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

The effect of two anti-oestrogens, 4-OH tamoxifen and ICI 164,384, on growth and progesterone receptor (PR) concentration was investigated in the endometrial carcinoma cell line, Ishikawa. Growth stimulation in response to 4-OH tamoxifen was antagonized by ICI 164,384, the latter having no agonist effect when used as a single agent. Similarly, ICI 164,384 antagonized oestradiol-stimulated cell growth. PR was significantly increased following treatment with 4-OH tamoxifen, this response being antagonized in the presence of ICI 164,384. Oestradiol increased PR, although to a lesser extent than did 4-OH tamoxifen; the effect of oestradiol on PR was also antagonized by ICI 164,384. Used as a single agent, ICI 164,384 induced a moderate but statistically significant increase in PR, thus demonstrating partial agonist activity. This agonist property of ICI 164,384 may provide a mechanism of maintaining PR, which is down-regulated during conventional progestin therapy, without undesirable mitogenic activity.
J Mol Endocrinol 1991 Jun
PMID:The effect of anti-oestrogens on cell growth and progesterone receptor concentration in human endometrial cancer cells (Ishikawa). 188 84

Three monoclonal antibodies, H222, H226 and D547, which provided evidence of the structural transformation and change in exposure of the functional domains of the oestrogen receptor from fetal guinea-pig uterus upon activation, were used to study the receptor bound to the anti-oestrogens 4-hydroxytamoxifen and ICI 164,384. No differences in the structure of non-activated 4-hydroxytamoxifen- and ICI 164,384-receptor complexes, as compared with the oestradiol-receptor complex, were detected by the three monoclonal antibodies. When heated at 28 degrees C, both anti-oestrogen-receptor complexes became capable of binding the D547 antibody, which reacts selectively with the activated receptor; however, this binding was lower than that of the oestradiol-receptor complex. The interaction with the H226 antibody showed that anti-oestrogens can induce receptor dimerization, but to a lesser extent than oestradiol. In addition, both anti-oestrogen-receptor complexes can bind to DNA-cellulose and are retained in nuclei from intact cells at 28 degrees C, but less efficiently than the oestradiol-receptor complex. On the other hand, the nuclear receptor seems to have a similar dimeric structure when bound to either anti-oestrogens or oestradiol, as detected by the three monoclonal antibodies. The data suggest that 4-hydroxytamoxifen and ICI 164,384 induce and impaired activation of the oestrogen receptor; this difference, although quantitative rather than qualitative, might be related to the partial agonistic action of these anti-oestrogens in the fetal guinea-pig uterus.
J Mol Endocrinol 1991 Aug
PMID:Studies on the activation of the oestrogen receptor bound to the anti-oestrogens 4-hydroxytamoxifen and ICI 164,384 by using three monoclonal antibodies. 189 45

The cathepsin D gene is differentially regulated by estrogens in hormone responsive breast cancer cells, by progestins in normal human endometrium and is highly expressed but not regulated by these steroids in estrogen (RE)- and progesterone receptor (RP)-negative breast cancer cells. We have stably transfected the RE-negative breast cancer cell line MDA-MB 231 and the Hela cell line with an expression vector for the human RE. The endogenous cathepsin D which is constitutively expressed was further stimulated by estradiol. However, the growth of both cell lines was not stimulated by estradiol and could not be inhibited by the antiestrogen ICI 164,384. By contrast, the cathepsin D gene in the estrogen responsive Ishikawa endometrial cancer cell line was unresponsive to estrogen or to progesterone even following stable transfection of expression vectors for the RP (both A and B isoforms). We conclude that the cathepsin D gene is potentially responsive to estrogens in MDA-MB 231 and Hela cells, which therefore express all of the transcriptional machinery (except the RE) necessary for this regulation. By contrast, cathepsin D remains unresponsive to estrogen and progesterone in Ishikawa cells. The cathepsin D gene is one of the first examples of an endogenous steroid responsive gene which can be controlled by steroids following stable transfection of a steroid receptor.
J Steroid Biochem Mol Biol 1991
PMID:Hormonal regulation of cathepsin D following transfection of the estrogen or progesterone receptor into three sex steroid hormone resistant cancer cell lines. 195 26

The electrophysiological effects mediated by beta 2-adrenoceptor stimulation were studied in sheep cardiac Purkinje fibers. beta 2-Adrenoceptor stimulation was achieved by using isoproterenol (ISO) in the presence of the highly selective beta 1-antagonist CGP 20712A. ICI 118,551 was used as a selective beta 2-antagonist. In driven preparations, ISO (0.1 to 1 microM) caused a positive inotropic effect which was associated with the shortening of action potential duration and was completely abolished only by the simultaneous presence of CGP 20712A (0.3 microM) and ICI 118,551 (50 nM). In previously quiescent preparations, ISO (0.1 to 1 microM) induced spontaneous activity in 15 out of 24 preparations. In the presence of CGP 20712A (0.3 microM) only five preparations out of 24 became automatic when exposed to ISO, and their rate of firing was significantly reduced (13 +/- 4 vs. 43 +/- 6 beats/min, P less than 0.05) with respect to ISO alone. CGP 20712A completely abolished the steepening of diastolic depolarization and the increase of the pacemaker current caused by ISO (0.1 to 1 microM). The beta 2-antagonist ICI 118,551 (50 nM) completely failed to modify the effect of ISO on the rate of spontaneous firing, the slope of diastolic depolarization and the pacemaker current. On the other hand, the increase of oscillatory afterpotential (OAP) amplitude caused by ISO in strophanthidin-treated preparations was significantly reduced only by the beta 1-antagonist CGP 20712A, but not by the beta 2-antagonist ICI 118,551. These results demonstrate that beta 2-adrenoceptors are functionally present in sheep Purkinje fibers where their stimulation consistently causes a positive inotropic effect. However, beta 2-adrenoceptors do not appear to affect the processes of normal automaticity, and do not greatly contribute to triggered activity due to OAPs.
J Mol Cell Cardiol 1990 Aug
PMID:Electrophysiological characterization of cardiac beta 2-adrenoceptors in sheep Purkinje fibers. 197 22

In a series of compounds with H2-antihistaminic activity, a conformational analysis was performed based on force field calculations. The drugs studied were cimetidine, ranitidine, famotidine, roxatidine and the conformationally more restricted ICI127032. For the compounds containing a flexible chain, the local minima conformations and the global minimum conformation were calculated. These conformations were used for a systematic structural comparison with all energetically allowed conformations of the ICI derivative, with regard to the best fit of the common structural features. In this way a pharmacophore could be developed consisting of four parts: (1) a polar planar group, uncharged at physiological pH; (2) a hydrophobic part formed by aromatic systems or flexible chains; (3) an--under physiological conditions--protonated nitrogen atom; and (4) a substructure, which contains a hydrogen bond donor site and a hydrogen bond acceptor site in a specific spatial arrangement.
J Comput Aided Mol Des 1990 Dec
PMID:Conformational analyses on histamine H2-receptor antagonists. 198 29

Guinea pig lung membranes were extracted with 1% digitonin and yielded a preparation that contained soluble leukotriene D4 (LTD4) receptor. Specific binding of the high affinity radiolabeled receptor antagonist [3H]ICI-198615 to the soluble LTD4 receptor was time dependent and reversible. The dissociation constant (Kd) and the density (Bmax) of [3H]ICI-198615 binding to the soluble LTD4 receptor was 0.2 +/- 0.08 nM and 380 +/- 40 fmol/mg of protein, respectively. Radioligand competition studies showed several classes of structurally diverse, functionally defined, receptor antagonists competed with [3H]ICI-198615 binding to the soluble receptor. The rank order of potency and specificity of these antagonists in binding to the soluble receptor were equivalent to those determined from the membrane-bound receptor binding assay and from the smooth muscle contraction assay. Binding of LTD4 to the soluble receptor was observed, in the competition assay, only in the low affinity state (Ki = 2 microM). Size-exclusion chromatography of the soluble LTD4 receptor showed that the apparent molecular weight of the LTD4 receptor in digitonin micelle was approximately 300,000.
Mol Pharmacol 1990 Jan
PMID:Post soluble binding to the leukotriene D4 receptor from guinea pig lung membranes. 215 9

To prepare large amounts of the human estrogen receptor (ER) for biochemical and biophysical studies we have employed the cloned ER sequences to construct Chinese hamster ovary (CHO) cell line derivatives that overexpress the receptor. We have employed an efficient expression vector (SV40 enhancer, human metallothionein IIA promoter) and a new system of gene amplification based on the human metallothionein IIA gene and stepwise selection in cadmium. Cells from the initial transfected pools, before gene amplification, had as much or more ER than human MCF7 cells and responded to the subsequent stepwise cadmium selection and amplification with increases in ER levels to about 2 million receptors/cell. Cell lines isolated from these pools are stable for human ER expression and display up to 6 million receptors/cell, or about 0.4% of the total cell protein. The CHO receptor activates a transfected reporter gene in responses to estrogen, is down-regulated in response to estrogens, displays the same electrophoretic mobility as the MCF7 receptor, and is free of degradation as initially extracted. CHO cells displaying 3 million or more human ER/cell (but not cells with lower levels) flatten and stop growing within the first 24 h after exposure to physiological estrogen concentrations. After several days in estrogen the majority of the cells lyse. The antiestrogen 4-hydroxytamoxifen also causes cell death, but another antiestrogen, ICI 164,384, is without toxic effect. The basis for these phenomena are unknown, but mutants isolated for survival of estrogen treatment have lost receptor expression, thereby confirming the role of receptor in cell death.
Mol Endocrinol 1990 Oct
PMID:Construction of cell lines that express high levels of the human estrogen receptor and are killed by estrogens. 217 15

The number of nuclear and cytosolic estrogen receptors (ER) per cell and the steady-state levels of the mRNA encoding a tissue-specific, estrogen-inducible protein (FOSP-1) were measured as a function of time following the addition of estradiol-17 beta (E2) to primary cultures of Xenopus oviduct cells. After a lag period of about 12 h, 10(-9) to 10(-7) M E2 caused a 10 to 15-fold increase in FOSP-1 mRNA by 60 h, whereas it was only 2-fold with 10(-7) M progesterone. Under the same conditions, E2 doubled its own total receptor content within the first 12 h, reaching a 4-fold increase in nuclear ER by 48 h. Cycloheximide treatment in the presence of 10(-7) M estradiol reduced the functional ER content by 75.90%. Treatment with the anti-estrogen ICI 164,384 of oviduct cells in which FOSP-1 mRNA was pre-induced to high levels with the hormones caused a drastic reduction in nuclear ER and a total loss of FOSP-1 mRNA in 72 h. The close correlation between the kinetics of autoinduction of ER and the induction of FOSP-1 mRNA, as was shown earlier for vitellogenin mRNA in hepatocytes (Perlman et al. (1984) Mol. Cell. Endocrinol. 38, 151-161), strongly suggests that Xenopus egg protein gene activation by estrogen requires the up-regulation of its own receptor by the hormone.
Mol Cell Endocrinol 1990 Jul 09
PMID:Autoinduction of estrogen receptor is associated with FOSP-1 mRNA induction by estrogen in primary cultures of Xenopus oviduct cells. 221 28

The present data confirm the very complicity of the response of antiestrogen when this compound is studied in different experimental conditions. The new and potent antiestrogen ICI 164,384, which is considered as a full antagonist in most models studied, concerning the progesterone receptor in the isolated cells of the uterus and vagina of guinea-pig acts as a real agonist. However, this compound antagonizes cell proliferation, progesterone receptor, and decreases the concentration of estradiol in different hormone-dependent mammary cancer cell lines. Another interesting aspect is the response of the antiestrogen 4-hydroxytamoxifen which in isolated cells of very close tissues such as the uterus and vagina is an antagonist for the former and agonist for the latter concerning the progesterone receptor. In conclusion, the present data added new information in the complicity of the mechanism of action of antiestrogens, but using new models interesting possibilities are opened to understand their responses and their mechanism.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:Antiestrogen action in mammary cancer and in fetal cells. 225 39

To investigate the effect of ligand (be it hormone, antihormone, or no hormone) on the interaction between estrogen receptor (ER) and chromatin, we have used formaldehyde as a cross-linking agent in intact MCF-7 human breast cancer cells. After a 1- to 2-h hormone treatment, the cells are exposed for 8 min to formaldehyde, which is added directly to their culture medium to minimize environmental perturbation. Nuclei are prepared from formaldehyde-treated cells and their contents are fractionated on CsCl density gradients to separate DNA-protein complexes from free protein. Peak gradient fractions are assayed for the presence of specific proteins by immunoblot of sodium dodecyl sulfate-polyacrylamide gel patterns. Using this approach, we find that 0.15% formaldehyde is optimal for cross-linking ER to chromatin. We detect ER and the large subunit of RNA polymerase II with DNA from formaldehyde-treated, but not from untreated cells. On the other hand, actin (a cytoplasmic protein) and small nuclear ribonucleoprotein particle proteins (nuclear RNA binding proteins) are not cross-linked to DNA. Therefore, cross-linking appears to be selective and fractionation is efficient. Interestingly, we detect similar levels of ER (as well as RNA polymerase II) with DNA from formaldehyde-treated cells, regardless of whether the cells are preexposed to estrogen (17 beta-estradiol at 10(-8) M), antiestrogen (ICI 164,384 at 10(-7) or 10(-6) M), or no hormone. These results, using covalent cross-linking in intact cells, indicate that both ligand-occupied and unoccupied ER are associated with chromatin.
Mol Endocrinol 1990 Nov
PMID:Cross-linking of estrogen receptor to chromatin in intact MCF-7 human breast cancer cells: optimization and effect of ligand. 228 Jul 70


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