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)

Studies on estrogen receptor (ER)-positive human breast cancer cell lines have shown that estrogen treatment positively modulates the expression of the genes encoding transforming growth factor-alpha (TGF alpha), 52-kDa cathepsin-D, and pS2. To determine whether these genes would be similarly regulated by estrogens in normal human mammary epithelial cells, we stably transfected immortal nontumorigenic human mammary epithelial cells with an ER-encoding expression vector. ER-negative tumor cells were also transfected for comparison. Levels of TGF alpha and 52-kDa cathepsin-D mRNA were enhanced by estrogen treatment of both ER-transfected immortal and tumorigenic cells, demonstrating that the ER by itself is sufficient to elicit estrogenic regulation of the expression of these genes. In contrast, expression of the pS2 gene was detected only in the ER-transfected tumor cells. The ER in both cell lines is capable of recognizing the pS2 promoter, however, since estrogen enhanced the activity of an introduced pS2-CAT reporter plasmid in transient expression analyses. These and other experiments with somatic cell hybrids between the immortal cells and ER+/pS2+ MCF-7 tumor cells, where pS2 gene expression is extinguished, support the conclusion that the immortal nontumorigenic cells encode gene products that block endogenous pS2 expression. These results also imply that such repressors are not active in the tumor cells.
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PMID:Induction of estrogen-regulated genes differs in immortal and tumorigenic human mammary epithelial cells expressing a recombinant estrogen receptor. 166 44

Thyroid hormone (T3) and estradiol (Est) modulate biological processes by binding to nuclear receptor proteins that, through interactions with specific response elements in the regulatory regions of genes, modulate gene transcription. Est stimulation of estrogen receptor (ER)-positive breast carcinoma cell growth occurs through its ability to bind to the ER and activate gene transcription. We now report that physiological concentrations of T3 significantly enhance Est stimulation of growth of a number of human breast carcinoma cell lines. The effect of T3 is specific for Est stimulation of growth and has no effect on insulin-like growth factor-I stimulation of growth. The effect of T3 on enhancing Est-mediated growth was specifically blocked by the addition of ligands inducing retinoid X receptor (RXR) homodimer receptor formation, suggesting that RXR-thyroid nuclear receptor (TR) heterodimer formation is required for the T3-mediated effect on estradiol-stimulated growth. Four thyroid nuclear receptors have been described in tissues, TR alpha 1, alpha 2, beta 1, and beta 2. Breast carcinoma cells were found to express TR beta 1 and TR alpha 2 mRNA and very low levels of TR alpha 1 mRNA. T3 did not increase ER mRNA or protein levels and did not enhance Est-mediated increases in gene transcription of a number of genes, i.e., transforming growth factor-alpha and pS2 which contain estrogen-response elements (EREs) in their regulatory regions. However, T3 enhanced Est-stimulated ERE-TK-CAT activity. Thus significant cross-talk appears to occur between the TRs and ER and T3 appears to enhance Est-mediated gene transcription.
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PMID:Thyroid hormone enhancement of estradiol stimulation of breast carcinoma proliferation. 773 50

Members of the trefoil family of peptides are generally small stable secreted molecules, structurally related by the presence of one, or up to six, compact 6-cysteine motifs. Several trefoil peptides are expressed in mammalian gut and Xenopus gut and skin, often in association with mucins. Chronic ulcerative conditions of the gut, such as Crohn's disease, result in the growth of glandular structures of the ulcer-associated cell lineage (UACL) that secrete epidermal growth factor/urogastrone, transforming growth factor-alpha, and at least three trefoil peptides [pS2, human spasmolytic polypeptide (hSP), and intestinal trefoil factor (hITF/hP1.B)]. Neuroendocrine and goblet cells near the UACL are "recruited" into expressing pS2 and hSP, but the purpose of this concerted expression is unclear. A role in mucosal healing has been proposed. Biological functions of trefoil peptides have been difficult to establish. Pancreatic spasmolytic polypeptide of porcine origin inhibits gastric acid secretion and smooth muscle contraction and is a growth factor for some cultured cells, but pS2, once thought to be breast cancer specific, is not a mitogen. Recombinant trefoil peptides have allowed localization of binding sites and will allow structure-activity relationships to be studied, once the functions are clear.
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PMID:Trefoil peptides: a newly recognized family of epithelial mucin-associated molecules. 836 6

Overexpression of transforming growth factor-alpha (TGF-alpha) in the gastric mucosa of metallothionein-TGF alpha (MT-TGF alpha) transgenic mice leads to a marked alteration in the ontogeny of the fundic cellular lineages. Induction of the transgene leads to the over-production of mucous cells with a concomitant diminution in the development of parietal cell and chief cell lineages. We have sought to define more precisely the mucous cell lineages involved in the mucous cell hyperplasia in MT-TGF alpha mice by investigating the expression of trefoil peptides in MT-TGF alpha mice. MT-TGF alpha mice and their non-transgenic littermates were treated with cadmium sulfate beginning at 13 days of age. Animals were then sacrificed at intervals over the following 2 weeks and gastric mucosa was examined for expression of trefoil peptides and TGF alpha by immunohistochemistry and in situ hybridization. No TGF alpha mRNA expression could be demonstrated by in situ hybridization in non-transgenic mice. In MT-TGF alpha mice, in situ grains for TGF alpha mRNA were detected at the base of fundic glands in 13 day old animals, whereas the expression was observed more widely in the mucosa of older animals (28 days). TGF alpha immunoreactivity was observed in foveolar mucous cells and residual parietal cells in MT-TGF alpha mice at all ages. By in situ hybridization, pS2 mRNA was detected in the surface mucous cells in normal gastric mucosa. In MT-TGF alpha mice, pS2 mRNA was found throughout the expanded foveolar region. By in situ hybridization, spasmolytic peptide (SP) expression was observed in the region of the progenitor zone in both groups of mice. By immunohistochemistry, SP expression was noted in a broad band of mucous neck cells deep to the progenitor zone. No gastric expression of intestinal trefoil factor (ITF) was noted in either group of mice. The results demonstrate that the expansion of the foveolar mucous cell compartment in MT-TGF alpha mice is due to the hyperplasia of normal surface cells expressing their particular mucin-associated trefoil peptide, pS2.
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PMID:Expression of trefoil peptides in the gastric mucosa of transgenic mice overexpressing transforming growth factor-alpha. 896 16

Genistein significantly inhibited cell growth (IC50 around 10 microM) of MCF-7, MDAMB-231 and HBL-100 cell lines, but not of skin-derived fibroblasts and counteracted the growth-stimulatory effects exerted by estradiol and growth factors. It abolished the paracrine stimulation observed in MCF-7 cells in co-culture with MDAMB-231 or fibroblasts. Genistein-treated cells accumulated in the S and G2/M phases of the cell cycle and underwent apoptosis. Genistein decreased tyrosine phosphorylation induced upon treatment with transforming growth factor-alpha. Finally, genistein bound the estrogen receptor (ER) (relative affinity constant Kd = 4 nM), induced pS2 and cathepsin-D transcription and increased nuclear ER levels.
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PMID:Genistein in the control of breast cancer cell growth: insights into the mechanism of action in vitro. 975 Dec 67

We compared the oestrogenic and anti-oestrogenic properties of the two well-known phyto-oestrogens, genistein and quercetin, on the oestrogen-sensitive breast cancer cell line MCF-7. Genistein exerted a biphasic effect on growth of MCF-7 cells, stimulating at low and inhibiting at high concentrations, whereas quercetin was only growth inhibitory. At doses which did not inhibit cell growth, respectively 5 and 1 microM, genistein and quercetin counteracted oestrogen- and transforming growth factor-alpha-promoted cell growth stimulation. Furthermore, genistein promoted transcription of the oestrogen-regulated genes pS2 and cathepsin-D, whereas quercetin interfered with the oestrogen-induced expression of the proteins. In in vitro binding experiments, genistein competed with oestradiol for binding to the oestrogen receptor (ER), but quercetin did not. Quercetin and genistein down-regulated cytoplasmic ER levels and promoted a tighter nuclear association of the ER, but only genistein was able to up-regulate progesterone receptor protein levels. In gel mobility assays, ER preincubation with oestradiol or with the two phyto-oestrogens led to the appearance of the same retarded band, excluding differences between the various complexes in binding to the consensus sequence. The data allowed us to conclude that quercetin acts like a pure anti-oestrogen, whereas genistein displays mixed agonist/antagonist properties, and to formulate a hypothesis on the possible mechanism of action of such phyto-oestrogens.
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PMID:The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function. 1037 65

CITED1, a CBP/p300-binding nuclear protein that does not bind directly to DNA, is a transcriptional coregulator. Here, we show evidence that CITED1 functions as a selective coactivator for estrogen-dependent transcription. When transfected, CITED1 enhanced transcriptional activation by the ligand-binding/AF2 domain of both estrogen receptor-alpha (ERalpha) and ERbeta in an estrogen-dependent manner, but it affected transcriptional activities of other nuclear receptors only marginally. CITED1 bound directly to ERalpha in an estrogen-dependent manner through its transactivating domain, and this binding activity was separable from its p300-binding activity. CITED1 was strongly expressed in nulliparous mouse mammary epithelial cells and, when expressed in ER-positive MCF-7 breast cancer cells by transduction, exogenous CITED1 enhanced sensitivity of MCF-7 cells to estrogen, stabilizing the estrogen-dependent interaction between p300 and ERalpha. The estrogen-induced expression of the transforming growth factor-alpha (TGF-alpha) mRNA transcript was enhanced in the CITED1-expressing MCF-7 cells, whereas estrogen-induced expression of the mRNA transcripts for progesterone receptor or pS2 was not affected. Chromatin immunoprecipitation assay revealed that endogenous CITED1 is recruited to the chromosomal TGF-alpha promoter in MCF-7 cells in an estrogen-dependent manner but not to the pS2 promoter. These results suggest that CITED1 may play roles in regulation of estrogen sensitivity in a gene-specific manner.
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PMID:Selective coactivation of estrogen-dependent transcription by CITED1 CBP/p300-binding protein. 1158 Nov 64

We previously established that the trefoil peptides (TFFs) pS2, spasmolytic polypeptide, and intestinal trefoil factor are involved in cellular scattering and invasion in kidney and colonic cancer cells. Using the chorioallantoic membrane (CAM) assay and the formation of tube-like structures by human umbilical vein endothelial cells (HUVEC) plated on the Matrigel matrix substratum, we report here that TFFs are proangiogenic factors. Angiogenic activity of TFFs is comparable to that induced by vascular endothelial growth factor, leptin, and transforming growth factor-alpha. Stimulation of angiogenesis by pS2 in the CAM assay is blocked by pharmacological inhibitors of cyclooxygenase COX-2 (NS-398) and epidermal growth factor receptor (EGF-R) tyrosine kinase (ZD1839), but is independent of KDR/Flk-1 and thromboxane A2 receptors. In contrast, the morphogenic switch induced by pS2 in HUVEC cells could be inhibited by the specific KDR heptapeptide antagonist ATWLPPR and by inhibitors of COX-2 and EGF-R signaling. These results implicate TFFs in the formation of new blood vessels during normal and pathophysiological processes linked to wound healing, inflammation, and cancer progression in the digestive mucosa and other human solid tumors associated with aberrant expression of TFFs.
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PMID:Trefoil peptides as proangiogenic factors in vivo and in vitro: implication of cyclooxygenase-2 and EGF receptor signaling. 1252 7

Quality of ulcer healing (QOUH) is defined as ideal ulcer healing featuring with the fine granular ulcer scar, high functional restoration and the resistance to recurrence. This study was designed to compare the rates of QOUH achievement in rat gastric ulcer model between acid suppressant treated group and gastroprotectant treated group accompanied with elucidations of molecular mechanisms. Serosal injection of acetic acids for generating gastric ulcer and intraperitoneal (ip) injection of recombinant interleukin 1-beta (IL-1beta) for recurring healed ulcer was done in SD rats. The 72 rats were divided into three groups according to treatment as follows; Group I, no further treatment, Group II, 8 weeks treatment of omeprazole, and Group III, 8 weeks of gastroprotectant treatment. IL-1beta was administered for ulcer recurrence after 28 weeks of acetic acid injection. At four weeks after gastric ulcerogenesis, 58.3% (7/12) of active gastric ulcer were converted to healing stage in Group III, but 16.7% (2/12) in Group II and none in Group I, for which significant levels of epidermal growth factor, mucin, and pS2/trefoil peptide1 were contributive to these accelerated healings of Group III. ip injections of rIL-1beta (200 microg/kg) at 28 weeks after acetic acid injection led to 100% of ulcer recurrence in Group I and 75.0% in Group II, but only 16.7% of Group III rats showed ulcer recurrence. Significantly attenuated levels of inflammatory cytokines including IL-2, transforming growth factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), nitrotyrosine were responsible for the resistance to ulcer recurrence in Group III. Conclusively, gastroprotectant might be prerequisite in order to achieve ideal QOUH through significant inductions of remodeling.
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PMID:Accelerated Ulcer Healing and Resistance to Ulcer Recurrence with Gastroprotectants in Rat Model of Acetic Acid-induced Gastric Ulcer. 1854 42

Several breast cancer tumor models respond to estradiol (E(2)) by undergoing apoptosis, a phenomenon known to occur in clinical breast cancer. Before the application of tamoxifen as an endocrine therapy, high-dose E(2) or diethystilbesterol treatment was successfully used, albeit with unfavorable side effects. It is now recognized that such an approach may be a potential endocrine therapy option. We have explored the mechanism of E(2)-induced tumor regression in our T47D:A18/PKCalpha tumor model that exhibits autonomous growth, tamoxifen resistance, and E(2)-induced tumor regression. Fulvestrant, a selective estrogen receptor (ER) down-regulator, prevents T47D:A18/PKCalpha E(2)-induced tumor growth inhibition and regression when given before or after tumor establishment, respectively. Interestingly, E(2)-induced growth inhibition is only observed in vivo or when cells are grown in Matrigel but not in two-dimensional tissue culture, suggesting the requirement of the extracellular matrix. Tumor regression is accompanied by increased expression of the proapoptotic FasL/FasL ligand proteins and down-regulation of the prosurvival Akt pathway. Inhibition of colony formation in Matrigel by E(2) is accompanied by increased expression of FasL and short hairpin RNA knockdown partially reverses colony formation inhibition. Classic estrogen-responsive element-regulated transcription of pS2, PR, transforming growth factor-alpha, C3, and cathepsin D is independent of the inhibitory effects of E(2). A membrane-impermeable E(2)-BSA conjugate is capable of mediating growth inhibition, suggesting the involvement of a plasma membrane ER. We conclude that E(2)-induced T47D:A18/PKCalpha tumor regression requires participation of ER-alpha, the extracellular matrix, FasL/FasL ligand, and Akt pathways, allowing the opportunity to explore new predictive markers and therapeutic targets.
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PMID:Estradiol-induced regression in T47D:A18/PKCalpha tumors requires the estrogen receptor and interaction with the extracellular matrix. 1937 79


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