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)

Calbindin-D(9k) (CaBP-9k) is a cytosolic calcium binding protein mainly expressed in duodenum, placenta and uterus. In order to understand the expression pattern and regulation of uterine CaBP-9k gene, the expression of CaBP-9k mRNA and its regulation by estrogen (E2) and progesterone (P4) were investigated in the mouse uterus during late pregnancy (from day 12 to 18) and lactation. The expression levels of uterine CaBP-9k, estrogen receptor alpha (ERalpha) and progesterone receptor (PR) mRNAs were measured by Northern blot analysis. The expression levels of mouse uterine CaBP-9k mRNA gradually increased from pregnancy day 16 (P16), peaked at P18 (6.0-fold vs. P12) and declined at birth and during lactation. The expression levels of ERalpha and PR mRNAs indicated a similar fluctuation as CaBP-9k mRNA, suggesting the role of sex steroids/receptors in the regulation of CaBP-9k gene. To investigate effect of steroid hormone on CaBP-9k mRNA expression, three groups of animals were injected (s.c) with steroid hormone antagonists (RU486, tamoxifen, and ICI182780), respectively. RU486, a P4 antagonist, induced a significant decrease in CaBP-9k mRNA expression at 48 (3.2-fold) and 72 h (3.8-fold). However, tamoxifen and ICI182780, E2 antagonists, had no effect on CaBP-9k mRNA expression. Combined treatment with RU486 and ICI182780 did not further decrease the expression level of CaBP-9k mRNA when compared with RU486 treatment at 48 and 72 h. In addition, the treatment with RU40555, a glucocorticoid/progesterone antagonist, resulted in a decrease at 48 and 72 h following treatment. These results indicate that E2 is not likely involved in the regulation of CaBP-9k gene in the mouse uterus during late pregnancy and lactation. In conclusion, the present results suggest that P4, not E2 is a key regulator of CaBP-9k mRNA expression during late pregnancy and lactation.
Mol Cell Endocrinol 2003 Jul 31
PMID:Mouse calbindin-D(9k) gene expression in the uterus during late pregnancy and lactation. 1289 May 69

The study was undertaken to identify the effect of tamoxifen on the expression and phosphorylation of motility related proteins in the adult male rats. For this purpose, tamoxifen, at a dose of 0.4 mg/kg/day, was administered per os to the male rats for a period of 60 days. Cauda sperms, epididymal fluid and tissue proteins were extracted and analyzed by electrophoresis. Testicular tissues fixed in paraffin wax were analyzed for changes in the immunoexpression of interstitial tissue estrogen receptor alpha. Phosphorylation pattern of sperm proteins was studied in vitro after incubating with 32P-ATP. The expression of dynein and tubulin in sperms, and estrogen receptors in epididymis were analyzed by immunoblotting. Tamoxifen treatment did not alter the protein profile in the cauda sperms, epididymal fluid and tissues. Endogenous phosphorylation pattern of sperm proteins in vitro was also not affected, though it is possible that 32P incorporation observed in the 66 kDa protein could be estrogen receptor. Expression of sperm dynein, tubulin and epididymal estrogen receptors was unchanged as was the expression of testicular estrogen receptors. It was concluded that tamoxifen administration alters forward motility pattern characteristic of cauda sperm without any demonstrable change in the expression or activation of motility related proteins and the phosphorylation of the sperm estrogen receptors may be involved in the regulation of sperm motility.
Cell Mol Biol (Noisy-le-grand) 2003 Jun
PMID:Effect of tamoxifen treatment on motility related proteins in rat spermatozoa. 1289 54

The nucleus contains different sets of functional compartments often called "speckles". The splicing factor compartment (SFC) has been speculated to consist of SFs and transcription factors, which thus make transcription-splicing coupling possible at the periphery of SFC. Androgen receptor (AR), as well as glucocorticoid receptor (GR), is unique since most, if not all, of its activities are mediated via the constitutive activity of the activation function-1 (AF-1) function. Transcriptionally active AR produces 250-400 subnuclear fine speckles11 shared with GR or estrogen receptor (ER), which colocalize with chiefly activation function-2 (AF-2)-interacting p160 family- or CBP-related speckles. We herein report the isolation of ANT-1 (AR N-terminal domain (NTD) transactivating protein-1) enhancing autonomous AF-1 transactivation function of AR or GR, but not of estrogen receptor alpha (ERalpha). The ANT-1 was identical to a binding protein of human splicing factor U5 snRNP (U5 snRNP-associated protein). ANT-1 was compartmentalized into 15-20 coarse SFC speckles which were spatially distinct from but surrounded by the AR compartments. Our results suggest that ANT-1 may play a key role in the molecular interaction between two spatially distinct subnuclear compartments in a receptor-specific fashion, and thereby induce the strong autonomous transactivation functions either of AR- or GR-AF-1.
J Steroid Biochem Mol Biol 2003 Jun
PMID:Activation function-1 domain of androgen receptor contributes to the interaction between two distinct subnuclear compartments. 1294 5

Menopause marks the start of a new phase in a woman's life that is associated with a decrease in circulating estrogen levels. Although the average age of women has increased from 50 to nearly 85 years, the average age at menopause has remained essentially constant at 50 years. Thus, women now spend nearly a third of their lives in an estrogen deficient state. This normal aging process in women is associated with increasing health problems such as osteoporosis, cardiovascular disease, neurodegenerative diseases, and cancer. Estrogen replacement therapy (ERT) has been shown to play an important beneficial role in the health and well being of postmenopausal women. Several estrogen preparations are available and among these conjugated equine estrogens (CEE) are most frequently used. The drug CEE, is a complex natural urinary extract of pregnant mare's urine and contains at least 10 estrogens in their sulfate ester form and these are the ring B saturated estrogens: estrone (E(1)), 17beta-estradiol (17beta-E(2)), 17alpha-estradiol (17alpha-E(2)), and the ring B unsaturated estrogens equilin (Eq), 17beta-dihydroequilin (17beta-Eq), 17alpha-dihydroequilin (17alpha-Eq), equilenin (Eqn), 17beta-dihydroequilenin (17beta-Eqn), 17alpha-dihydroequilenin (17alpha-Eqn), and Delta(8)-estrone (Delta(8)-E(1)). All of these estrogens in their unconjugated form are biologically active and can interact with recombinant human estrogen receptor alpha (ERalpha) and beta (ERbeta) with 17beta-estradiol and 17beta-dihydroequilin having the highest affinity for both receptors. A number of the ring B unsaturated estrogens had nearly twofold higher affinity for the ERbeta. The pharmacokinetics of these estrogens in postmenopausal women indicate that the unconjugated estrogens compared to their sulfated forms are cleared more rapidly. The 17-keto estrogens are metabolized to the more potent 17beta-reduced products which are cleared at a slower rate. In postmenopausal women, the extent of 17beta-activation is much higher with the ring B unsaturated estrogens than with ring B saturated estrogens. Oxidized LDL and oxidative stress are thought to contribute to both atherosclerosis and neurodegenerative disorders. Neurons in particular are at a high risk from damage resulting from oxidative stress. In vivo and in vitro studies indicate that the oxidation of LDL isolated from postmenopausal women was inhibited differently by various estrogens and other antioxidants. The unique ring B unsaturated estrogens were the most potent while the red wine component t-resveratrol was the least potent. Studies were designed to explore the cellular and molecular mechanisms that may be involved in the neuroprotective effects of CEE components. The data indicate that the neurotoxic effects of oxidized LDL and glutamate can be inhibited by various estrogens, with the ring B unsaturated estrogens being the most active. These effects are involved in the inhibition of DNA fragmentation and up-regulation of anti-apoptotic protein Bcl-2 and down-regulation of pro-apoptotic protein Bax. These combined data suggest that some of the neuroprotective benefits associated with long-term estrogen therapy may occur by the above mechanism(s). Because estrogens such as the Delta(8)-estrogens are relatively less feminizing than the classical estrogen 17beta-estradiol, they may be important in the development of more neuro-specific estrogens that will be useful in the prevention of neurodegenerative diseases, such as Alzheimer's and Parkinson disease, in both men and women.
J Steroid Biochem Mol Biol 2003 Jun
PMID:Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's. 1294 38

The yeast Saccharomyces cerevisiae was used to reconstruct a human estrogen receptor alpha (ERalpha)-mediated transcription activation system. The level of reporter gene activation was dependent on both the position of the estrogen response element (ERE) relative to the translation start site and the number of EREs in the hybrid promoter. A G400V amino acid alteration in the ERalpha polypeptide decreased sensitivity to 17beta-estradiol (E(2)), demonstrating the hormone responsiveness of ERalpha to be qualitatively and quantitatively similar in yeast and mammalian cells. Coexpression of SRC-1a, a potent stimulator of ERalpha function in mammalian cells, potentiated ERalpha-mediated gene expression over fivefold in a E(2)-dependent manner. Deletion of 56 amino acids at the C-terminal end of SRC-1a resulted in a protein with enhanced ability to potentiate ERalpha-mediated gene expression, which mimics the activity of the same truncation in human SRC-1a as well as the SRC-1e isoform that has the 56 C-terminal residues replaced with a different 14 amino acid peptide. The selective estrogen receptor modulator tamoxifen acted as a weak agonist of ERalpha-mediated gene expression and this weak activity was potentiated by SRC-1. Tamoxifen had no effect on E(2)-induced gene activation in either the presence or absence of SRC-1. In contrast to previously reported yeast-based ERalpha-transactivation systems, the system reported here in which SRC-1 functions as a bona fide coactivator should permit a more thorough dissection of the factors involved in ERalpha-mediated transcriptional activation.
J Steroid Biochem Mol Biol 2003 Jul
PMID:Potentiation of human estrogen receptor alpha-mediated gene expression by steroid receptor coactivator-1 (SRC-1) in Saccharomyces cerevisiae. 1294 41

MCF-7 breast tumor cells form multicellular nodules (foci) over a confluent monolayer in an estradiol (E2)-dependent, antiestrogen-sensitive reaction. A cell line cloned from MCF-7 that displays these phenotypes was probed to determine the effects of long term exposure to tamoxifen on the growth of foci, estrogen receptor alpha (ERalpha) status, and gene responsiveness to E2. In one of two experiments, a heterogeneous cell population emerged (TMX2) that over-expressed estrogen receptor alpha wild type mRNA (ERalpha mRNA) (approximately 20-fold) missing exon 3 (ERDelta3 mRNA) and its corresponding protein (ERDelta3P). On a per mRNA to protein basis, ERDelta3P and wild-type ERalpha were equivalently expressed. Return of the TMX2 population to medium without tamoxifen eventually selected for a population that expressed predominately wild-type ERalpha, whereas TMX2 clones over expressing ERDelta3 mRNA and ERDelta3P retained this phenotype in tamoxifen-free media. In both experiments, expression of all ERalpha mRNAs and proteins declined to barely detectable levels during 6-12 months exposure, concomitant with a progressive increase in the ability of the cells to form foci independently of E2 or tamoxifen. Selection for these various populations suggests that tamoxifen can induce and/or support certain cellular changes that lead to altered ERalpha expression, E2-independent cell growth and resistance to antiestrogens.
Mol Cell Endocrinol 2003 Aug 29
PMID:Phenotypic changes in MCF-7 cells during prolonged exposure to tamoxifen. 1294 88

The human uterus undergoes profound physiological tissue remodelling during pregnancy. In the myometrium, altered gene expression must underlie these extensive molecular and structural changes. The purpose of this study was to compare expression profiles of pregnant and non-pregnant myometrium, in order to identify genes that participate in this process. mRNA from 14 non-pregnant and four pregnant human myometrial samples were analysed using a human UniGEM V microarray with 7075 cDNA elements. A total of 602 transcripts from the microarray were up-regulated >/=2.0-fold in pregnant myometrium, with 37 transcripts up-regulated >/=4.0-fold. In contrast, eight transcripts were down-regulated >/=2.0-fold in pregnancy. To ensure accurate representation of differential gene expression, Northern blot analyses using total RNA from 16 samples of non-pregnant and pregnant myometrium were used to examine mRNA levels for four of the genes that were differentially expressed by microarray analysis, namely plasminogen activator inhibitor type 1 (PAI-1), milk fat globule-EGF factor 8 protein (MFGE8), secreted frizzled-related protein 4 (sFRP4) and estrogen receptor alpha (ERalpha). On the microarray these transcripts were up-regulated 7.5-fold for PAI-1 and 4.9-fold for MFGE8 in pregnant myometrium, and down-regulated 3.7-fold for sFRP4 and 2.9-fold for ERalpha in pregnancy. Northern blot analyses confirmed these changes. Our findings suggest that microarray technology is a useful tool for examining global changes in gene expression that occur as the myometrium differentiates from non-pregnant to pregnant status. Defining these changes provides new insight into the structural and functional adaptations of human myometrium during pregnancy.
Mol Hum Reprod 2003 Nov
PMID:Human myometrial adaptation to pregnancy: cDNA microarray gene expression profiling of myometrium from non-pregnant and pregnant women. 1456 11

The binding of ligand to a nuclear receptor causes conformational changes that can result in coactivator or corepressor recruitment and subsequent regulation of transcription. Several peptides have previously been identified that bind to the liganded estrogen receptor (ER). One interacting peptide, pepalphaII, was used in the present studies to assess the ability of ligands to induce spatial changes within both the full-length human estrogen receptor alpha (ER-alpha) and a truncated receptor containing the ligand-binding domain (LBD). pepalphaII interacted weakly with the full-length estrogen receptor alpha in the presence of both agonists and antagonists. In contrast, the interaction of pepalphaII with the truncated receptor containing the ligand-binding domain was strongly induced by antagonists and only weakly induced by agonists. Thus, the same ligand can induce different spatial configurations of the full-length and ligand-binding domain of estrogen receptor alpha as measured by pepalphaII affinity. Crystal structures of nuclear hormone receptors solved to date have used ligand-binding domains and therefore may not accurately predict surface interaction domains present in the liganded full-length receptor. Furthermore, the ability of a ligand to induce a strong interaction of pepalphaII with the estrogen receptor alpha ligand-binding domain predicts that the ligand will have greater antagonist activity on the full-length receptor.
J Steroid Biochem Mol Biol 2003 Aug
PMID:Full-length estrogen receptor alpha and its ligand-binding domain adopt different conformations upon binding ligand. 1456 65

Estrogens have well-documented effects on lung development and physiology. However, the classical estrogen receptor alpha (ERalpha) is undetectable in the lung, and this has left many unanswered questions about the mechanism of estrogen action in this organ. Here we show, both in vivo and in vitro, that ERbeta is abundantly expressed and biologically active in the lung. Comparisons of lungs from wild-type mice and mice with an inactivated ERbeta gene (ERbeta(-/-)) revealed decreased numbers of alveoli in adult female ERbeta(-/-) mice and findings suggesting deficient alveolar formation as well as evidence of surfactant accumulation. Platelet-derived growth factor A (PDGF-A) and granulocyte-macrophage colony-stimulating factor (GM-CSF), key regulators of alveolar formation and surfactant homeostasis, respectively, were decreased in lungs of adult female ERbeta(-/-) mice, and direct transcriptional regulation of these genes by ERbeta was demonstrated. This suggests that estrogens act via ERbeta in the lung to modify PDGF-A and GM-CSF expression. These results provide a potential molecular mechanism for the gender differences in alveolar structure observed in the adult lung and establish ERbeta as a previously unknown regulator of postnatal lung development and homeostasis.
Mol Cell Biol 2003 Dec
PMID:Regulation of postnatal lung development and homeostasis by estrogen receptor beta. 1461 99

Long term exposure to estradiol increases the risk of breast cancer in a variety of animal species, as well as in women. The mechanisms responsible for this effect have not been firmly established. The prevailing theory proposes that estrogens increase the rate of cell proliferation by stimulating estrogen receptor-mediated transcription and thereby the number of errors occurring during DNA replication. An alternative hypothesis proposes that estradiol can be metabolized to quinone derivatives which can react with DNA and then remove bases from DNA through a process called depurination. Error prone DNA repair then results in point mutations. We postulate that these two processes, increased cell proliferation and genotoxic metabolite formation, act in an additive or synergistic fashion to induce cancer. If correct, aromatase inhibitors would block both processes whereas anti-estrogens would only inhibit receptor-mediated effects. Accordingly, aromatase inhibitors would be more effective in preventing breast cancer than use of anti-estrogens. Our studies initially demonstrated that catechol estrogen (CE) quinone metabolites are formed in MCF-7 human breast cancer cells in culture. Measurement of estrogen metabolites and conjugates involved utilization of an HPLC separation coupled with an electrochemical detector. We then utilized an animal model that allows dissociation of estrogen receptor-mediated function from that of the effects of estradiol metabolites. Wnt-1 transgenic mice harboring a knock-out of ERalpha provides a means of examining the effect of estrogen deprivation in the absence of the ER in animals with a high incidence of breast tumors. ERbeta was shown to be absent in the breast tissue of these animals by RNase protection assay. In the breast tissue of these estrogen receptor alpha knock-out (ERKO)/Wnt-1 transgenic mice, we demonstrated formation of genotoxic estradiol metabolites. The ERKO/Wnt-1 breast extracts contained picomole amounts of the 4-catechol estrogens, but not their methoxy conjugates nor the 2-CE or their methoxy conjugates. The 4-CE conjugates with glutathione or its hydrolytic products (cysteine and N-acetylcysteine) were detected in picomole amounts in both tumors and hyperplastic mammary tissue, demonstrating the formation of CE-3,4-quinones. These results are consistent with the hypothesis that mammary tumor development is primarily initiated by metabolism of estrogens to 4-CE and, then, to CE-3,4-quinones, which may react with DNA to induce oncogenic mutations. The next set of experiments examined the incidence of tumors formed in Wnt-1 transgenic mice bearing wild type ERalpha (ER+/+), the heterozygous combination of genes (ER+/ER-) or ERalpha knock-out (ER-/-). To assess the effect of estrogens in the absence of ER, half of the animals were oophorectomized on day 15 and the other half were sham operated. Castration reduced the incidence of breast tumors in all animal groups and demonstrated the dependence of tumor formation upon estrogens. A trend toward reduction in tumor number (not statistically significant at this interim analysis) occurred in the absence of functional ER since the number of tumors was markedly reduced in ERKO animals which were castrated early in life. In aggregate, our results support the concept that metabolites of estradiol may act in concert with ER mediated mechanisms to induce breast cancer.
J Steroid Biochem Mol Biol 2003 Sep
PMID:Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. 1462 47


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