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)

The oestrogen-inducible pS2 protein isolated from human breast-cancer cells appears to have prognostic significance in breast-cancer patients. Using both monoclonal and polyclonal pS2 anti-sera, we have carried out an immunocytochemical survey of 9 epithelial cancers. Some degree of specific tumour staining was observed in 4 tissues, the extent varying greatly between specimens. Most (11/13) of the colorectal cancers showed immunoreactivity, as did 4/5 pancreatic carcinomas. In some of these cases, patchy staining was also observed in adjacent non-tumour cells. Two bronchio-alveolar carcinomas showed positivity, but 5 poorly differentiated adenocarcinomas of the lung did not. In the ovary, staining was observed in 3/3 mucinous cystadenocarcinomas but only in 1/8 of the serous type. No reactivity was seen in specimens of salivary gland, kidney, liver, prostate or uterus. This pilot study indicates that pS2 may be a useful marker of adenocarcinomas in human neoplasms apart from those in the breast, and suggests that more extensive surveys might be worthwhile.
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PMID:An immunohistochemical survey of pS2 expression in human epithelial cancers. 173 May 24

Treatment of immature 21-day-old female Sprague-Dawley rats with 17 beta-estradiol (E2) (0.5 microgram/rat) caused a significant increase in uterine wet weight, DNA synthesis, progesterone receptor (PR) binding, and peroxidase activity. At doses as high as 40 mg/rat, the bioflavonoid naringenin did not cause a significant increase in any of these E2-induced responses. However, in rats cotreated with E2 (0.5 microgram/rat) plus naringenin (30 mg/rat); there was a significant decrease in E2-induced uterine wet weight, DNA synthesis, PR binding, and peroxidase activity, indicating that naringenin exhibits antiestrogenic activity in the immature rodent uterus. The binding of uterine nuclear extracts to a 32P-labeled estrogen responsive element (ERE) or progesterone responsive element (PRE) was determined using gel electrophoretic band shift assays. Incubation of [32P]ERE with uterine nuclear extracts from rats treated with naringenin or E2 resulted in the formation of estrogen receptor (ER):ERE complexes; a higher mobility complex was prominent in the extracts from E2-treated rats, whereas a lower mobility complex was observed using nuclear extracts from naringenin-treated animals. There was a significant decrease in the intensity of the E2-induced complex using nuclear extracts from rats treated with E2 plus naringenin. In contrast, transformed cytosol from control rats gave an intense ER:ERE complex, whereas the intensity of the band was decreased markedly using transformed uterine cytosol from treated rats. Formation of a PR:PRE complex was also determined using transformed uterine cytosol. Cytosol from E2-treated rats gave an intense retarded band, whereas only weak bands were observed using cytosols from DMSO- (solvent), naringenin-, or naringenin plus E2-treated cells. The results of in vitro studies showed that 1 nM E2 increased (3- to 4-fold) the growth of MCF-7 human breast cancer cells, whereas 1-1000 nM naringenin had no effect on cell proliferation. In cells cotreated with 1 nM E2 plus 1000 nM naringenin, there was a significant decrease in E2-induced cell growth. In MCF-7 cells transiently transfected with a pS2 promoter-regulated luciferase reporter gene, naringenin exhibited weak estrogenic activity. In cells cotreated with 0.1 or 1.0 microM naringenin plus 1 nM E2, naringenin inhibited E2-induced luciferase activity. The results of these studies confirmed that naringenin is a weak estrogen that also exhibits partial antiestrogenic activity in the female rat uterus and MCF-7 human breast cancer cells.
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PMID:Naringenin: a weakly estrogenic bioflavonoid that exhibits antiestrogenic activity. 750

The six-cysteine P-domain motif forms the basic repeat unit of a growing family of mucin-associated peptides. A precursor for a human secretory polypeptide has been discovered by molecular cloning and deduced to have a single P-domain, termed hP1.B. The pre-pro-peptide has 67% amino acid identity with rat intestinal trefoil factor. We find, using the techniques of RNA analysis and in situ hybridization, that this P-domain peptide is expressed in the human gastrointestinal tract, where a number of pathological conditions affect its expression, and surprisingly find it is expressed in the uterus also. In the intestine, hP1.B is expressed by goblet cells, but in Crohn disease this peptide is synthesized and secreted additionally by the ulcer-associated cell lineage that is known to secrete two other trefoil peptides, pS2 and spasmolytic polypeptide (hSP). In the stomach, hP1.B mRNA is relatively scarce but is more abundant in foci of intestinal metaplasia and near to ulceration. Mucin-rich epithelial cells in hyperplastic polyps of the colon also express this peptide. The discovery of this P-domain peptide and its expression in association with mucins support the hypothesis that P-domains with mucins may subserve related functions in the maintenance and repair of mucosal function.
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PMID:hP1.B, a human P-domain peptide homologous with rat intestinal trefoil factor, is expressed also in the ulcer-associated cell lineage and the uterus. 834 3

The estrogenic action of some persistent organochlorine pesticide residues may play a role in the progression of hormonally responsive tumors of the breast and uterus. The prototypical xenoestrogen o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT) acts by binding and activating the estrogen receptor (ER). The present study focuses attention on the mechanisms through which another organochlorine compound, beta-hexachlorocyclohexane (beta-HCH), exerts estrogen-like effects in human breast cancer cells. Both o,p'DDT and beta-HCH stimulated proliferation in a dose-dependent manner in the ER-positive cell lines MCF-7 and T47D but not in the ER-negative lines MDA-MB231, MDA-MB468, and HS578T. Both compounds produced an increase in the steady state level of pS2 mRNA in MCF-7 cells. These responses were equal in magnitude to the maximal effect of estradiol, and they were inhibited by inclusion of the antiestrogen ICI164384. On the other hand, when tested in a competitive binding assay, beta-HCH did not displace 17beta-[3H]estradiol from the ER even at a concentration that was 40,000-fold higher than the tracer steroid. Furthermore, nuclear retention of the ER during homogenization procedures was induced by a 2- or 24-h treatment of MCF-7 cells with o,p'-DDT and 17beta-estradiol but not by treatment with beta-HCH; this indicates that beta-HCH nether activates the ER, nor is it converted intracellularly to an ER ligand. Transcriptional activation by beta-HCH occurs in estrogen-responsive GH3 rat pituitary tumor cells transfected with a luciferase reporter construct driven by a complex 2500-bp portion of the PRL gene promoter; this trans-activation response is inhibited by inclusion of ICI164384. However, beta-HCH is ineffective in stimulating a reporter construct driven only by a consensus estrogen response element and a minimal promoter derived from the herpes simplex virus thymidine kinase gene. Thus, beta-HCH cannot act on a simple, single estrogen response element; rather, it requires the combinatorial regulation found in a complex promoter. These data are consistent with the notion that beta-HCH stimulation of cell proliferation and gene expression is ER dependent, but its action is not through the classic pathway of binding and activating the ER. beta-HCH may represent a new class of xenobiotic that produces estrogen-like effects through nonclassic mechanisms and, therefore, may be of concern with regard to breast and uterine cancer risk.
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PMID:Novel estrogenic action of the pesticide residue beta-hexachlorocyclohexane in human breast cancer cells. 896 93

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds induce a broad spectrum of biochemical and toxic responses and disrupt multiple endocrine pathways. Research in this laboratory has focused on characterizing aryl hydrocarbon receptor (AhR)-mediated antiestrogenicity in the rodent uterus and mammary and in human breast cancer cells. TCDD inhibits multiple estrogen (E2)-induced responses in these tissues including development or growth of human mammary and endometrial cancer cells, carcinogen-induced mammary cancer in rats, and mammary cancer in mice bearing breast cancer cell xenografts. The mechanisms of AhR-mediated antiestrogenicity are complex; however, studies on the molecular biology of cross-talk between the AhR and estrogen-receptor (ER) signaling pathways have been initiated using several E2-regulated genes as models. The results indicate that the nuclear AhR complex targets specific genomic core inhibitory dioxin responsive elements (iDREs) in promoter regions of some E2-responsive target genes to inhibit hormone-induced transactivation. The pS2, cathepsin and c-fos genes have functional iDREs, whereas the iDRE in the progesterone receptor gene promoter was not functional. Research has also focused on development of AhR-based antiestrogens which inhibit mammary tumor development and growth but do not exhibit prototypical AhR-induced toxic responses.
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PMID:Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms. 1002 76

To determine the molecular mechanisms underlying the "cross talk" between the activity of 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), which binds to arylhydrocarbon receptor (AHR) and estradiol (E2)-liganded estrogen receptor (ER), we first examined the initial step of estrogen action, ligand binding to ER. None of the AHR ligands tested, i.e. TCDD, benzo[a]pyrene, 3,3',4,4',5-pentachlorobiphenyl, beta-naphthoflavone, or alpha-naphthoflavone, bound to ER alpha. We report the first examination of TCDD interaction with ER beta: TCDD did not displace E2 from ER beta. We then examined a second possible mechanism, i.e. direct inhibition of ER alpha binding to estrogen response elements (EREs) by the AHR/AHR nuclear translocator (ARNT) complex. The AHR/ARNT heterodimer did not bind either a full or half-site ERE. However, AHR/ARNT bound specifically to oligomers containing naturally occurring EREs derived from the human c-fos, pS2, and progesterone receptor (PR) gene promoters that include xenobiotic response element (XRE)-like sequences. In contrast, neither purified E2-liganded-ER from calf uterus or recombinant human ER alpha bound a consensus XRE. TCDD inhibited E2-activated reporter gene activity from a consensus ERE and from EREs in the pS2, PR, and Fos genes in transiently transfected MCF-7 human breast cancer cells. However, this inhibition was not reciprocal since E2 did not inhibit TCDD-stimulated luciferase activity from the CYP1A1 promoter in transiently transfected MCF-7 or human endometrial carcinoma HEC-1A cells. We propose that at least part of the mechanism by which the AHR/ARNT complex inhibits estrogen action is by competitively inhibiting ER alpha binding to imperfect ERE sites, adjacent to or overlapping XREs.
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PMID:The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements. 1061 2

TFF-peptides (i.e. TFF1, TFF2, TFF3; formerly P-domain peptides, trefoil factors) have been established as secretory products typical of the gastrointestinal tract. Their synthesis has recently been recognized in a number of mucin-producing epithelial cells, for example, of the respiratory tract, the salivary glands, the uterus and of the conjunctiva. They have a pivotal role in maintaining the surface integrity of these delicate epithelia as constituents of mucus gels as well as by their anti-apoptotic properties and their motogenic activity modulating cell migratory processes. The latter is important for rapid healing in particular of gastrointestinal and respiratory epithelia by a process termed "restitution". On the other hand, one of these peptides--namely TFF3--has been detected as a new neuropeptide of the human hypothalamo-pituitary axis where it is synthesized in oxytocinergic neurons of the paraventricular and supraoptic nuclei. From there it is transported to the posterior pituitary where it is released into the blood stream. Synthesis of TFF-peptides also occurs pathologically as result to chronic inflammatory diseases, for example of the gastrointestinal tract. Aberrant synthesis of TFF-peptides is observed in many tumors.
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PMID:Molecular medicine of TFF-peptides: from gut to brain. 1119 8

TFF-peptides (formerly P-domain peptides, trefoil factors) are typical secretory products of mucin-producing cells and are thought to influence the rheological properties of mucous gels. Here, the localization of these peptides in the human uterus was investigated. An analysis of TFF-peptides mRNA by the polymerase chain reaction revealed TFF3 mainly in the endocervix and smaller amounts in the endometrium. TFF1 and TFF2 mRNA was detectable occasionally in the endocervix and very rarely in the endometrium. Western blot analysis detected only TFF3 in tissue extracts of the endocervix and as a constituent of human cervical mucus. Immunofluorescence localized TFF3 in the surface epithelium of the endocervix and in gland-like structures of the cervical epithelium.
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PMID:Synthesis and localization of the mucin-associated TFF-peptides in the human uterus. 1123 98

The "TFF domain" is an ancient cysteine-rich shuffled module forming the basic unit for the family of secretory TFF peptides (formerly P-domain peptides and trefoil factors). It is also an integral component of mosaic proteins associated with mucous surfaces. Three mammalian TFF peptides are known (i.e., TFF1-TFF3); however, in Xenopus laevis the pattern is more complex (xP1, xP4.1, xP4.2, and xP2). TFF peptides are typical secretory products of a variety of mucin-producing epithelial cells (e.g., the conjunctiva, the salivary glands, the gastrointestinal tract, the respiratory tract, and the uterus). Each TFF peptide shows an unique expression pattern and different mucin-producing cells are characterized by their specific TFF peptide/secretory mucin combinations. TFF peptides have a pivotal role in maintaining the surface integrity of mucous epithelia in vivo. They are typical constituents of mucus gels, they modulate rapid mucosal repair ("restitution") by their motogenic and their cell scattering activity, they have antiapoptotic effects, and they probably modulate inflammatory processes. Pathological expression of TFF peptides occurs as a result of chronic inflammatory diseases or certain tumors. TFF peptides are also found in the central nervous system, at least in mammals. In particular, TFF3 is synthesized from oxytocinergic neurons of the hypothalamus and is released from the posterior pituitary into the bloodstream.
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PMID:Cell type specific expression of secretory TFF peptides: colocalization with mucins and synthesis in the brain. 1183 92

Tamoxifen, a breast cancer therapeutic, is a tissue-selective estrogen receptor modulator (SERM), which acts as an antiestrogen in the mammary tissue and displays estrogenic activity in other tissues such as bone and uterus. In order to understand the mechanisms underlying the antiestrogenic effect of this prototype SERM, we performed an analysis of the cofactors that interact with ER complexed with 4-hydroxytamoxifen (OHT) at natural target genes in a human breast tumor cell line MCF-7. Employing chromatin immunoprecipitation (ChIP), we observed that treatment with OHT rapidly induces the binding of ERalpha to the E-responsive promoter regions of pS2 and c-myc genes. Promoter-bound OHT-complexed ERa coordinately recruited the components of a multiprotein complex containing the corepressor NCoR, histone deacetylase 3 (HDAC3), and a WD40-repeat protein TBL1. Surprisingly, the OHT-complexed ERalpha also recruited a chromatin-remodeling NuRD complex in which histone deacetylase 1 (HDAC1) is associated with several polypeptides including metastasis-associated protein 1/2 (MTA1/2), and SWI2/SNF2-related ATPase Mi2. Kinetic studies revealed that following OHT addition the recruitment of these HDAC complexes to pS2 or the c-myc promoter occurs in a sequential manner; the NCoR-HDAC3 complex is recruited earlier than the NuRD complex. Serial ChIP experiments indicated that the ER-NCoR-HDAC3 and ER-NuRD complexes are distinct, and they do not occupy the target gene promoter simultaneously. We also established a close temporal link between the appearance of the HDAC complexes at the E-responsive regions of pS2 and c-myc promoters, local hypoacetylation of specific lysine residues in N-terminal tails of histones H3 and H4, and disappearance of RNA polymerase II from the target gene loci. Collectively, our studies indicated that transcriptional repression by tamoxifen-bound ER at E-regulated gene promoters involves a dynamic interplay of multiple distinct chromatin-modifying/remodeling complexes.
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PMID:Recruitment of distinct chromatin-modifying complexes by tamoxifen-complexed estrogen receptor at natural target gene promoters in vivo. 1472 73


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