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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The estrogen receptor (ER) functions as a ligand-activated transcription factor which mediates the actions of estrogens and antiestrogens in target tissues. Other investigators have shown that artificial point mutations in the transcriptional activation domain AF-2 of the ligand binding domain (LBD) of the ER can increase the estrogenic properties of antiestrogens, determined by transcriptional activation of estrogen-responsive reporter constructs cotransfected into cells. Although these data provide valuable information about ER function there is no evidence that these mutations occur naturally. We have taken a different approach and examined the naturally occurring codon 351 asp --> tyr mutation in the LBD of ER to stimulate the expression of an endogenous target gene. This approach avoids dependence on artificial reporter constructs and their idealized estrogen response elements (EREs). In this report we describe the regulation of transforming growth factor alpha (TGF alpha) mRNA by estradiol and the antiestrogens keoxifene and ICI 182,780 in our stable transfectants of ER-negative MDA-MB-231 breast cancer cells, which express either the wild-type (S30 cells) or codon 351 asp --> tyr mutant ER (BC-2 cells). The mutant receptor was identified in a tamoxifen-stimulated human breast tumor. Our results demonstrate, for the first time, that a naturally occurring mutation in the ER changes the pharmacology of the antiestrogen keoxifene by increasing estrogenic activity, and that keoxifene exhibits a gene-specific estrogen-like effect with mutant ER but not with wild-type ER. The pure antiestrogen ICI 182,780 maintained complete antagonistic activities in both ER transfectants, demonstrating that its action is unaffected by the mutation.
J Steroid Biochem Mol Biol 1997 Mar
PMID:Estrogenic activity is increased for an antiestrogen by a natural mutation of the estrogen receptor. 921 16

This work has allowed a comparison between the interaction of two principal plasma estradiol-binding proteins, serum albumin and Sex Hormone Binding Globulin (SHBG), with human breast cancer cells in culture (MCF-7 and MDA-MB 231), using a protocol which protects the integrity of cell structure. We showed that serum albumin was highly internalized by cells whereas SHBG interacted essentially at the plasma membrane level, and this whatever the contents of the receptor estrogen cells. If, by its high plasma concentration, serum albumin is internalized in a non-specific way and can thus fit into intracellular traffic, SHBG, by its membrane binding, seems to have a specific action toward target cells.
Cell Mol Biol (Noisy-le-grand) 1997 Jun
PMID:Use of confocal microscopy to localize the SHBG interaction with human breast cancer cell lines--a comparison with serum albumin interaction. 922 Jan 43

Although lipid phosphoric acid mediators such as lysophosphatidic acid (LPA) are now recognized widely as intercellular signaling molecules, the medicinal chemistry of these mediators is poorly developed. With the goal of achieving a better understanding of the structure activity relationships in LPA, we have synthesized and tested a series of LPA analogs that lack the 2-hydroxyl moiety. Our series consisted of compounds with 2, 3, or 4 carbon diol or amino alcohol backbones and oleoyl or palmitoleoyl acyl groups. These molecules cannot be acylated further to form phosphatidic acids, nor do they have chiral centers. The rank order potency of these compounds in mobilization of calcium in MDA MB-231 cells suggested a maximum optimal chain length of 24-25 atoms. However, high potency for the inhibition of adenylyl cyclase in these cells was achieved only by one compound that also contained a dissociable proton five bond lengths from the phosphorus atom. That compound, N-oleoyl-2-hydroxyethyl-1-phosphate, was nearly equipotent to 1-oleoyl LPA in both assays. The striking mimicry of LPA by the ethanolamine-based compound and the presence of fatty acid amides in tissue prompts us to propose that phosphorylated N-acyl ethanolamides occur naturally.
Mol Pharmacol 1997 Jul
PMID:Structure/activity relationships in lysophosphatidic acid: the 2-hydroxyl moiety. 922 15

Peptides with high affinities and specificities for numerous proteins and nucleic acids have been previously identified from random peptide bacteriophage display libraries. Here, random peptide bacteriophage display libraries were used to identify sequences that bound the cancer-associated Thomsen-Friedenreich glycoantigen (T antigen). The T antigen, present on most malignant cells, contains an immunodominant Gal beta1 --> 3GalNAc alpha disaccharide unmasked on the surfaces of most carcinomas. This antigen has been postulated to be involved in tumor cell aggregation and metastasis. Two 15 amino acid random peptide bacteriophage display libraries were affinity selected with glycoproteins displaying T antigen on their surfaces. Sequence analysis revealed that many of the peptides shared homology with sugar recognition sites in several carbohydrate-binding proteins. A comparison of affinity selected sequences from both libraries yielded a common motif (W-Y-A-W/F-S-P) rich in aromatic amino acids. Four peptides, corresponding to the affinity selected sequences, were chemically synthesized and characterized for their carbohydrate recognition properties. The synthetic peptides exhibited high specificities and affinities to T antigen displayed on asialofetuin or conjugated to bovine serum albumin (Kd = 5 nM for MAP-P30 binding to asialofetuin) as well as free T-antigen disaccharide in solution (Kd = 10 microM for MAP-P30, 20 microM for P10). Two peptides, P30 and P10, demonstrated high affinities and specificities for both asialofetuin and T antigen in solution. Iodination of a lone tyrosine residue in each sequence dramatically reduced their abilities to bind T antigen, suggesting that the tyrosine residue plays an important role in carbohydrate recognition. That these peptides are of functional significance is evidenced by the ability of both P30 and P10 to inhibit asialofetuin-mediated melanoma cell aggregation in vitro and to compete with peanut lectin for binding to T antigen displayed on the surface of MDA-MB-435 breast carcinoma cells in situ.
J Mol Biol 1997 Jul 18
PMID:Characterization of peptides that bind the tumor-associated Thomsen-Friedenreich antigen selected from bacteriophage display libraries. 923 4

The levels of lipid peroxidation product (malondialdehyde = MDA) and vitamin C and the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were determined in the liver and its mitochondrial fraction, in the rats 2 and 18 hr after the injection of phorone, a glutathione (GSH) depleting agent. GSH levels decreased in liver homogenate and its mitochondrial fraction after 2 hr of phorone treatment, but these values returned to normal levels at 18 hr. In GSH depleted conditions, hepatic vitamin C levels increased, GSH-Px and SOD activities remained unchanged in mitochondrial and post-mitochondrial fractions. These results indicate that GSH depletion per se does not influence lipid peroxidation and GSH-Px and SOD activities in the liver and the mitochondrial fraction.
Res Commun Mol Pathol Pharmacol 1997 Jun
PMID:Mitochondrial lipid peroxides and antioxidant enzymes in the liver following phorone-induced glutathione depletion. 926 94

Protein tyrosine kinases activate the STAT (signal transducer and activator of transcription) signaling pathway, which can play essential roles in cell differentiation, cell cycle control, and development. However, the potential role of the STAT signaling pathway in the induction of apoptosis remains unexplored. Here we show that gamma interferon (IFN-gamma) activated STAT1 and induced apoptosis in both A431 and HeLa cells, whereas epidermal growth factor (EGF) activated STAT proteins and induced apoptosis in A431 but not in HeLa cells. EGF receptor autophosphorylation and mitogen-activated protein kinase activation in response to EGF were similar in both cell lines. The breast cancer cell line MDA-MB-468 exhibited a similar response to A431 cells, i.e., STAT activation and apoptosis correlatively resulted from EGF or IFN-gamma treatment. In addition, in a mutant A431 cell line in which STAT activation was abolished, no apoptosis was induced by either EGF or IFN-gamma. We further demonstrated that both EGF and IFN-gamma induced caspase 1 (interleukin-1beta converting enzyme [ICE]) gene expression in a STAT-dependent manner. IFN-gamma was unable to induce ICE gene expression and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1-deficient cells (U3A). However, ICE gene expression and apoptosis were induced by IFN-gamma in U3A cells into which STAT1 had been reintroduced. Moreover, both EGF-induced apoptosis and IFN-gamma-induced apoptosis were effectively blocked by Z-Val-Ala-Asp-fluoromethylketone (ZVAD) in all the cells tested, and studies from ICE-deficient cells indicated that ICE gene expression was necessary for IFN-gamma-induced apoptosis. We conclude that activation of the STAT signaling pathway can induce apoptosis through the induction of ICE gene expression.
Mol Cell Biol 1997 Sep
PMID:Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. 927 10

A GC-rich oligonucleotide containing an estrogen responsive element (ERE) half-site from the heat shock protein 27 (Hsp 27) gene promoter (-105 to -84) [ie. GGGCGGG(N)10GGTCA; Sp1(N)10ERE] forms a complex with the Sp1 and estrogen receptor (ER) proteins. Moreover, promoter-reporter constructs containing this sequence (-108 to -84 or -108 to +23) are also estrogen-responsive. Mutation of the ERE half-site in the Hsp 27-derived oligonucleotides did not result in loss of estrogen responsiveness in transient transfection studies, suggesting that estrogen inducibility was mediated through the Sp1-DNA motif. Gel mobility shift assays using 32P-labeled wild type and ERE mutant Sp1(N)10ERE and consensus Sp1 oligonucleotides showed that Sp1 protein formed a DNA-protein complex with all three nucleotides, and the intensities of retarded bands were enhanced by coincubation with wild type ER and 11C-ER, which does not contain the DNA-binding domain. ER mutants in which N-terminal (19C-ER) and C-terminal (15C-ER) regions were deleted did not enhance Sp1-DNA binding or hormone-induced transactivation of GC-rich promoter-reporter constructs in ER-negative MDA-MB-231 cells, whereas both wild type and 11C-ER restored inducibility. Immunoprecipitation studies also confirmed that the Sp1 and ER proteins physically interact. The interaction of the Sp1 and ER proteins and the resulting enhanced Sp1-DNA binding is observed in the presence or absence of estrogen (hormone-independent), whereas transactivation of promoter-reporter constructs is estrogen-dependent. Thus, the results illustrate a new estrogen-dependent transactivation pathway that involves ER-protein interactions and is ERE-independent.
Mol Endocrinol 1997 Oct
PMID:Functional synergy between the transcription factor Sp1 and the estrogen receptor. 932 40

All-trans-retinoic acid (trans-RA) and other retinoids exert anticancer effects through two types of retinoid receptors, the RA receptors (RARs) and retinoid X receptors (RXRs). Previous studies demonstrated that the growth-inhibitory effects of trans-RA and related retinoids are impaired in certain estrogen-independent breast cancer cell lines due to their lower levels of RAR alpha and RARbeta. In this study, we evaluated several synthetic retinoids for their ability to induce growth inhibition and apoptosis in both trans-RA-sensitive and trans-RA-resistant breast cancer cell lines. Our results demonstrate that RXR-selective retinoids, particularly in combination with RAR-selective retinoids, could significantly induce RARbeta and inhibit the growth and induce the apoptosis of trans-RA-resistant, RAR alpha-deficient MDA-MB-231 cells but had low activity against trans-RA-sensitive ZR-75-1 cells that express high levels of RAR alpha. Using gel retardation and transient transfection assays, we found that the effects of RXR-selective retinoids on MDA-MB-231 cells were most likely mediated by RXR-nur77 heterodimers that bound to the RA response element in the RARbeta promoter and activated the RARbeta promoter in response to RXR-selective retinoids. In contrast, growth inhibition by RAR-selective retinoids in trans-RA-sensitive, RAR alpha-expressing cells most probably occurred through RXR-RAR alpha heterodimers that also bound to and activated the RARbeta promoter. In MDA-MB-231 clones stably expressing RAR alpha, both RARbeta induction and growth inhibition by RXR-selective retinoids were suppressed, while the effects of RAR-selective retinoids were enhanced. Together, our results demonstrate that activation of RXR can inhibit the growth of trans-RA-resistant MDA-MB-231 breast cancer cells and suggest that low cellular RAR alpha may regulate the signaling switch from RAR-mediated to RXR-mediated growth inhibition in breast cancer cells.
Mol Cell Biol 1997 Nov
PMID:Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids. 934 23

Estrogen receptor (ER)-negative MDA-MB-468 human breast cancer cells were stably transfected with wild-type human ER and utilized as a model for investigating estrogen- and aryl hydrocarbon (Ah)-responsiveness. Treatment of the stably transfected cells with 10 nM 17 beta-estradiol (E2) resulted in a significant inhibition (> 60%) of cell proliferation and DNA synthesis, which was blocked by 10(-7) M ICI 182 780. Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0/G1 (from 68.8 to 89.4) and decreased cells in S (from 18.4 to 3.4) and G2/M (from 12.8 to 7.2) phases of the cell cycle. The effects of E2 on the major cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors, retinoblastoma protein (RB), E2F-1, and cyclin-dependent kinase activities were also investigated in the stably transfected MDA-MB-468 cells. The results demonstrated that the growth inhibitory effects of 10(-8) M E2 in ER stably transfected MDA-MB-468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis, including significant induction of the cyclin-dependent kinase inhibitor p21cip-1 ( > 4-fold increase after 12 h) and decreased E2F1 and PCNA protein levels. These results show that the growth-inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0/G1 and inhibition of DNA synthesis.
Mol Cell Endocrinol 1997 Sep 30
PMID:17 beta-Estradiol-mediated growth inhibition of MDA-MB-468 cells stably transfected with the estrogen receptor: cell cycle effects. 935 72

The aim of the study was to determine whether dietary iron within the normal range is (i) responsible for oxidative changes in the liver, erythrocytes and plasma; and (ii) make the heart more susceptible to ischemia/reperfusion injury. Female rats were allocated to four groups according to diet supplemented with either 15, 35, 150, or 300 mg iron/kg diet. After 4 months the following statistical difference in the two higher dietary groups were observed compared to the lower ones: (i) decreased antioxidant concentrations in liver, plasma and erythrocytes (alpha-tocopherol and ascorbic acid); (ii) increased plasma nitrite concentration; (iii) ischemia/reperfusion elevated LMWI and MDA concentrations and decreased ascorbate concentrations. This study clearly showed that increased dietary iron concentration causes oxidative changes in plasma, erythrocytes and liver. Higher dietary iron aggravated the outcome of ischemia/reperfusion injury as indicated by an elevated malondialdehyde concentration in the two higher dietary iron groups.
Res Commun Mol Pathol Pharmacol 1997 Sep
PMID:Dietary iron alters liver, erythrocyte and plasma antioxidant and nitrite levels, and also sensitizes the heart to ischemia/reperfusion. 938 94


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