Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we demonstrate that Rosiglitazone (Rosi), a thiazolidinedione and PPARgamma agonist, induces ERE (Estrogen Receptor Response Element) reporter activity, pS2 (an endogenous ER gene target) expression, and proliferation of ER positive breast cancer (MCF-7) cells. By performing a dose-response assay, we determined that high concentrations of Rosi inhibit proliferation, while low concentrations of Rosi induce proliferation. Using the anti-estrogen ICI, ER negative breast cancer (MDA-MB-231) cells, and a prostate cancer cell line (22Rv1) deficient in both ERalpha and PPARgamma, we determined that Rosiglitazone-induced ERE reporter activation and proliferation is through an ERalpha dependent mechanism. Rosiglitazone-induced ERE activation is also dependent on activation of the Extracellular Signal-Regulated Kinase-Mitogen Activated Protein Kinase (ERK-MAPK) pathway, since it is inhibited by co-treatment with U0126, a specific inhibitor of this pathway. We also demonstrate that when ERalpha and PPARgamma are both present, they compete for Rosi, inhibiting each others transactivation. To begin to unravel the pharmacological mechanism of Rosi-induced ER activation, sub-maximally effective concentrations of E(2) were used in combination with increasing concentrations of Rosi in luciferase reporter assays. From these assays it appears that E(2) and Rosi both activate ERalpha via similar pharmacological mechanisms. Furthermore sub-maximally effective concentrations of E(2) and Rosi additively increase both ERE reporter activity and MCF-7 cell proliferation. The results of this study may have clinical relevancy for Rosi's use both as an anti-diabetic in post-menopausal women and as an anti-cancer drug in women with ER positive breast cancer.
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PMID:Transactivation of ERalpha by Rosiglitazone induces proliferation in breast cancer cells. 1745 34

4-Methoxyequilenin (4-MeOEN) is an O-methylated metabolite in equine estrogen metabolism. O-methylation of catechol estrogens is considered as a protective mechanism; however, comparison of the properties of 4-MeOEN with estradiol (E(2)) in human breast cancer cells showed that 4-MeOEN is a proliferative, estrogenic agent that may contribute to carcinogenesis. 4-MeOEN results from O-methylation of 4-hydroxyequilenin, a major catechol metabolite of the equine estrogens present in hormone replacement therapeutics, which causes DNA damage via quinone formation, raising the possibility of synergistic hormonal and chemical carcinogenesis. 4-MeOEN induced cell proliferation with nanomolar potency and induced estrogen response element (ERE)-mediated gene transcription of an ERE-luciferase reporter and the endogenous estrogen-responsive genes pS2 and TGF-alpha. These estrogenic actions were blocked by the antiestrogen ICI 182,780. In the standard radioligand estrogen receptor (ER) binding assay, 4-MeOEN showed very weak binding. To test for alternate ligand-ER-independent mechanisms, the possibility of aryl hydrocarbon receptor (AhR) binding and ER-AhR cross talk was examined using a xenobiotic response element-luciferase reporter and using AhR small interfering RNA silencing in the ERE-luciferase reporter assay. The results negated the possibility of AhR-mediated estrogenic activity. Comparison of gene transcription time course, ER degradation, and rapid activation of MAPK/ERK in MCF-7 cells demonstrated that the actions of 4-MeOEN mirrored those of E(2) with potency for classical and nonclassical estrogenic pathways bracketing that of E(2). Methylation of 4-OHEN may not represent a detoxification pathway because 4-MeOEN is a full, potent estrogen agonist.
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PMID:Activation of estrogen receptor-mediated gene transcription by the equine estrogen metabolite, 4-methoxyequilenin, in human breast cancer cells. 1758 65

Metallo-estrogens are a new class of potent environmental estrogens. This study investigates whether tobacco smoke condensate (TSC), which contains metals and metalloids, elicits estrogen-like effects at environmentally relevant doses. Treatment of human breast cancer cells, MCF-7, with 40 microg/ml TSC resulted in a 2.5-fold stimulation of cell growth. TSC decreased the concentration of estrogen receptor (ER)-alpha protein and mRNA (63 and 62%, respectively), and increased the expression of the estrogen-regulated genes, progesterone receptor and pS2 (5- and 2-fold, respectively). In addition, TSC activated ER-alpha in COS-1 or CHO cells transiently transfected with wild-type ER-alpha and an ERE-CAT or an ERE-luciferase reporter gene (11- and 6-fold, respectively). TSC also activated a chimeric receptor (GAL-ER) containing the hormone binding domain of ER-alpha (3.5-fold). It blocked the binding of estradiol to the receptor without altering the affinity of estradiol (K(d) = 2.2-6.8 x 10(-10) m). Transfection assays with ER-alpha mutants identified C381, C447, H524, N532, E523, and D538 in the hormone binding domain as important for activation by TSC. In ovariectomized rats, low doses of TSC [10 or 20 mg/kg body weight (bw)] increased uterine wet weight (1.7- and 2.1-fold), and induced the expression of progesterone receptor and complement C3 in the uterus (2- and 26-fold) and mammary gland (4.4- and 15-fold). Both the in vitro and in vivo TSC effects were blocked by the antiestrogen ICI 182,780, suggesting the involvement of ER. Collectively, these results provide strong evidence that low doses of TSC, acting through the hormone binding domain, exert estrogen-like effects in cell culture and animals.
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PMID:Effects of tobacco smoke condensate on estrogen receptor-alpha gene expression and activity. 1764 Sep 96

The ethanol extract of the fruits of Vitex rotundifolia (VRE) and its four major compounds (casticin, luteolin, rotundifuran and agnuside) were tested for their estrogen-like activity by using the modified cell proliferation assay (E-SCREEN assessment system), as well as the estrogen receptor (ER(alpha)), estrogen receptor-regulated progesterone receptor and pS2 mRNA expression in MCF-7 cells. The results showed that only agnuside and rotundifuran could stimulate the proliferation of MCF-7 cells. These actions were dose dependent (range from 100 nM to 10 microM) and could be significantly inhibited by the specific estrogen receptor antagonist ICI 182,780. The estrogen receptor ER(alpha) and the estrogen receptor-regulated progesterone receptor and pS2 mRNA levels were increased by treatment with rotundifuran and agnuside within 24 h, and the effects could be reversed by ICI 182,780. The standardization of the extract and constituents were carried out by means of a high-performance liquid chromatography-fingerprint. It was concluded that VRE and its compounds showed estrogen-like activity and that the estrogenic effects of rotundifuran and agnuside were mediated by the estrogen inducible gene, which may be useful in regulating the hormone levels to treat related diseases. However, further studies are required to assess the physiological significance of VRE in animals and man.
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PMID:Evaluation of the estrogenic activity of the constituents in the fruits of Vitex rotundifolia L. for the potential treatment of premenstrual syndrome. 1788 2

Alcohol consumption is an increased risk factor for hormone-dependent breast cancer but the underlying molecular bases are unknown. Several studies suggest that ethanol could activate the estrogen signaling pathway. We have performed an in vitro study in order to investigate the molecular players involved in this phenomenon. Exposure of MCF-7 breast cancer cells to ethanol induced an increase in the mRNA level of two well known estrogen target genes: progesterone receptor (PR) and pS2. This result was confirmed by an increase in luciferase activity in pEREtkLuc-transfected MCF-7 cells exposed to ethanol. These effects, whose intensity was similar to those of E2, were observed also in steroid-free medium and were inhibited by the antiestrogen ICI 182,780. This suggested a ligand-independent activation of ERalpha that was confirmed by the absence of ERalpha proteolysis in ethanol-treated cells. Using PKA inhibitor (H89), the study of phospho-CREB by Western blot and transfection experiments with a CRE-reporter construct demonstrated that PKA was involved in ethanol-induced transcription of ERalpha target genes. Adenylyl cyclase inhibition impaired the activation of estrogen signaling pathway induced by ethanol. The results obtained in vitro, are discussed in regard to alcohol consumption and relevance to humans.
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PMID:Ethanol-induced ligand-independent activation of ERalpha mediated by cyclic AMP/PKA signaling pathway: an in vitro study on MCF-7 breast cancer cells. 1798 78

We investigated the estrogenic activity of Cirsium japonicum water extracts, which have long been used to treat vascular-related diseases. The activity of the extracts was characterized in a transient transfection system, using estrogen receptor isoforms and estrogen-responsive luciferase plasmids in HEK 293 cells. The extract activated both and estrogen receptors. Activation was inhibited by the estrogen receptor antagonist ICI 182,780, indicating that the effects were mediated through the estrogen receptor isoforms. Treatment with the extracts increased expression of the progesterone receptor and pS2 genes and expression of estrogen receptor was decreased in MCF-7 cells. These results suggested that the Cirsium japonicum water extracts showed estrogenic effects and may be a potential clinical application for treatment of estrogen related vascular diseases.
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PMID:Modulation of the genomic estrogen receptor pathway by water extracts of Cirsium japonicum. 1836 94

Estrogens play a key role in bone structural integrity, which is maintained by the opposing activity of bone forming osteoblasts and bone resorbing osteoclasts. The cellular effects of estrogens are mediated by estrogen receptors, however, the detailed molecular mechanism of ER regulation in osteoclasts has not yet been elucidated. We provide here a detailed analysis of the expression profile and functionality of ER during osteoclast differentiation. We employed a human primary osteoclast cell culture model to evaluate the regulation of estrogen receptor (ER) variant expression. We characterized the expression profile of estrogen receptors and studied the regulation of the predominant estrogen receptor-alpha (ER-alpha) during differentiation into osteoclasts. In addition to the full-length ER-alpha, a shorter ER-alpha mRNA variant is expressed and both ER-alpha variants are regulated during osteoclastogenesis. Furthermore, we show that the pS2 gene is an estrogen-regulated gene in osteoclasts. Analysis of the activity of the pS2 gene throughout differentiation, using chromatin immunoprecipitation (ChIP), revealed the functionality of ER-alpha during differentiation and shows that the occupancy of ER-alpha and activated polymerase II on the pS2 promoter decrease with time and can be blocked by the ER antagonist ICI 182780. These results help to dissect the molecular events relevant to estrogen signaling and provide a better understanding of the role of ER-alpha regulation during bone resorption mediated by osteoclasts.
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PMID:Expression of the estrogen receptor during differentiation of human osteoclasts. 1840 38

Synthetic pyrethroids are widely used in both agricultural and urban environments for insect control. Lambda-cyhalothrin (LCT) is one of the most common pyrethroids and is used mainly for controlling mosquitoes, fleas, cockroaches, flies, and ants around households. Previous studies have addressed the environmental behaviors and acute toxicities of LCT, but little is known about its chronic toxicity, such as estrogen-like activity. In the present study, the estrogenic potential of LCT was evaluated using the MCF-7 human breast carcinoma cell line. The in vitro E-screen assay showed that 10(-7) M LCT could significantly promote MCF-7 cell proliferation, with a relative proliferative effect ratio of 45%. The cell proliferation induced by LCT could be blocked completely, however, by the addition of 10(-9) M of the estrogen receptor (ER)-antagonist ICI 182,780. The semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) results showed that the Trefoil factor 1 (pS2) and progesterone receptor gene expression were up-regulated by 10(-7) M LCT for 2- and 1.5-fold, respectively. On the other hand, RT-PCR, Western blot analysis, and immunofluorescent assay demonstrated that LCT significantly repressed the mRNA and protein expression levels of ERalpha and ERbeta. These observations indicate that LCT possesses estrogenic properties and may function as a xenoestrogen, likely via a mechanism similar to that of 17beta-estradiol. The endocrine-disruption potential of LCT should be considered when assessing the safety of this compound in sensitive environmental compartments.
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PMID:Estrogenic activity of lambda-cyhalothrin in the MCF-7 human breast carcinoma cell line. 1841 97

In this study, the ability of nitrite and nitrate to mimic the effects of estradiol on growth and gene expression was measured in the human breast cancer cell line MCF-7. Similar to estradiol, treatment of MCF-7 cells with either 1 mumol/L nitrite or 1 mumol/L nitrate resulted in approximately 4-fold increase in cell growth and 2.3-fold to 3-fold increase in progesterone receptor (PgR), pS2, and cathepsin D mRNAs that were blocked by the antiestrogen ICI 182,780. The anions also recruited estrogen receptor-alpha (ERalpha) to the pS2 promoter and activated exogenously expressed ERalpha when tested in transient cotransfection assays. To determine whether nitrite or nitrate was the active anion, diphenyleneiodonium was used to inhibit oxidation/reduction reactions in the cell. The ability of diphenyleneiodonium to block the effects of nitrate, but not nitrite, on the induction of PgR mRNA and the activation of exogenously expressed ERalpha suggests that nitrite is the active anion. Concentrations of nitrite, as low as 100 nmol/L, induced a significant increase in PgR mRNA, suggesting that physiologically and environmentally relevant doses of the anion activate ERalpha. Nitrite activated the chimeric receptor Gal-ER containing the DNA-binding domain of GAL-4 and the ligand-binding domain of ERalpha and blocked the binding of estradiol to the receptor, suggesting that the anion activates ERalpha through the ligand-binding domain. Mutational analysis identified the amino acids Cys381, His516, Lys520, Lys529, Asn532, and His547 as important for nitrite activation of the receptor.
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PMID:Activation of estrogen receptor-alpha by the anion nitrite. 1914 90

Third generation aromatase inhibitors (AI) have shown good clinical efficacy in comparison to the anti-estrogen tamoxifen. The steroidal AI, exemestane (EXE) has previously been shown to act as an androgen, but this report demonstrates the estrogen-like activity of EXE. Based on genome-wide microarray analysis, high correlation was seen between EXE-Only (EXE O, hormone-free) and hormone-containing AI-resistant lines. In addition, the top regulated genes in the EXE O lines were mostly estrogen-responsive genes. This estrogen-like activity of EXE was further validated using estrogen receptor (ER) activity assays, where in comparison to 17beta-estradiol (E2), EXE was able to induce ER activity, though at a higher concentration. Also, this EXE-mediated ER activity was blocked by the ER antagonist ICI as well as the ERalpha-specific antagonist methyl-piperidino-pyrazole (MPP). Similarly, EXE was able to induce proliferation of breast cancer cell lines, MCF-7 and MCF-7aro, as well as activate transcription of known estrogen-responsive genes, i.e., PGR, pS2 and AREG. These results suggest that EXE does have weak estrogen-like activity.
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PMID:Characterization of the weak estrogen receptor alpha agonistic activity of exemestane. 1867 58


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