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

Estradiol is active in proliferation and differentiation of sex-related tissues like ovary and breast. Glandular steroid metabolism was for a long time believed to dominate the estrogenic milieu around any cell of the organism. Recent reports verified the expression of estrogen receptors in "non-target" tissues as well as the extraglandular expression of steroid metabolizing enzymes. Extraglandular steroid metabolism proved to be important in the brain, skin and in stromal cells of hormone responsive tumors. Aromatase converts testosterone into estradiol and androstenedione into estrone, thereby activating estrogen precursors. The group of 17 beta-hydroxysteroid dehydrogenases catalyzes the oxidation and/or reduction of the forementioned compounds, e.g. estradiol/estrone, thereby either activating or inactivating estradiol. Aromatase is expressed and regulated in the human THP 1 myeloid leukemia cell line after vitamin D/GMCSF-propagated differentiation. Aromatase expression is stimulated by dexamethasone, phorbolesters and granulocyte/macrophage stimulating factor (GMCSF). Exons I.2 and I.4 are expressed in PMA-stimulated cells only, exon I.3 in both PMA- and dexamethasone-stimulated cells. Vitamin D-differentiated THP 1 cells produce a net excess of estradiol in culture supernatants, if testosterone is given as aromatase substrate. In contrast, the 17 beta-hydroxysteroid dehydrogenase type 4 (17 beta-HSD 4) is abundantly expressed in unstimulated THP 1 cells and is further stimulated by glucocorticoids (2-fold). The expression is unchanged after vitamin D/GMCSF-propagated differentiation. 17 beta-HSD 4 expression is not altered by phorbolester treatment in undifferentiated cells but is abolished after vitamin D-propagated differentiation along with downregulation of beta-actin. Protein kinase C activation therefore appears to dissociate the expression of aromatase and 17 beta-HSD 4 in this differentiation stage along the monocyte/phagocyte pathway of THP 1 myeloid cells. The expression of steroid metabolizing enzymes in myeloid cells is able to create a microenvironment which is uncoupled from dominating systemic estrogens. These findings may be relevant in the autocrine, paracrine or iuxtacrine cellular crosstalk of myeloid cells in their respective states of terminal differentiation, e.g. in bone metabolism and inflammation.
J Steroid Biochem Mol Biol 1995 Dec
PMID:Expression and regulation of aromatase and 17 beta-hydroxysteroid dehydrogenase type 4 in human THP 1 leukemia cells. 854 82

Estradiol-liganded estrogen receptor (E2-ER) binds EREs with a stoichiometry of one E2-ER dimer per estrogen response element (ERE). In contrast, although 4-hydroxytamoxifen (4-OHT)-liganded ER (4-OHT-ER) binds EREs with high affinity, its saturation ERE binding capacity is consistently half that of E2-ER, giving an apparent stoichiometry of one 4-OHT-ER monomer per ERE. Here we show that one molecule of 4-OHT ligand dissociates from the ER dimer apparently during the process of binding to DNA. Under equilibrium conditions, the type I antiestrogen tamoxifen aziridine (TAz), covalently attached to ER (TAz-ER), binds a single ERE with high affinity (Kd = 0.27 nM), comparable to that of E2-ER and 4-OHT-ER. In contrast to 4-OHT-ER, the ERE binding stoichiometry of TAz-ER was identical to that of E2-ER: one dimeric receptor per ERE. By measuring [3H]ligand that was initially bound to ER, a significant loss of [3H]4-OHT from ER was detected after ERE binding, whereas all [3H]E2 or [3H]TAz remained ER-bound. These results confirm that one molecule of 4-OHT ligand dissociates from the ER dimer as a consequence of ERE binding. Binding of 4-OHT and TAz are likely to induce a conformation in ER dimers that alters their capacity for gene activation. Upon ER binding to DNA, this conformation reveals itself by allowing 4-OHT dissociation, and predictably would allow TAz dissociation were it not bound covalently.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Dissociation of 4-hydroxytamoxifen, but not estradiol or tamoxifen aziridine, from the estrogen receptor as the receptor binds estrogen response element DNA. 864 17

We and others previously reported that up-regulation of retinoic acid receptor-alpha (RAR alpha) RNA and protein levels is elicited by estrogen in human breast cancer cells. We set out to determine the mechanism by which estrogen up-regulates RAR alpha. Cloning of 500 bp of the human (h) RAR alpha 1 promoter has been reported previously; we obtained this 500-bp DNA sequence by PCR techniques from human genomic DNA and tested its activity in the context of a luciferase-containing reporter vector in Hep G2 cell contransactivation assays. Estradiol elicited a 6- to 8-fold increase in luciferase activity from the reporter vector driven by hRAR alpha promoter sequence between -491 and +36 bp that was dependent on the presence of contransfected estrogen receptor (ER). Analysis of various truncated versions of this promoter sequence indicated that two regions of the sequence are sensitive to estrogen stimulation. The first resides in the region -49 to -79 bp upstream from the transcription start site and conferred approximately 2-fold activation by estrogen. This region does not contain a consensus estrogen response element, and ER binding to this DNA sequence was not observed. The second responsive sequence lies at -455 to -491 bp and conferred in additional 4- to 6-fold activation by estrogen. This upstream sequence contains two A/TGGTCA half-sites; however, direct binding of ER to this sequence was not observed. Additionally, ER DNA-binding domain mutants that are not capable of binding to DNA were just as effective as wild type ER in their ability to confer estrogen responsiveness to the RAR alpha promoter, implying that ER DNA-binding ability is not required for the estrogen-induced increase in transcriptional activity. Mutation of either half-site or of an additional immediate downstream sequence in the context of the -491 to +36 bp construct reduced the luciferase activity induction by estrogen from 6-fold to 1.5- to 2-fold. Placement of the region between -455 to -491 bp upstream of an SV40 promoter-driven luciferase vector conferred approximately 20- to 30-fold stimulation of luciferase activity by estrogen in an ER-dependent manner. The ER antagonists, 4-hydroxy-tamoxifen, keoxifene, and ICI 164384, each acted as weak agonist via the hRAR alpha promoter in contransactivation assays, exhibiting 20-30% of the efficacy that was demonstrated by estradiol. Interestingly, upon treatment of MCF7 cells with estradiol or the ER antagonists, increased levels of RAR alpha RNA and protein were observed with the antagonists as well as with estrogen.
Mol Endocrinol 1996 May
PMID:Estrogen and estrogen receptor antagonists stimulate transcription from the human retinoic acid receptor-alpha 1 promoter via a novel sequence. 873 79

The developmental and hormonal regulation of three male-dominant rat hepatic sulfotransferases (STs) was studied in male and female rats. ST1A1 (phenol ST) mRNA levels increased gradually in both male and female rats after birth until puberty and then declined to a greater extent in female than in male rats. In adult rats, hepatic ST1A1 mRNA levels were approximately 2-3-fold higher in males than in females. However, ST1C1 and ST1E2 mRNAs (corresponding to N-hydroxy-2-acetylaminofluorene ST and estrogen ST, respectively) increased dramatically at puberty in male rats but remained low in female rats. ST1C1 and ST1E2 expression is > 10-fold higher in adult male than in adult female rats. Estradiol, progesterone, and testosterone administration to hypophysectomized rats did not have marked effects on hepatic ST expression. Hypophysectomy decreased ST1A1 gene expression in rat liver, but neither intermittent growth hormone (GH) injection (male pattern) nor continuous GH infusion (female pattern) restored ST1A1 mRNA levels. ST1C1 gene expression was abolished by hypophysectomy and reversed by GH injection. Hypophysectomy did not dramatically decrease hepatic ST1E2 mRNA in male rats but markedly increased ST1E2 expression in female rats. GH infusion (female pattern) in hypophysectomized male and female rats decreased ST1E2 mRNA levels. Prolactin increased hepatic ST1C1 mRNA levels, which is similar to the effect of GH. It is concluded that the three male-dominant rat hepatic STs are regulated differently because the developmental pattern of ST1A1 is markedly different from that for ST1C1 and ST1E2. The high expression of ST1C1 in adult males is determined by male GH secretory pattern, whereas male dominance of ST1E2 is due to the suppressive effect of female GH secretory pattern in adult female rats.
Mol Pharmacol 1996 Sep
PMID:Ontogeny and hormonal basis of male-dominant rat hepatic sulfotransferases. 879 95

Cystatin-related protein (CRP) and the C3 component of prostatic binding protein (C3) are synthesized in vivo under androgen control in the lacrimal gland and ventral prostate of adult male rats [1,2]. Androgen administration to female or 7-day castrated male rats, which do not express CRP, can induce its synthesis [3]. In this study, we show androgen-dependent expression of CRP1 and C3 in primary cultures of acinar cells of the lacrimal gland of female rats. Addition of androgens to the culture medium results in the synthesis and secretion of both proteins in a time- and dose-dependent way. Estradiol or progesterone are unable to induce their expression. Dexamethasone in low concentrations and present as a basal component of the serum free defined medium, is needed to sensitize the culture system for androgens. In high concentrations, this synthetic glucocorticoid seems to play a similar role as androgens in CRP1 and C3 regulation.
Mol Cell Endocrinol 1996 Aug 09
PMID:Androgenic induction of cystatin-related protein and the C3 component of prostatic binding protein in primary cultures from the rat lacrimal gland. 889 21

The activities of estrogen sulfotransferase, estrogen sulfatase and estradiol 17beta-dehydrogenase change considerably in the guinea pig uterine compartment during gestation. This study was undertaken to inquire if the chorion membrane could influence the pattern of estrogen resulting when substrates were applied to the fetal surface of the chorion while it was attached, late in gestation, to the uterine wall. This tissue system resulted in a differential handling of estrone and estradiol. Estrone was largely excluded from the tissue, remaining mainly in free steroidal form. Estradiol was considerably converted to its 3-sulfate which was mainly retained by the chorion. Parallel experiments with chorion and uterus separately failed to discriminate between the two substrates. Hydrolysis of estrone sulfate and estradiol 3-sulfate was similar in all three tissue systems. It appears that the interaction of chorion with uterus late in gestation causes a difference in tissue action towards the two steroid substrates of closely related structure. The results suggest a limitation in tissue uptake of estrone compared with estradiol, or a much greater sulfotransferase activity towards estradiol. Whole cytosols of late gestational chorion catalyzed sulfation of estradiol at about double the velocity of estrone. This may only partly account for the difference in the intact chorion-uterine tissue system.
J Steroid Biochem Mol Biol 1996 Dec
PMID:Sulfation by guinea pig chorion and uterus: differential action towards estrone and estradiol. 901 Mar 53

Estrogens play a critical role in the etiology of found breast cancer. Estradiol promotes the growth of breast cancer cells in vivo and in vitro. Exogenous estrogens in both the environment and in the human diet increase the growth of breast cancer cells in vitro. A role for xenoestrogens in breast cancer etiology has been proposed but remains controversial. We examined the effects of the xenoestrogenic pesticide 1,1,1-trichloro-2,2-bis(chlorophenyl)ethane (DDT) on estrogen-receptor (ER)-positive MCF-7 and T-47D human breast cancer cells as well as on ER-negative HS 578Bst breast cancer cells and rat liver cells. Estradiol and DDT were found to increase the growth of MCF-7 cells in the presence of insulin. The activity of cyclin-dependent kinase (Cdk)2 increased in growth-arrested T-47D and MCF-7 cells treated with beta-estradiol or DDT. The steroidal antiestrogen ICI 182,780 prevented both growth and Cdk2 activation induced by estradiol or DDT. Increased phosphorylation of Cdk2 and the retinoblastoma protein (pRb1O5) was observed in ER-positive cells treated with DDT or estradiol. Cdk2 activity was not affected by DDT or estradiol in ER-negative HS 578Bst breast cancer cells or in rat liver epithelial cells. Cyclin D1 protein synthesis was increased by DDT and estradiol in MCF-7 cells. DDT and estradiol-induced ER-dependent transcriptional activation of estrogen response elements (EREs) in stably transfected MVLN cells, and ERE activation by low doses of DDT was increased by insulin. These findings suggest that DDT can stimulate breast cancer cells to enter into the cell cycle by directly affecting key regulatory elements. The relative potency of DDT in inducing cell-cycle progression appears to be only 100-300 times less than that of estradiol when measured in the presence of insulin. Therefore, the cancer risks associated with DDT exposure may be greater than first thought, especially when additional mitogenic stimuli are present.
Mol Carcinog 1997 Feb
PMID:DDT mimicks estradiol stimulation of breast cancer cells to enter the cell cycle. 904 86

Leukemia inhibitory factor (LIF) has been shown to be essential for the implantation of mouse blastocysts. The present study was designed to determine how LIF protein was hormonally regulated in rabbit and mouse uterus using immunohistochemistry. In unmated rabbits, LIF protein was at a low level in the uterine epithelium and glands, and up-regulated by progesterone alone or estradiol-17 beta and progesterone combined. Estradiol-17 beta alone had no apparent effect. In ovariectomized mice, the level of LIF protein was very low in the uterine epithelium and glands, and was up-regulated by estradiol-17 beta alone or estradiol-17 beta and progesterone combined. Progesterone alone had no apparent effect. These results suggest that LIF protein is differentially regulated in rabbit and mouse uterus by progesterone and estrogen, respectively. This would explain the high level of LIF protein observed in uterine epithelium and glands prior to blastocyst implantation in the two species with different hormonal requirements for implantation.
Mol Reprod Dev 1996 Apr
PMID:Differential hormonal regulation of leukemia inhibitory factor (LIF) in rabbit and mouse uterus. 905 38

Ortho-substituted polychlorinated biphenyls (PCBs) have been shown to alter microsomal Ca2+ transport by selective interaction with ryanodine receptors (RyRs) of muscle sarcoplasmic reticulum (SR) and brain endoplasmic reticulum. The mechanism underlying the actions of PCBs on Ca2+ transport is further elucidated with skeletal SR enriched in Ry1R. Disruption of the association between immunophilin FKBP12 and Ry1R with FK 506 or rapamycin completely eliminates PCB 95-enhanced binding of [3H]ryanodine (IC50 approximately 35 microM) to Ry1R and PCB 95-induced release of Ca2+ from actively loaded SR vesicles (IC50 approximately 11 microM), demonstrating a FKBP12-dependent mechanism. FK 506 selectively eliminates PCB 95-induced Ca2+ release from SR because Ry1R maintains responsiveness to caffeine and Ca2+. PCB 95 and FK 506 are used to examine the relationship between ryanodine-sensitive Ca2+ channels and ryanodine-insensitive Ca2+ leak pathways present in SR vesicles. Micromolar ryanodine completely blocks ryanodine-sensitive Ca2+ efflux but neither eliminates the ryanodine-insensitive Ca2+ leak unmasked by thapsigargin nor enhances the loading capacity of SR vesicles. PCB 95 alone enhances thapsigargin evoked Ca2+ release and therefore diminishes the loading capacity of SR vesicles. However, in the presence of micromolar ryanodine, PCB 95 dose-dependently eliminates the Ca2+ leak unmasked by thapsigargin and significantly enhances the loading capacity of SR vesicles. The actions of PCB 95 on SR-loading capacity are additive with those of FK 506. Structural specificity for these novel actions are further demonstrated with coplanar PCB 126, which is inactive toward Ry1R and lacks the ability to alter the Ca2+ leak pathway. The results reveal that FKBP12 relates ryanodine-insensitive Ca2+ "leak" and ryanodine-sensitive Ca2+ channel efflux pathways of SR by modulating distinct conformations Ry1R complexes. Noncoplanar PCBs, like PCB 95, alter SR Ca2+ buffering by an FKBP12-mediated mechanism. An immunophilin-based mechanism could account for the toxic actions attributed to certain noncoplanar PCB congeners.
Mol Pharmacol 1997 May
PMID:Noncoplanar PCB 95 alters microsomal calcium transport by an immunophilin FKBP12-dependent mechanism. 914 7

Seasonal levels of LH, FSH, testosterone (T), estradiol, progesterone (P), and prolactin (PRL) were determined in the plasma of five adult bulls, and five barren and four pregnant cows of Alaskan reindeer (Rangifer tarandus), which were sampled every 3 weeks for 54 weeks. The male reproductive axis was sequentially activated; LH peaked in May-June (2 ng/ml), FSH in June (51 ng/ml), and T in September (11.8 ng/ml). LH levels in females reached a maximum in both groups at the end of August (the beginning of the rut). Seasonal variation in FSH was minimal in pregnant cows, but exhibited one elevation (41 ng/ml) in barren ones in November. T levels in cows remained at barely detectable levels. The decrease of T values observed in both groups in December and March was not significant. PRL peaked in May in cows (135 ng/ml pregnant, 140 ng/ml non-pregnant) and in June in bulls (92 ng/ml). Estradiol was highest in bulls in the rut (August), in non-pregnant cows in January and in pregnant cows in April, shortly before parturition. P levels in the pregnant cows rose from September and peaked (9 ng/ml) shortly before parturition in April. In the non-pregnant females P values increased and decreased several times before peaking (5 ng/ml) in March. In the males, the variation of T and estradiol levels correlated relatively well with the antler cycle but in the females the variation of neither estradiol, progesterone nor T appeared to be related to mineralization or casting of antlers.
Comp Biochem Physiol B Biochem Mol Biol 1997 Feb
PMID:Seasonal levels of reproductive hormones and their relationship to the antler cycle of male and female reindeer (Rangifer tarandus). 915 90


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