UNIPROT:P04155 - FACTA Search

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Query: UNIPROT:P04155 (pS2)
1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The winged helix transcription factors HNF-3/FKH (forkhead homologs) activate endodermal-derived and acute-phase gene expression and control gut development in Drosophila. Trefoil factor family (TFFs) peptides are vertebrate products secreted by mucin-producing epithelial cells of the gastrointestinal tract involved in restitution and repair of the mucosa. They are positively regulated in ulcerative and neoplastic conditions. We describe a consensus sequence in human and rodent TFF promoters close to the TATAA box showing striking similarity to the binding site of the HNF-3/FKH family. In gel retardation assays, HNF-3 alpha and beta bound predominantly to the site in TFF1 (formerly pS2) and, to a lesser extent, to the sites in TFF2 or TFF3. Mutations generated in this motif severely impaired transcription of TFF1 reporter genes. Cotransfection with expression vectors of HNF-3alpha and beta, but not the related HFH 11A and B, specifically activated the wild-type TFF1 reporter genes. Activation of endogenous expression of TFF1 by HNF-3 alpha and beta gene products was more than 1000 fold in the pancreatic cell line Capan-2 and fivefold in the gastric cell line MKN-45, whereas the intestinal cell lines HUTU 80 and HT-29 displayed no effect. Thus, HNF-3/FKH factors contribute causally to cell-specific regulation of TFF genes and may explain the acute-phase response of TFF peptides.
DNA Cell Biol 1999 Feb
PMID:Hepatocyte nuclear factor 3 (winged helix domain) activates trefoil factor gene TFF1 through a binding motif adjacent to the TATAA box. 1007 75

Members of the trefoil factor (TFF) family are highly expressed in endodermal ulcerative wound healing and selectively in neoplastic proliferation of various glandular epithelia. There is some evidence that TFF1 and TFF3 affect cell motility, are indirectly involved in growth suppression, and are associated with mucin expression. TFF2 is co-expressed with TFF1 in gastric surface epithelial cells, but its potential role in vivo is unclear. We analyzed potential effects on cell proliferation and morphogenesis of TFF2 on a panel of epithelial and mesenchymal cell lines. TFF2 had no measurable effect on the proliferation of any of the cell lines tested. In type 1 collagen lattices, TFF2 at a low concentration (25-100 nM) induced the formation of highly complex branched structures in the breast carcinoma cell line MCF-7 over a period of 14 to 42 days. No significant effect was shown with other cell lines. This morphogenic effect was abolished by monoclonal antibodies specific for either TFF2 or TFF1. TFF2 did not affect cell motility in MCF-7 cells as measured by videomicroscopy, in contrast to previous studies using TFF1. TFF2-treated MCF-7 colonies showed a 30% reduction in the number of apoptotic bodies, corroborated by trypan blue exclusion and DNA fragmentation ELISA, indicating TFF2 promotes cell survival via inhibition of apoptosis and can act as a morphogen in the presence of TFF1. These properties may complement the actions of TFF1 as a motogen and may explain differential expression in endodermal wound healing.
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PMID:Trefoil factor-2, human spasmolytic polypeptide, promotes branching morphogenesis in MCF-7 cells. 1033 65

Estrogen receptor (ER)-negative breast carcinomas are often difficult to treat as they do not respond to hormone therapy. In an attempt to determine if expressing the human estrogen receptor in an ectopic manner could restore the hormone responsiveness of these cells, we have expressed the human ER in ER-negative MDA-MB 231 breast cancer cells using a recombinant adenovirus gene delivery system that allows high level expression of ER in essentially all cells. In these cells, the ER was correctly translated, had a wild type hormone binding affinity (Kd = 0.6 nM), bound well to estrogen response element-containing DNA, and showed an activation pattern of estrogen response element-reporter gene activity by estrogen and antiestrogens very similar to that observed in MCF-7 breast cancer cells containing endogenous ER (stimulation by estrogen, no stimulation by the antiestrogens trans-hydroxytamoxifen or ICI 164384, and blockade of estradiol stimulation by trans-hydroxytamoxifen or ICI 164384). Intriguingly, estradiol stimulation of these cells was also able to induce expression of pS2, an estrogen regulated gene considered to be a favorable prognostic marker for endocrine therapy in ER-positive breast cancer cells. Expression of the ER had no effect by itself on the proliferation rate of MDA-MB 231 cells. However, treatment of the ER-containing cells with estradiol or with the pure antiestrogen ICI 164 384 suppressed proliferation of the cells while the antiestrogen trans-hydroxytamoxifen had little effect on proliferation; and cotreatment with trans-hydroxytamoxifen reversed the estradiol- or ICI 164 384-evoked suppression of proliferation. To understand the mechanism underlying the inhibition of proliferation by estradiol, we examined the expression of several growth related endogenous genes. c-Myc protooncogene expression was strongly inhibited by treatment with estradiol as was expression of BRCA1 and BRCA2 genes, which is in agreement with their mitogenic-dependent expression, while expression of beta-actin, a housekeeping gene, was not affected by hormone treatment. Together, these data suggest that reexpressing the human ER in breast cancer cells that no longer express this protein renders them sensitive to hormone treatment. The ability of the antiestrogen ICI 164 384 to suppress the proliferation of ER-negative breast cancer cells that reexpress ER might be useful ultimately as an endocrine gene therapy approach for controlling the growth of ER-negative breast cancer cells. The application of recombinant adenoviruses expressing the human ER presents interesting features which might be used as a basis for designing more powerful and effective treatments for ER-negative breast cancers.
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PMID:Expression of human estrogen receptor using an efficient adenoviral gene delivery system is able to restore hormone-dependent features to estrogen receptor-negative breast carcinoma cells. 1037 22

Under acidic conditions, indole-3-carbinol (13C) is converted to a series of oligomeric products thought to be responsible for the biological effects of dietary 13C. Chromatographic separation of the crude acid mixture of 13C, guided by cell proliferation assay in human MCF-7 cells, resulted in the isolation of 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr-1) as a major antiproliferative component. LTr-1 inhibited the growth of both estrogen-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cells by approximately 60% at a non-lethal concentration of 25 microM. LTr-1 had no apparent effect on the proliferation of MCF-7 cells in the absence of estrogen. LTr-1 was a weak ligand for the estrogen receptor (ER) (IC50 70 microM) and efficiently inhibited the estradiol (E2)-induced binding of the ER to its cognate DNA responsive element. The antagonist effects of LTr-1 also were exhibited in assays of endogenous pS2 gene expression and in cells transiently transfected with an estrogen-responsive reporter construct (pERE-vit-CAT). LTr-1 activated both binding of the aryl hydrocarbon (Ah) receptor to its cognate DNA responsive element and expression of the Ah receptor-responsive gene CYP1A1. LTr-1 was a competitive inhibitor of CYP1A1-dependent ethoxyresorufin-O-deethylase (EROD) activity. In summary, these results demonstrated that LTr-1, a major in vivo product of I3C, could inhibit the proliferation of both estrogen-dependent and -independent breast tumor cells and that LTr-1 is an antagonist of estrogen receptor function and a weak agonist of Ah receptor function.
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PMID:Cytostatic and antiestrogenic effects of 2-(indol-3-ylmethyl)-3,3'-diindolylmethane, a major in vivo product of dietary indole-3-carbinol. 1044 93

The molecular mechanisms underlying the apparent "cross-talk" between estrogen receptor (ER)- and arylhydrocarbon receptor (AHR)-mediated activities are unknown. To determine how AHR ligand 2, 3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may inhibit ER action and, conversely, to examine how 17-beta-estradiol (E(2)) affects AHR activity, we examined discrete activities of each receptor, i.e., protein-protein interactions, DNA binding, and transcriptional activation. We report that AHR interacts directly with ERalpha, COUP-TF, and ERRalpha1, in a ligand-specific manner in vitro. Unoccupied or beta-napthoflavone (beta-NF)-occupied AHR showed stronger interaction with ERalpha, COUP-TF, and ERRalpha1 than when AHR was occupied by the partial antagonist alpha-naphthoflavone (alpha-NF), indicating a role for ligand in AHR interaction with these proteins. We also report that AHR interacts with COUP-TF in transfected CV-1 cells. In contrast, the AHR nuclear translocator protein (ARNT) did not interact with COUP-TF, ERRalpha1, or ERalpha. We next examined the interaction of either ERalpha or COUP-TF with a consensus xenobiotic response element (XRE). Purified ERalpha did not bind the consensus XRE, but COUP-TFI bound the consensus XRE, suggesting a role for COUP-TF as a AHR/ARNT competitor for XRE binding. In transiently transfected MCF-7 human breast cancer cells, overexpression of COUP-TFI inhibited TCDD-activated reporter gene activity from the CYP1A1 promoter. TCDD inhibited estradiol (E(2))-activated reporter gene activity from a consensus ERE and from the EREs in the pS2 and Fos genes, and COUP-TFI did not block the antiestrogenic activity of TCDD. The specific interaction of COUP-TF with XREs and AHR together with the inhibition of TCDD-induced gene expression by COUP-TF suggests that COUP-TF may regulate AHR action both by direct DNA binding competition and through protein-protein interactions.
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PMID:The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1. 1062 Mar 35

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.
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PMID:Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. 1065 Sep 64

pS2, a member of the trefoil peptide family, has been suggested to be a gastric-specific tumor suppressor. We examined the expression of pS2 in gastric carcinomas, adenomas and non-neoplastic mucosa and analyzed the DNA methylation in the pS2 promoter. Reduced expression of pS2 was frequently associated with well-differentiated adenocarcinomas. The CpG sites within the promoter region of the pS2 gene were methylated in pS2-negative gastric carcinoma cell lines whereas it was not in pS2-positive cell line. The promoter methylation was detected in gastric carcinoma tissues and intestinal metaplasia with reduced pS2 expression whereas none of the carcinomas with preserved pS2 expression showed the promoter methylation. These findings suggest that reduced expression of pS2 due to the promoter methylation may participate in an early stage of stomach carcinogenesis, especially of well differentiated type.
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PMID:DNA hypermethylation at the pS2 promoter region is associated with early stage of stomach carcinogenesis. 1073 16

An accumulation of multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, cell adhesion molecules, and the growth factor/receptor system is involved in the course of multistep conversion of normal epithelial cells to clinical gastric cancer. Some of them differ depending on the histological type, well-differentiated (intestinal) and poorly differentiated (diffuse) types, suggesting the presence of two distinct genetic pathways. Genetic instability, chromosomal instability (telomere reduction), and immortality (activation of telomerase and expression of telomerase reverse transcriptase: TERT) participate in the initial step of stomach carcinogenesis. Because TERT protein expression precedes the telomerase activities in precancerous lesions, TERT expression may be a prerequisite for telomerase activation. The cyclin E gene is amplified in 15%-20% of gastric cancer. Reduced expression of a cyclin-dependent kinase (CDK) inhibitor, p27Kip1, is frequently found in gastric cancer associated with high grade malignancy. E2F-1, an important downstream target of cyclins/CDKs, is overexpressed in about 40% of gastric carcinomas, whereas gene amplification of E2F-1 rarely occurs. Loss of heterozygosity (LOH) of p73, the p53-related new tumor suppressor gene, preferentially occurs in well-differentiated adenocarcinomas of foveolar type expressing pS2, a gastric-specific trefoil factor, indicating the importance of p73 LOH in the genesis.
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PMID:Genetic and epigenetic alterations in multistep carcinogenesis of the stomach. 1077 29

Trefoil factors are wound-healing peptides important in protection and healing of the human gastrointestinal tract. Their potential for therapy of gastrointestinal ulcers has been established. This study investigated the hypothesis that trefoil factors are also present in human salivary gland. Tissues from surgical biopsy specimens were collected fresh into ice and stored in liquid nitrogen. Breast, stomach, and colon constituted positive controls. Trefoil factor mRNAs were detected by reverse transcription polymerase chain reaction (RT-PCR) or by in situ hybridization (ISH) with formalin-fixed, paraffin-embedded sections. Amplified DNA fragments were ligated into pGEM-T Easy vector and used to transform competent Escherichia coli JM109, allowing sequencing to confirm identity of cloned fragments. Generation of amplifiable cDNA was confirmed using primers specific to the ubiquitously expressed abl gene. By RT-PCR, TFF1 (pS2) mRNA was detected in 14 of 15 glands, TFF3 (hITF) mRNA in 13, and TFF2 (hSP) in only 1 gland. ISH of 15 glands (7 of which had been studied by RT-PCR) showed the same pattern of expression and indicated that TFF1 mRNA was usually expressed at low levels by a few mucous cells, whereas TFF3 was produced abundantly by most mucous cells. There was no difference in patterns of expression comparing parotid, submandibular, and minor mucous glands. Nor was there an obvious relationship between trefoil factor expression and pathology, but those glands not expressing TFF1 or TFF3 had evidence of chronic inflammation or atrophy. Trefoil factors are likely to be important in healing, predisposition to, and therapy of, oral diseases.
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PMID:Trefoil factor expression in normal and diseased human salivary glands. 1082

3,3'-Diindolylmethane (DIM), a major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol (I3C), is a promising anticancer agent present in vegetables of the Brassica genus. We investigated the effects of DIM on estrogen-regulated events in human breast cancer cells and found that DIM was a promoter-specific activator of estrogen receptor (ER) function in the absence of 17beta-estradiol (E(2)). DIM weakly inhibited the E(2)-induced proliferation of ER-containing MCF-7 cells and induced proliferation of these cells in the absence of steroid, by approximately 60% of the E(2) response. DIM had little effect on proliferation of ER-deficient MDA-MB-231 cells, suggesting that it is not generally toxic at these concentrations. Although DIM did not bind to the ER in this concentration range, as shown by a competitive ER binding assay, it activated the ER to a DNA-binding species. DIM increased the level of transcripts for the endogenous pS2 gene and activated the estrogen-responsive pERE-vit-CAT and pS2-tk-CAT reporter plasmids in transiently transfected MCF-7 cells. In contrast, DIM failed to activate transcription of the simple E(2)- and diethylstilbesterol-responsive reporter construct pATC2. The estrogen antagonist ICI 182780 (7alpha-[9-[(4,4,5,5, 5-pentafluoropentyl)sulfonyl]nonyl]-estra-1,3,5(10)-triene-3, 17beta-diol) was effective against DIM-induced transcriptional activity of the pERE-vit-CAT reporter, which further supports the hypothesis that DIM is acting through the ER. We demonstrated that ligand-independent activation of the ER in MCF-7 cells could be produced following treatment with the D1 dopamine receptor agonist SKF-82958 [(+/-)6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepinehydrobromide]. We also demonstrated that the agonist effects of SKF-82958 and DIM, but not of E(2), could be blocked by co-treatment with the protein kinase A (PKA) inhibitor H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide). These results have uncovered a promoter-specific, ligand-independent activation of ER signaling for DIM that may require activation by PKA, and suggest that this major I3C product may be a selective activator of ER function.
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PMID:Ligand-independent activation of estrogen receptor function by 3, 3'-diindolylmethane in human breast cancer cells. 1082 61

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