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)

Bisphenols constitute a family of compounds, which includes many substances that have as a common chemical structure two phenolic rings joined together through a bridging carbon. In the present study, we aimed to determine whether several events triggered by 17 beta-estradiol (E(2)) in MCF-7 breast cancer cells were also observed in response to various bisphenol-A (BPA) analogues. We studied the expression of estrogen controlled genes by measuring the induction of pS2 (mRNA and protein) and progesterone receptor (PgR) as well as the expression of a luciferase reporter gene transfected into MVLN cells. These data were compared to the cell proliferation potency and effectiveness as the latest expression of estrogen controlled functions. Bisphenols showed an agonistic effect in all our assays, suggesting that these compounds may act through all the response pathways triggered by the natural hormone. We found differences between the assays in the potency of bisphenols, defined as the minimum concentration required to produce a maximal effect. In the cell proliferation assay, all tested compounds needed a lower concentration than in the other assays to give maximal response. Our results suggest that the polarity and nature of the substituent in the central carbon determines the estrogenic potency. Presence of two propyl chains at the central carbon appears to confer the greatest potency in both gene and protein expression assays.
J Steroid Biochem Mol Biol 2002 Sep
PMID:Estrogenic effect of a series of bisphenol analogues on gene and protein expression in MCF-7 breast cancer cells. 1242 38

The trefoil factors (TFFs) are pleiotropic factors involved in organization and homeostasis of the gastrointestinal tract, estrogen responsiveness, inflammatory disorders, and carcinogenesis. In an earlier study using cDNA array technologies to identify new genes expressed in irradiated cell survivors, we isolated a cDNA clone corresponding to the reported human TFF1 gene (E. K. Balcer-Kubiczek et al., Int. J. Radiat. Biol., 75: 529-541, 1999). To determine whether expression of other TFFs is altered by ionizing radiation, we quantified changes in expression of TFF3 as well as TFF1 in RNA samples obtained from irradiated and control human tumor breast, colon, and gastric tumor cells and examined expression kinetics up to 2 weeks after irradiation. X-ray-induced TFF1 and TFF3 expression profiles were compared with those induced by hydrogen peroxide (H2O2) or 17beta-estradiol (ES). The results revealed that TFF1 and TFF3 mRNA are coinduced by X-irradiation in a subset of the lines, but substantial heterogeneity in their responses was observed in cells derived from a single cell type. TFF1 and TFF3 transcriptional response to X-irradiation differed from that to H2O2 or ES in the timing of their induction as well as tissue-type dependence, i.e., their induction pattern after X-irradiation was late and sustained, whereas their induction by H2O2 or ES was early and transient. TFF1 mRNA, protein production in the cytoplasm, and secretion in the culture supernatant were coordinately regulated after X-irradiation. There was no requirement for TP53 in this induction. These results demonstrate the existence of a novel class of radiation-responsive genes that might be involved in bystander effects.
Mol Cancer Ther 2002 Apr
PMID:Coordinate late expression of trefoil peptide genes (pS2/TFF1 and ITF/TFF3) in human breast, colon, and gastric tumor cells exposed to X-rays. 1247 53

Licorice root contains chemically diverse compounds that exhibit estrogenic effects in vitro and in vivo. The chalcone isoliquiritigenin (ISL) is a component of licorice extract exhibiting either antitumorigenic activity or estrogen receptor (ER) alpha-dependent growth promoting effects on breast cancer cells. In order to contribute to a better understanding of this apparent paradox, we synthesized and ascertained the estrogenic properties of ISL using, as model systems, the hormone-sensitive MCF7 breast cancer cells and the steroid-independent HeLa cells. Transfection experiments reveal that ISL is able to transactivate the endogenous ER alpha in MCF7 cells and this is supported by the capability to induce down-regulation of ER alpha protein levels and up-regulation of pS2 mRNA. Moreover, by using chimeric proteins consisting of the hormone binding domains of ER alpha and ER beta fused to the Gal4 DNA binding domain, we have determined that ISL is an estrogenic agonist of both ER isoforms. As a biological counterpart, low and intermediate ISL concentrations that induce substantial transcriptional activity stimulate the proliferation of MCF7 cells. However, high levels of ISL become cytotoxic even in steroid-receptor negative HeLa cells. Thus, the activity of ISL and the balance between risk or chemopreventive factor for estrogen-dependent breast cancer may depend on dietary intake.
J Steroid Biochem Mol Biol 2002 Nov
PMID:Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. 1258 38

We have examined the possibility that a component of Panax ginseng, ginsenoside-Rh1, acts by binding to steroid hormone receptors such as receptors for estrogen, glucocorticoid, androgen, and retinoic acid. Ginsenoside-Rh1 activated the transcription of the estrogen-responsive luciferase reporter gene in MCF-7 breast cancer cells at a concentration of 50 microM. Activation was inhibited by the specific estrogen receptor antagonist ICI 182,780, indicating that the estrogenic effect of ginsenoside-Rh1 is estrogen receptor dependent. Ginsenoside-Rh1 induction of luciferase activity was dose-dependent in CV-1 cells transiently transfected with estrogen receptor and reporter plasmids. Next, we evaluated the ability of ginsenoside-Rh1 to induce the estrogen-responsive genes in MCF-7 cells. Ginsenoside-Rh1 increased c-fos and pS2 at the mRNA levels at 24h after treatment, although the effects were not as prominent as 17beta-estradiol. Western blot analysis showed that progesterone receptor protein was induced at 24h of treatment of ginsenoside-Rh1. However, ginsenoside-Rh1 failed to activate the glucocorticoid receptor, the androgen receptor, or the retinoic acid receptor in CV-1 cells transiently transfected with the corresponding steroid hormone receptors and hormone responsive reporter plasmids. These data support our hypothesis that ginsenoside-Rh1 acts as a weak phytoestrogen, presumably by binding and activating the estrogen receptor.
J Steroid Biochem Mol Biol 2003 Mar
PMID:A ginsenoside-Rh1, a component of ginseng saponin, activates estrogen receptor in human breast carcinoma MCF-7 cells. 1273 91

Antiestrogens are efficient inhibitors of estrogen-mediated growth of human breast cancer. Besides inhibiting estradiol-stimulated growth, antiestrogens may have a direct growth-inhibitory effect on estrogen receptor (ER) positive cells and thus be more efficient than aromatase inhibitors, which will only abrogate estrogen-dependent tumor growth. To address this issue, we have used the human breast cancer cell line MCF-7/S9 as a model system which is maintained in a chemically defined medium without serum and estrogen. The addition of estradiol results in an increase in cell growth rate. Thus, the MCF-7/S9 cell line is estrogen-responsive but not estrogen-dependent. Three different types of antiestrogens, namely tamoxifen, ICI 182,780 and EM-652 were found to exert a significant and dose-dependent inhibition of basal growth of MCF-7/S9 cells. The growth-inhibitory effect of the three antiestrogens was prevented by simultaneous estradiol treatment. Antiestrogen treatment also reduced the basal pS2 mRNA expression level, thus indicating spontaneous estrogenic activity in the cells. However, treatment with the aromatase inhibitor had no effect on basal cell growth, excluding that endogenous estrogen synthesis is involved in basal growth. These data demonstrate that in addition to their estrogen antagonistic effect, antiestrogens have a direct growth-inhibitory effect which is ER-mediated. Consequently, in the subset of ER positive breast cancer patients with estrogen-independent tumor growth, antiestrogen therapy may be superior to treatment with aromatase inhibitors which only inhibit estrogen formation but do not affect cancer cell growth in the absence of estrogens.
J Steroid Biochem Mol Biol 2003 Mar
PMID:Effect of antiestrogens and aromatase inhibitor on basal growth of the human breast cancer cell line MCF-7 in serum-free medium. 1273 92

TFF1/pS2, TFF2/SP and TFF3/ITF are soluble peptides with trefoil domain(s) and C-terminal dimerization domain, which are conserved among human, cow, mouse and rat. TFF1 mRNA is expressed in stomach (mucous cells in fundus and antrum), TFF2 mRNA in stomach (mucous neck cells in fundus and basal cells in antral and pyloric glands) and duodenum (Brunner's gland), TFF3 mRNA in small intestine and large intestine (goblet cells). Expression of TFF1, TFF2 and TFF3 mRNAs are differentially regulated by FGF2/bFGF, FGF7/KGF, estrogen, aspirin, arachidonic acid, X-ray irradiation, and hydrogen peroxide. Gastric cancer is classified into the intestinal type and the diffuse type. TFF mRNAs are preferentially expressed in diffuse-type gastric cancer cells. Custom-made microarray (TFF mRNAs) and ELISA (TFF proteins) might be applicable for screening methods of peritoneal and bone marrow dissemination from diffuse-type gastric cancer. TFF1 and TFF2 mRNAs are frequently down-regulated in intestinal-type gastric cancer. TFF1 gene, inactivated by deletion, missense mutation and promoter hypermethylation, is a tumor suppressor gene implicated in gastric cancer. TFF2 is a candidate tumor suppressor gene; however, genetic and epigenetic alterations of TFF2 gene in human gastric cancer remain unclear. TFF1, TFF2 and TFF3 play key roles in mucosal protection through mucous-barrier formation, and also in mucosal repair through promotion of restitution after injury. Patients with chronic atrophic gastritis and those with ulcerative colitis are at risk of gastric cancer and colorectal cancer, respectively. TFF1, TFF2 and TFF3 proteins might be applicable for chemoprevention of gastrointestinal cancer associated with chronic persistent inflammation.
Int J Mol Med 2003 Jul
PMID:Trefoil factors and human gastric cancer (review). 1279 1

Estrogen receptors (ERs) are transcription factors that can be modulated by both estrogen-dependent and growth factor-dependent phosphorylation. A yeast two-hybrid screening identified a serine/threonine protein phosphatase (PP5) as an interactant of ERbeta (1-481), a dominant negative ERbeta mutant. Glutathione S-transferase pull-down assays, mammalian two-hybrid assays, and immunoprecipitation studies showed that PP5 directly binds to both ERalpha and ERbeta via its tetratricopeptide repeat domain. E domains of ERalpha and ERbeta, without containing activation domain core regions in transcription activation function 2, were required for the binding to PP5. In ERalpha-positive breast cancer MCF7 cells, estrogen- and epidermal growth factor-dependent phosphorylation of ERalpha on serine residue 118, a major phosphorylation site of the receptor, was reduced by expressing PP5 but enhanced by PP5 antisense oligonucleotide. Estrogen-induced transcriptional activities of both ERalpha and ERbeta and mRNA expression of estrogen-responsive genes, including pS2, c-myc, and cyclin D1, were suppressed by PP5 but enhanced by PP5 antisense oligonucleotide. A truncated PP5 mutant consisting only of its tetratricopeptide repeat domain acted as a dominant negative PP5 that enhanced serine residue 118 phosphorylation of ERalpha and transactivations by ERalpha and ERbeta. We present the first evidence that PP5 functions as an inhibitory regulator of ER phosphorylation and transcriptional activation in vivo.
Mol Endocrinol 2004 May
PMID:Protein phosphatase 5 is a negative regulator of estrogen receptor-mediated transcription. 1476 52

Hormone-activated nuclear receptors (NR) activate transcription by recruiting multiple coactivator complexes to the promoters of target genes. One important coactivator complex includes a p160 coactivator (e.g., GRIP1, SRC-1, or ACTR) that binds directly to activated NR, the histone acetyltransferase p300 or CBP, and the arginine-specific histone methyltransferase CARM1. We previously demonstrated that the coactivator function of CARM1 depends both on the methyltransferase activity and on additional unknown proteins that bind to CARM1. In this study a yeast two-hybrid screen for proteins that bind CARM1 identified the protein Flightless I (Fli-I), which has essential roles in Drosophila and mouse development. Fli-I bound to CARM1, GRIP1, and NRs and cooperated synergistically with CARM1 and GRIP1 to enhance NR function. Fli-I bound poorly to and did not cooperate with PRMT1, a CARM1-related protein arginine methyltransferase that also functions as an NR coactivator. The synergy between GRIP1, CARM1, and Fli-I required the methyltransferase activity of CARM1. The C-terminal AD1 (binding site for p300/CBP) and AD2 (binding site for CARM1) activation domains of GRIP1 contributed to the synergy but were less stringently required than the N-terminal region of GRIP1, which is the binding site for Fli-I. Endogenous Fli-I was recruited to the estrogen-regulated pS2 gene promoter of MCF-7 cells in response to the hormone, and reduction of endogenous Fli-I levels by small interfering RNA reduced hormone-stimulated gene expression by the endogenous estrogen receptor. A fragment of Fli-I that is related to the actin binding protein gelsolin enhanced estrogen receptor activity, and mutations that reduced actin binding also reduced the coactivator function of this Fli-I fragment. These data suggest that Fli-I may facilitate interaction of the p160 coactivator complex with other coactivators or coactivator complexes containing actin or actin-like proteins.
Mol Cell Biol 2004 Mar
PMID:Developmentally essential protein flightless I is a nuclear receptor coactivator with actin binding activity. 1496 89

How nuclear receptors (NRs) coordinate the sequential, ligand-dependent recruitment of multiple coactivator complexes (e.g., SRC complexes and Mediator) that share similar receptor binding determinants is unclear. We show that although the receptor binding subunits of these complexes (i.e., SRCs and Med220, respectively) share overlapping binding sites on estrogen receptor alpha (ERalpha), information contained in the receptor-coactivator interface allows the receptor to distinguish between them. In support of this conclusion, we have identified an ERalpha AF-2 point mutant (L540Q) that selectively binds and recruits Med220, but not SRCs, both in vitro and in vivo. In cells expressing this mutant, the recruitment of Med220 to the pS2 promoter is delayed, and the expression of the vast majority of estrogen target genes is impaired, suggesting a nearly global functional interdependence of these coactivators. Collectively, our results suggest that "facilitated recruitment," rather than competition, drives the sequential recruitment of SRC complexes and Mediator by NRs.
Mol Cell 2004 Mar 12
PMID:Selective recognition of distinct classes of coactivators by a ligand-inducible activation domain. 1502 42

We explored, by cDNA mini-arrays, gene expression measurements of MVLN, a human breast carcinoma cell line derived from MCF-7, after 4 days of exposure to 17beta-estradiol (E(2)) treatment, in order to extend our understanding of the mechanism of the pharmacological action of estrogens. We focused on 22 genes involved in estrogen metabolism, cell proliferation regulation and cell transformation. The specificity of the E(2) response was reinforced by comparison with 4-hydroxytamoxifen (OH-Tam), ICI 182,780 and E(2)+OH-Tam expression profiles. Real-time quantitative PCR (RTQ-PCR) confirmed the variation of expression of known (TFF1, AREG, IRS1, IGFBP4, PCNA, ERBB2, CTSD, MYC) as well as novel (DLEU2, CCNA2, UGT1A1, ABCC3, ABCC5, TACC1, EFNA1, NOV, CSTA, MMP15, ZNF217) genes. The temporal response of these gene expression regulations was then investigated after 6 and 18 h of E(2) treatment and this allowed the identification of different time-course patterns. Cycloheximide treatment studies indicated first that estrogen affected the transcript levels of ABCC3 and ABCC5 through dissimilar pathways, and secondly that protein synthesis was needed for modulation of the expression of the CCNA2 and TACC1 genes by estrogens. Western blot analysis performed on TFF1, IRS1, IGFBP4, amphiregulin, PCNA, cyclin A2, TACC1 and ABCC5 proteins confirmed the mini-array and RTQ-PCR data, even for genes harboring low variations of mRNA expression. Our findings should enhance the understanding of changes induced by E(2) on the transcriptional program of human E(2)-responsive cells and permit the identification of new potential diagnostic/prognostic tools for the monitoring of estrogen-related disease conditions such as breast cancer.
J Mol Endocrinol 2004 Apr
PMID:Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation. 1507 47


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