha or ERbeta. E2 inhibited serum LH, cholesterol, LDL and HDL concentrations in the blood and increased gene expression of IGF1, HbEGF and C3 in the uterus, while silymarin was totally ineffective or antagonistic in altering these parameters. Both, E2 and silymarin inhibited expression of uterine ERbeta gene. Hence, in the pituitary, liver (where the lipoproteins are synthesized) and uterus E2 acts primarily via the ERalpha. Exclusive estrogenic effects of silymarin were observed in the metaphysis of the femur (MF), on osteoblast parameters (gene expression of IGF1, TGFbeta1, osteoprotegerin, collagen-1alpha1, osteocalcin (OC)) and on the osteoclast activity marker tartrate resistant acid phosphatase (TRAP) gene expression of adult ovx rats. Our RT-PCR method detects ERbeta gene expression in all organs including developing bones but not in the MF of adult ovx rats. We conclude therefore, that the effects of silymarin in this part of the bone cannot be exerted via the ERalpha because it does not bind to this receptor subtype. Despite the failure to detect ERbeta mRNA in the MF of our animals the possibility exists that ERbeta protein is present and may mediate the effects of silymarin. Another possibility may be that the effect of silymarin and therefore possibly also of E2 in the MF may be mediated via other possibly not yet identified receptors or via an ERbeta splice variant which is not detected by our PCR-method.
J Steroid Biochem Mol Biol 2003 Aug
PMID:Silymarin is a selective estrogen receptor beta (ERbeta) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats. 1456 70

Mammary gland development involves complex cycles of proliferation, differentiation, and morphogenesis, regulated by hormones including estrogens, prolactin (PRL), and epidermal growth factor (EGF). The mouse mammary epithelial cell line HC11 has been shown to be valuable for investigations of differentiation of mammary gland. In this study, we show that HC11 cells express estrogen receptor (ER)alpha and ER beta proteins at all developmental stages. We have established two different stable HC11 cell lines; H-estrogen response element (ERE) containing an ERE-reporter and H-Bc containing a beta-casein reporter. Transcription of the ERE-reporter was activated only in proliferating cells in the presence of EGF. When the cells entered the differentiation program, in the absence of EGF, estradiol-induced transcription of the ERE reporter was repressed, and similar results were obtained when MAPK signaling was inhibited in proliferating cells. We propose that these findings are related to changes in ER corepressor levels, regulated by EGF. We also report that the beta-casein reporter was activated in terminally differentiated cells and that this induction was effectively repressed by estradiol treatment. Finally, we show a physical interaction between endogenous ER alpha and signal transducer and activator of transcription 5 in differentiated HC11 cells. In summary, our results show that ER functional activity changes during differentiation of HC11 cells.
Mol Endocrinol 2004 Feb
PMID:Estrogen receptor functional activity changes during differentiation of mammary epithelial cells. 1460 98

We present the results from a Comparative Molecular Field Analysis (CoMFA) and docking study of a diverse set of 36 estrogen receptor ligands whose relative binding affinities (RBA) with respect to 17beta-Estradiol were available in both isoforms of the nuclear estrogen receptors (ER alpha, ER beta). Initial CoMFA models exhibited a correlation between the experimental relative binding affinities and the molecular steric and electrostatic fields; ER alpha: r2 = 0.79, q2 = 0.44 ER beta: r2 = 0.93, q2 = 0.63. Addition of the solvation energy of the isolated ligand improved the predictive nature of the ER beta model initially; r2 = 0.96, q2 = 0.70 but upon rescrambling of the data-set and reselecting the training set at random, inclusion of the ligand solvation energy was found to have little effect on the predictive nature of the CoMFA models. The ligands were then docked inside the ligand binding domain (LBD) of both ER alpha and ER beta utilizing the docking program Gold, after-which the program CScore was used to rank the resulting poses. Inclusion of both the Gold and CScore scoring parameters failed to improve the predictive ability of the original CoMFA models. The subtype selectivity expressed as RBA(ER alpha/ER beta) of the test sets was predicted using the most predictive CoMFA models, as illustrated by the cross-validated r2. In each case the most selective ligands were ranked correctly illustrating the utility of this method as a prescreening tool in the development of novel estrogen receptor subtype selective ligands.
J Comput Aided Mol Des
PMID:CoMFA and docking study of novel estrogen receptor subtype selective ligands. 1463 24

An endocrine-disrupting chemical (EDC) can alter endocrine functions through a variety of mechanisms, including nuclear receptor-mediated changes in protein synthesis, interference with membrane receptor binding, steroidogenesis or synthesis of other hormones. Although major chemicals have been shown to disrupt estrogenic actions mainly through their binding to estrogen receptor (ER) or androgen receptor, it is not clear how EDCs affect endocrine functions in vivo. We present evidence that the EDCs bisphenol A and phthalate activate ER-mediated transcription through interaction with TRAP220. Moreover, bisphenol A had positive effects on the interaction between ER-beta and TRAP220 and on the expression of ER-beta and TRAP220 compared with phthalate and estradiol in uterine tIssue. These data suggested that some EDCs might alter endocrine function through the change of the receptor and coactivator levels in uterine tIssue and through the different effect on the interaction between ERs and coactivator TRAP220.
J Mol Endocrinol 2003 Dec
PMID:The different effects of endocrine-disrupting chemicals on estrogen receptor-mediated transcription through interaction with coactivator TRAP220 in uterine tissue. 1466 15

In this study, we explored the potential association between estrogen receptor beta (ERbeta) and disease in a group of bulimic women. Eating disorders are much more common in females than in males, suggesting a possible role for female sex hormone signalling in the pathogenesis of these diseases. Furthermore, estrogen has been implicated in appetite regulation. The occurrence of menstrual disturbances is also increased in bulimic women. We studied 76 bulimic women and 60 controls, and found an association between two common polymorphisms in the ERbeta gene with disease in this group of bulimic women. More detailed characterisation of the ERbeta gene identified a novel variant changing the primary structure of ERbeta protein in one bulimic patient. An initial functional characterization of this variant did not reveal any differences compared to the wild-type protein. Our findings point towards a possible role of ERbeta and/or neighboring genes in the etiology of disease in bulimic patients.
Mol Psychiatry 2004 Jan
PMID:Association of estrogen receptor beta gene polymorphisms with bulimic disease in women. 1469 39

The two known estrogen receptors, ER alpha and ER beta, are hormone inducible transcription factors that have distinct roles in regulating cell proliferation and differentiation. The natural ligand, 17 beta-estradiol (E2), binds with high affinity to both ER alpha and ER beta. However, a close analogue, 16 alpha-iodo-17 beta-estradiol (16 alpha IE2) showed about 10-fold selectivity for ER alpha over ER beta. From X-ray studies, it has been shown that the ligand-binding domains (LBD) of the two receptors are strikingly similar, and that only two changes fall within the binding cavity (ER alpha Leu384 to ER beta Met336, and ER alpha Met421 to ER beta Ile373). To understand the molecular basis for the ER alpha selectivity of 16 alpha IE2, mutants and chimeras of ER alpha and ER beta were generated, and ligand-binding and transactivation functions were studied. The ER alpha Leu384 Met mutant behaved like ER alpha WT in the presence of 16 alpha IE2; whereas the profile of the ER alpha Met421 Ile mutant was similar to that of ER beta WT. The ER beta mutant Ile373 Met behaved like ER alpha with 16 alpha IE2. The results clearly demonstrate the role of ER alpha Met421 in the ER alpha selectivity of 16 alpha IE2.
J Steroid Biochem Mol Biol 2004 Jan
PMID:Molecular determinants of ER alpha and ER beta involved in selectivity of 16 alpha-iodo-7 beta estradiol. 1502 80

There has been much discussion concerning endocrine disrupting chemicals suspected of exerting adverse effects in both wildlife and humans. Since the majority of these compounds are estrogenic, a large number of in vitro tests for estrogenic characteristics have been developed for screening purpose. One reliable and widely used method is the reporter gene assay employing estrogen receptors (ERs) and a reporter gene with a cis-acting estrogen responsive element (ERE). Other elements such as AP1 also mediate estrogenic signals and the manner of response could be quite different from that of ERE. Since this has yet to be explored, the ER mediated AP1 activity in response to a series of environmental estrogens was investigated in comparison with ERE findings. All the compounds exhibited estrogenic properties with ERE-luc and their AP1 responses were quite similar. These was one exception, however, p,p'-DDT (1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane) did not exert any AP1-luc activity, while it appeared to be estrogenic at 10(-7) to 10(-5)M with the ERE action. None of the compounds demonstrated ER beta:AP1 activity. These data suggest that significant differences can occur in responses through the two estrogen pathways depending on environmental chemicals.
J Steroid Biochem Mol Biol 2004 Jan
PMID:Effects of environmental estrogenic chemicals on AP1 mediated transcription with estrogen receptors alpha and beta. 1502 83

The expression levels of three estrogen receptor (ER) isotypes alpha, beta, and gamma were quantified in female largemouth bass (Micropterus salmoides) (LMB) liver, ovary, brain, and pituitary tissues. ER alpha and beta expression predominated in the liver, while ERs beta and gamma predominated in the other tissues. Temporally in females, ER alpha was highly up-regulated, ER gamma was slightly up-regulated, and ER beta levels remained unchanged in the liver when plasma 17-beta estradiol (E2) and vitellogenin (Vtg) levels were elevated in the spring. In ovarian tissue from these same fish, all three ERs were maximally expressed in the fall, during early oocyte development and prior to peak plasma E2 levels. When males were injected with E2, ER alpha was highly inducible, ER gamma was moderately up-regulated, and ER beta levels were not affected. None of the ER isotypes were induced by E2 in gonadal tissues. These results combined suggest that the ERs themselves are not regulated in the same manner by E2, and furthermore, do not contribute equally to the transcriptional regulation of genes involved in fish reproduction such as Vtg.
Mol Cell Endocrinol 2004 Apr 15
PMID:Differential expression of largemouth bass (Micropterus salmoides) estrogen receptor isotypes alpha, beta, and gamma by estradiol. 1513 May 15

The balance between ER-alpha and ER-beta in fibroblasts may be crucial in the physiological response to ligands. Up- or down-regulation of the ERs in response to different compounds could mediate the reversal of certain age-related changes in skin and connective tissue. The time-dependent effects of 17-beta estradiol, raloxifene and tamoxifen on ER-alpha and ER-beta mRNA expression in the skin fibroblast cultures were performed. Experiments were carried out in primary cultures of human skin fibroblasts obtained from postmenopausal women. The cells were cultured in medium containing: 2 micromol/l estradiol (E2), 4 micromol/l tamoxifen (Tx) or 4 micromol/l raloxifene (Rx) for 7, 24 and 32 h. ER-alpha and ER-beta mRNAs were measured by quantitative assays based on reverse transcription (RT) of the mRNA and polymerase chain reaction (PCR) amplification of the cDNA. We suggest that ER-alpha and ER-beta are co-expressed in human postmenopausal skin fibroblast and documented that the level of mRNA expression of ERs in this tissue is estradiol, raloxifene or tamoxifen regulated as a mechanism to control the action of those ligands on the cell. On the basis of ER mRNA expression levels, fibroblast response to estradiol appears to be modulated by up-regulation of ER-beta rather than ER-alpha. Two of the examined SERMs appear to have different response to modulation of ERs: response of raloxifen is modulated by up-regulation of ER-beta, and no changes in expression of ER-alpha and tamoxifen response seem to be modulated by ER down-regulation in short-term or up-regulation during longer treatment.
Int J Mol Med 2004 Jun
PMID:Differential effects of estradiol, raloxifene and tamoxifen on estrogen receptor expression in cultured human skin fibroblasts. 1513 33

Prostate cancer remains the number one cause of noncutaneous cancer, with 220,900 new cases predicted for the year 2003 alone. Of the more promising classes of compounds studied thus far for the treatment of prostate cancer, estrogens of various types have consistently exhibited antitumor activities both in vitro and in vivo. For this reason, we have synthesized and screened a library of unique 17alpha/11beta modified 17beta-estradiol (E(2)) analogues designed for estrogen receptor beta (ER-beta) specificity and a potential for cytotoxic activity directed toward prostate cancer cells. From this library, the novel compound 17alpha-20Z-21-[(4-amino)phenyl]-19-norpregna-1,3,5(10),20-tetraene-3,17beta-diol (APVE(2)) was identified as the primary lead, found to induce a high level (>90%) of cell death through an apoptotic mechanism, with an EC(50) of 1.4, 2.7, and 16 nM in the LNCaP, PC3, and DU145 cell lines, respectively. APVE(2) was found to bind to ER-beta, albeit weakly, with an EC(50) of 250 nM and a binding activity of 6.2% relative to E(2), nearly two orders of magnitude less than the concentration required to induce apoptosis. APVE(2) bound preferentially to ER-beta by 7-fold over ER-alpha, and did not induce growth in the MCF-7 cell line, thus indicating that it is not a classical ER agonist. Furthermore, the cytotoxic actions of APVE(2) were not reversed by co-treatment with a 50-fold excess E(2). In summary, a novel 17 modified estrogen APVE(2) was identified as a lead compound, capable of inducing apoptosis in three prostate cancer cell lines at low nanomolar concentrations, through a mechanism inconsistent with an ER-mediated mechanism.
Mol Cancer Ther 2004 May
PMID:The novel estrogen 17alpha-20Z-21-[(4-amino)phenyl]-19-norpregna-1,3,5(10),20-tetraene-3,17beta-diol induces apoptosis in prostate cancer cell lines at nanomolar concentrations in vitro. 1514 Oct 16


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