Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DP-TAT-59, (Z)-2-(4-(1-(4-hydroxyphenyl)-2-(4-isopropylphenyl)-1-butenyl) phenoxy)-N, N-dimethylethylamine, has been reported to inhibit estrogen-stimulated growth of MCF-7 cells as well as rat uterus at lower concentrations than the hydroxymetabolite of tamoxifen (4-OH-TAM). In the present study, the growth of mouse Leydig cell tumor, B-1F cells were also more effectively inhibited by DP-TAT-59 than 4-OH-TAM. Additionally, the expression of estrogen responsive element ligated CAT gene transfected into B-1F cells was also suppressed by DP-TAT-59. Thus, the interaction of DP-TAT-59 with estrogen receptor (ER) was characterized and compared with that of 4-OH-TAM using immature rat and bovine uteri. The dissociation constant of DP-TAT-59 to ER of immature rat uterus was 0.24 nM and was similar to that of 4-OH-TAM (Kd = 0.20 nM) and estradiol (Kd = 0.29 nM). Using sucrose density gradients, the sedimentation constant of DP-TAT-59 with bovine uterus was 4.9S, which was similar to that of estradiol (5.1S) and 4-OH-TAM (5.3S). However, the elution profile of the DP-TAT-59-ER complex from a DEAE-Sephadex column was different for both estradiol-and 4-OH-TAM-ER complexes. These results suggest that ER forms different complexes with DP-TAT-59 than estradiol or 4-OH-TAM, while the ER binding affinity of these compounds are similar to each other.
J Steroid Biochem Mol Biol 1992 Nov
PMID:Interaction of DP-TAT-59, an active metabolite of new triphenylethylene-derivative (TAT-59), with estrogen receptors. 141 85

We have examined the effects of medroxyprogesterone acetate (MPA) and 4-hydroxytamoxifen (OH-TAM) on the cell proliferation and the expression of TGF-alpha and TGF-beta genes in Ishikawa cells and HEC-50 human endometrial adenocarcinoma cells. The effects of exogenous TGF-alpha, TGF-beta and anti-EGF receptor monoclonal antibody on cell proliferation were also determined. Antisense oligonucleotides were used to determine the effects of endogenous expression of TGF-alpha and TGF-beta. In both cell lines, MPA resulted in a time and dose-dependent inhibition of cell proliferation whereas OH-TAM had no effect on HEC-50 cell proliferation. The relative abundance of TGF-alpha mRNA was significantly reduced by MPA in Ishikawa cells but not in HEC-50 cells. In Ishikawa cells, a reduction in TGF-alpha mRNA abundance was observed with OH-TAM under conditions where both inhibition and stimulation of cell proliferation were demonstrated. Anti-EGF receptor monoclonal antibody inhibited Ishikawa cell growth but had little effect on HEC-50 cell proliferation. Exogenous TGF-alpha stimulated proliferation of both cell lines whereas exogenous TGF-beta inhibited proliferation of Ishikawa cells but stimulated proliferation of HEC-50 cells. Antisense oligonucleotides to TGF-beta inhibited proliferation of HEC-50 cells. From these data we conclude that the antiproliferative effects of progestins and OH-TAM on endometrial cancer cells appear to be mediated by different mechanisms.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Regulation of transforming growth factor gene expression in human endometrial adenocarcinoma cells. 153 2

Glandular kallikrein, a trypsin-like serine protease, and prolactin (PRL) are both estrogen-induced proteins in rat anterior pituitary lactotrophs. The estrogen agonist and antagonist effects of tamoxifen (TAM, a triphenylethylene antiestrogen) and chlorotrianisene (TACE, a triphenylethylene estrogen) on anterior pituitary glandular kallikrein and PRL were examined to see if TAM and TACE differentially affect these estrogen response of lactotrophs after in vivo dosing of rats. TAM and TACE acted as partial agonists on PRL and uterine weight induction. In contrast, on glandular kallikrein induction TAM acted as a pure estrogen antagonist and TACE acted as an almost pure antagonist. The results document that both TAM and TACE exhibit protein-specific estrogen agonist and antagonist efficacies in lactotrophs, with the estrogen induction of glandular kallikrein being particularly sensitive to antagonism by TAM in vivo. The marked antiestrogen character of TACE was surprising since TACE has been classified and clinically used as an estrogen.
Mol Cell Endocrinol 1989 Sep
PMID:Differential responses of pituitary kallikrein and prolactin to tamoxifen and chlorotrianisene. 258 66

Purified mRNA's encoding the HLA-A and -B antigen heavy chains or beta 2-microglobulin were prepared from human B lymphoid cells by positive hybridization selection procedures. The role of chain association in the biosynthesis and intracellular transport of HLA-A and -B antigens was investigated by injecting these mRNA species into Xenopus laevis oocytes and following the fates of the translated products by immunoprecipitation. When mRNA encoding beta 2-microglobulin from the B lymphoblastoid cell line MST was coinjected with mRNA encoding the HLA-A and -B antigen heavy chains from the Burkitt lymphoma cell line Daudi, fully assembled class I antigens were detected using the monoclonal antibody W6/32. This result suggested that there may be no defect in the mRNA encoding Daudi HLA-A and -B antigen heavy chains. When the state of maturity of the N-linked glycan units on these class I antigen heavy chains was assessed, they were found to have undergone some processing. In contrast, when mRNA encoding immunoglobulin M (IgM) was injected into oocytes, the glycan units of the IgM heavy chains were found to be in the unprocessed (high mannose) form. This result shows that Xenopus oocytes can process some eukaryotic glycoproteins of exogenous origin.
Mol Immunol 1986 May
PMID:The synthesis and expression of HLA-A and -B antigens in Xenopus laevis oocytes. 309 30

We previously identified a codon 351 (Asp-->Tyr) mutant estrogen receptor (ER) in a tamoxifen-stimulated human breast tumor line. To examine its biological activity, we have constructed cell lines from the ER-negative human breast cancer cell line MDA-MB-231 that stably express either the wild type (S30) or mutant ER (BC-2). ER expression was confirmed by Western blot, ligand-binding studies, and ER-enzyme immunoassay. The growth characteristics of the S30 and BC-2 cell lines were compared when treated with estradiol, fixed-ring 4-hydroxytamoxifen [(fr) 4-OH TAM], or ICI 182,780. (fr) 4-OH TAM is a stable, high affinity tamoxifen analog. Many investigators have recognized that growth of ER-negative cell lines stably transfected with ER is inhibited by estradiol. Similarly, both S30 and BC-2 cell lines are inhibited by estradiol in a concentration-dependent manner. (fr) 4-OH TAM has no effect on S30 proliferation but inhibits the growth of BC-2 cells. The pure antiestrogen ICI 182,780 can block the growth-inhibitory effect of estradiol in both cell lines and the growth-inhibitory effect of (fr) 4-OH TAM in the BC-2 cells. In transient transfection analyses using a luciferase reporter plasmid containing two copies of the Xenopus vitellogenin A2 estrogen response element, estradiol stimulated luciferase transcription through both the wild type and mutant estrogen receptors, while (fr) 4-OH TAM stimulated transcription to a greater extent through the mutant receptor. These results demonstrate that the estrogenicity of (fr) 4-OH TAM is increased by binding to the codon 351 mutant ER, and that ER activation and growth inhibition are associated.
Mol Endocrinol 1995 Aug
PMID:A naturally occurring estrogen receptor mutation results in increased estrogenicity of a tamoxifen analog. 747 79

Estrogen receptors of human endometrial cancer Ishikawa cells were found to be present in moderate amounts (160-200 fmol/mg protein), and to specifically bind moxestrol (R2858) with a very high affinity characterized by a Kd around 60 pM, when measured under equilibrium conditions. The binding specificity respected a decreasing order as follows: estradiol (E2: 100%) > 4-hydroxy-tamoxifen (4OHTAM: 52.7%) > estriol (E3: 5.7%) > estrone (E1: 2.1%) > TAM (0.2%). The induction of alkaline phosphatase activity (APase) used as an estrogen-specific response, confirmed the intrinsic estrogenicity of progestins derived from 19-nor-testosterone (19NT): norethindrone (NOR), norethynodrel and levonorgestrel, at concentrations ranging from 10(-8) to 10(-6) M. The effect of NOR was partially blocked by the antiestrogen 4OHTAM, which was also partially agonistic in this model, but neither by the antiprogestin mifepristone (RU486) nor by the aromatase inhibitor aminoglutethimide. A simulatory effect was also detected at 10(-7) or 10(-6) M with ethindrone, the testosterone- (T) derived progestin homologous to NOR, and with both androgenic parent-compounds, i.e. T and 19NT themselves. In contrast, progesterone (P) derivatives like medroxyprogesterone acetate (MPA) and chlormadinone acetate (CMA) remained totally inactive, as well as 19-nor-progesterone (19NP) itself or its progestagenic derivatives: ORG 2058 and nomegestrol acetate (NOM). Structure-activity relationships deduced from these studies suggest that it is not the absence of the 19-methyl group which can account for the estrogenic potential of the so-called "19-norprogestins", but rather their steroid structure derived from T in a broad sense (including the 19NT derivatives), as opposed to the non-estrogenic therapeutic progestins derived from P like MPA or CMA, or from 19NP like NOM.
J Steroid Biochem Mol Biol 1995 Oct
PMID:Lack of estrogenic potential of progesterone- or 19-nor-progesterone-derived progestins as opposed to testosterone or 19-nor-testosterone derivatives on endometrial Ishikawa cells. 757 23

Internucleosomal DNA fragmentation and cell death were induced dose- and time-dependently by incubation of mouse thymocytes with bis(2,6-dioxopiperazine) derivatives, ICRF-154 and MST-16, inhibitors of topoisomerase II, which do not induce cleavable complex formation. The process was inhibited by actinomycin D and cycloheximide, indicating that the process was an active apoptotic process. Bis(2,6-dioxopiperazine) derivatives have been known to inhibit the etoposide-induced DNA cleavage, but ICRF-154 did not inhibit etoposide-induced apoptosis in thymocytes at 6 h incubation, suggesting that DNA cleavage is not essential for induction of apoptosis by topoisomerase II inhibitors. The alteration of DNA helicity induced by a subtle inhibition of topoisomerase II activity may have an important role in the induction of apoptosis in thymocytes, since topoisomerase II is a major component of the nuclear matrix that can regulate gene expression.
Biochem Mol Biol Int 1994 Jan
PMID:bis(2,6-dioxopiperaxine) derivatives, topoisomerase II inhibitors which do not form a DNA cleavable complex, induce thymocyte apoptosis. 801 76

The influence of estrogens and tamoxifen on estrogen receptor (ER)-positive human breast cancer (MCF-7) cells transplanted into athymic nude mice was investigated. The mice were divided into the following three groups: (1) an E2 group with mice receiving 17 beta-estradiol dipropionate; (2) a TAM group with mice receiving tamoxifen; (3) a control group with mice given no hormone. (1) Tumor growth was significantly increased in the E2 group, but significantly decreased in the TAM group compared to control; (2) the tumor contents of insulin-like growth factor-I (IGF-I) and the rate of IGF-I-positive cells were significantly lower in the E2 group, but significantly higher in the TAM groups compared to control; (3) the IGF-I-positive cell rates were in significant inverse correlation with the [3H]thymidine-labeled cell rates in the E2, TAM and control groups. Thus, the tumor contents of IGF-I and the rate of IGF-I-positive cells were inversely correlated to the tumor growth and the [3H]thymidine-labeled cell rate in this in vivo study, although IGF-I is known to be a mitogen for breast cancer cells in vitro. Further studies are necessary to answer the questions as to the in vivo roles of immunoreactive IGF-I in ER-positive breast cancer.
Mol Cell Endocrinol 1993 Mar
PMID:Influence of hormones on tumor growth, cell kinetics, estrogen receptor and insulin-like growth factor-I-related protein of human breast cancer (MCF-7) cells transplanted in nude mice. 847 69

Quercetin, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and okadaic acid are found in various foods and have been shown to have mutagenic or promoter-like activity. The effects of these three compounds on the transmission of the inactive X chromosome were examined in MST-C6 murine tumor cells, which were derived from hybrid F1 mice from matings between C57BL/6 and MSM mice. Polymerase chain reaction analysis using polymorphic markers on the X chromosome detected transmission distortion of the inactive X chromosome due to nondisjunction as a copy-number imbalance in allelic bands. The cells exposed to all three chemicals (but not untreated cells) exhibited such imbalances at high frequencies under exposure conditions similar to those in previous experiments in which tumor progression and recombination were observed. The cells also showed increased frequencies of tumor formation when subcutaneously injected. These results suggest that the three chemicals are capable of inducing transmission distortion of the inactive X chromosome and that such activity may be a causative factor in promoting the tumorigenicity of MST-C6 cells.
Mol Carcinog 1995 Dec
PMID:Induction of karyotype instability in a murine tumor cell line by quercetin, 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine, and okadaic acid, as revealed by transmission distortion of the inactive X chromosome. 851 20

The estrogen receptor (ER) contains two transcriptional activation domains: AF-1 and AF-2. AF-2 is dependent on a highly species-conserved region of the ER. It has been shown that site-directed point mutations of conserved hydrophobic amino acids within this region reduce estrogen-dependent transcriptional activation. In addition, when these mutated ERs are transfected into HeLa cells, both tamoxifen and ICI 164,384 become strong agonists. The implication is that mutations in this region could account for the tamoxifen-stimulated tumors seen clinically. We performed single stranded conformational polymorphism (SSCP) analysis spanning the entire ER along with DNA sequencing of the AF-2 region of the ER isolated from two different tamoxifen-stimulated breast cancers, MCF-7/TAM and MCF-7/MT2, and a tamoxifen-stimulated endometrial cancer, EnCa 101. In addition, a tamoxifen-stimulated endometrial carcinoma cell line, the Ishikawa cell line, was also studied. There were no mutations found by SSCP analysis and sequencing of all four AF-2 regions also revealed no mutations. Mutations within the AF-2 region of the human ER do not appear to account for the growth of human breast and endometrial carcinomas that are used as reproducible laboratory models of tamoxifen-stimulated growth observed clinically.
J Steroid Biochem Mol Biol 1996 Aug
PMID:An analysis of tamoxifen-stimulated human carcinomas for mutations in the AF-2 region of the estrogen receptor. 891 73


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