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

Insulin-like growth factors (IGFs) I and II are two single-chain polypeptide hormones that are structurally related to each other and to proinsulin. Among the large number of growth factors involved in ovarian physiology, IGF-I and IGF-II are considered to be important progression factors for ovarian follicular development. To explore the ovarian expression of IGF-I, IGF-II and their receptor genes, a solution hybridization/RNase protection assay, was used. IGF-I mRNA was seen in the granulosa cells, and IGF-II mRNA in the theca-interstitial compartment. To study the hormonal regulation of the IGF-I and IGF-II gene, immature (21-day-old) hypohysectomized rats were treated with FSH (10 micrograms/day), GH (150 micrograms/day) and diethylstilbestrol (DES subcutaneous implant/5 days). Estrogen differentially regulated ovarian IGF-I and IGF-II gene expression. In concert with GH, estrogen up-regulated ovarian IGF-I mRNA, but significantly decreased hepatic IGF-I gene expression. Both IGF receptors (type I and type II) as well as the insulin receptor gene, were expressed in both ovarian cells. The expression of the type I IGF receptor gene (but not the type II IGF gene) was up-regulated by FSH and estrogen in vivo. In conclusion, these studies may serve to better understand the auto paracrine role of IGF, and their receptors in the pathophysiology of follicle recruitment, oocyte maturation and potentially embryo development.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Regulation of the genes for insulin-like growth factor (IGF) I and II and their receptors by steroids and gonadotropins in the ovary. 762 58

Estrogen exerts a profound effect on mood and mental function in man. Based on our finding that estradiol selectively stimulates the expression of 5-hydroxytryptamine(2A) (5-HT2A) receptor mRNA in the dorsal raphe nucleus of the female rat, we investigated the effects of estradiol on the density of 5-HT2A receptors in brain. The distribution and density of 5-HT2A receptors were determined by in vitro binding of [3H]ketanserin in the presence of prazosin to exclude binding to alpha 1-adrenoreceptors. Brains were collected, processed and analysed in pairs from six estradiol- and six vehicle-treated animals. Our results show that a single pulse of estradiol induces a significant increase in the density of 5-HT2A receptors in female rat forebrain, particularly the anterior frontal, anterior cingulate and primary olfactory cortex and the nucleus accumbens. Since these brain regions play a pivotal role in cognition and emotion, as well as neuroendocrine and motor control, our findings provide the first experimental evidence for the fact that estrogen could alter mood and mental state by increasing the density of 5-HT2A receptors in cerebral cortex and nucleus accumbens.
J Steroid Biochem Mol Biol 1995 Jul
PMID:Estrogen increases the density of 5-hydroxytryptamine(2A) receptors in cerebral cortex and nucleus accumbens in the female rat. 763 10

Bone metabolism is regulated by a balance between bone resorption caused by osteoclasts and bone formation caused by osteoblasts. This balance is disturbed in postmenopausal women as a result of lower serum estrogen levels. Estrogen, which is used in hormone replacement therapy to prevent postmenopausal osteoporosis, downregulates expression of the interleukin 6 (IL-6) gene in osteoblasts and bone marrow stromal cells. IL-6 is directly involved in bone resorption by activating immature osteoclasts. We show here that NF-kappa B and C/EBP beta are important regulators of IL-6 gene expression in human osteoblasts. Importantly, the IL-6 promoter is inhibited by estrogen in the absence of a functional estrogen receptor (ER) binding site. This inhibition is mediated by the transcription factors NF-kappa B and C/EBP beta. Evidence is presented for a direct interaction between these two factors and ER. We characterized the protein sequence requirements for this association in vitro and in vivo. The physical and functional interaction depends in part on the DNA binding domain and region D of ER and on the Rel homology domain of NF-kappa B and the bZIP region of C/EBP beta. The cross-coupling between ER, NF-kappa B, and C/EBP beta also results in reduced activity of promoters with ER binding sites. We further show that the mechanism of IL-6 gene repression by estrogen is clearly different from that of activation of promoters with ER binding sites. Therefore, drugs that separate the transactivation and transrepression functions of ER will be very helpful for treatment of osteoporosis without causing undesirable side effects.
Mol Cell Biol 1995 Sep
PMID:Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. 765 15

Estrogen levels in breast tumors of post-menopausal women are at least 10 times higher than estrogen levels in plasma. The high level of estrogen in these tumors is postulated to be due to in situ formation of estrogen, possibly through conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Thus, inhibitors of estrone sulfatase are potential agents for the treatment of hormone-dependent breast cancers. We designed and synthesized a series of estra-1,3,5(10)triene-17-one, 3-amino and estra-1,3,5(10)triene-17-one, 3-thio derivatives. We have shown previously that several of these compounds substantially inhibit estrone sulfatase, exceeding Danazol in their inhibitory activity. However, little is known about the metabolism of these compounds and the possible effects of their metabolites in vivo. Two probable metabolites of the synthetic estrone analogs are estra-1,3,5(10)triene-17-one, 3-amine (E1-NH2), and estra-1,3,5(10)triene-17-one, 3-thiol (E1-SH). We tested these two compounds for estrogenicity, antiestrogenicity and inhibition of estrone sulfatase activity using a combination of in vivo and in vitro assays. The ovariectomized rat uterine weight gain assay was used to test for estrogenicity. Neither E1-NH2 nor E1-SH were estrogenic, as indicated by a lack of uterine weight gain when given at 25 micrograms/day for 7 days. The test compounds also were not antiestrogenic, in that they did not block estrone-induced uterine weight gain when given (100 micrograms/day) simultaneously with estrone (2 micrograms/day). Both compounds showed low affinity for the estrogen receptor. Using rat uterine cytosol as a source of estrogen receptor, the compounds displaced only a small percentage of [3H]estradiol binding, even when present at 1000-fold excess. Inhibition of estrone sulfatase activity was tested using human placental microsomes as a source of estrone sulfatase. E1-NH2 and E1SH showed very low levels of estrone sulfatase inhibition (15.1 and 9.8%, respectively) under conditions where Danazol showed more than 60% inhibition. Our results indicate that neither of these two compounds would present significant problems if they were the primary metabolite in a treatment involving estrone sulfatase inhibition of estrogen-dependent breast cancer.
J Steroid Biochem Mol Biol 1995 Mar
PMID:Estrogenicity, antiestrogenicity and estrone sulfatase inhibition of estrone-3-amine and estrone-3-thiol. 769 50

In the rat, reproduction and sexual behavior are controlled by the gonadal steroid regulation of synaptic interactions within the sexually dimorphic limbic-hypothalamic system. The effects of estrogen on the ventromedial nucleus of the hypothalamus, one nucleus within the circuit, are central to the modulation of this behavior. Involvement of the neuropeptide substance P, a member of the tachykinin family of neuropeptides, has been implicated in the regulation of both lordosis behavior and gonadotropin release. However, previous studies have provided conflicting evidence as to whether levels of substance P in the ventromedial nucleus of the hypothalamus are modulated by circulating estrogens. To study this question further, in situ hybridization histochemistry was used to examine levels of beta-preprotachykinin mRNA, which encodes substance P and other tachykinins, in the ventrolateral subdivision of the ventromedial hypothalamus at 10 consecutive timepoints over a 4 day period subsequent to an acute administration of estrogen. Following estrogen treatment, beta-preprotachykinin mRNA expression was increased in cells of the ventrolateral portion of the ventromedial nucleus of the hypothalamus which constitutively express beta-preprotachykinin mRNA; however, there were no statistically significant changes in the number of cells that express detectable levels of beta-preprotachykinin mRNA in the ventrolateral portion of the ventromedial nucleus. Estrogen treatment produced two peaks of beta-preprotachykinin mRNA expression, the first at 2 h and the second at 48 h after the injection of estrogen. These data indicate that estrogen has both rapid and prolonged effects on beta-preprotachykinin mRNA levels, suggesting that estrogen may affect different cellular mechanisms relevant to the induction of beta-preprotachykinin mRNA expression.
Brain Res Mol Brain Res 1995 Jan
PMID:Temporal regulation by estrogen of beta-preprotachykinin mRNA expression in the rat ventromedial nucleus of the hypothalamus. 770 79

Growth hormone-releasing factor (GRF) and vasoactive intestinal peptide (VIP) are two structurally homologous peptides sharing common target cell receptor and known to enhance FSH-induced steroidogenesis of undifferentiated granulosa cell in vitro. Although VIP, has been reported to stimulate plasminogen activator (PA) activity in rat granulosa cells, our knowledge on the actions and interactions of these two peptides with FSH in the regulation of rat granulosa cell PA system during follicular development remains incomplete. Undifferentiated and differentiated rat granulosa cells from pre-antral (DES-treated rats) and antral (eCG-treated rats) follicles, respectively, were cultured in a chemically defined medium in the absence and presence of FSH (400 ng/ml), GRF (10(-8)-10(-5) M) and/or VIP (10(-9)-10(-5) M). Net secreted (PAs) and cell-associated (PAc) PA activities was measured by the fibrinolysis assay and characterized by the fibrin overlay method. Granulosa cell differentiative (progestin secretion) and proliferative (DNA synthesis) responses were analyzed by radioimmunoassay and [3H]thymidine incorporation, respectively. Both GRF and VIP stimulated PAs and PAc activities in a concentration-dependent manner in 24-h cultures of granulosa cells from the two stages of follicular development. They (10(-5) M) enhanced FSH-stimulated PAs activity in granulosa cell cultures of pre-antral follicles, with GRF being more effective than VIP. On the contrary, only GRF (10 microM) potentiated FSH-induced PAs and PAc activities in cultures of granulosa cell from antral follicles. The stimulation of PA activity by these agonists decreased with the duration of culture irrespective of the stage of follicular development.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1995 Jan
PMID:Growth hormone releasing factor and vasoactive intestinal peptide stimulate rat granulosa cell plasminogen activator activity in vitro during follicular development. 779 29

Estrogen responsiveness of breast tumors can be correlated with the presence or absence of the estrogen receptor (ER). Breast cancer cells that contain ER are, in general, responsive to stimulation by estrogen both in vivo and in vitro; therefore hormonal control is possible. Breast tumors that lose the ER, and become hormone-independent are refractory to the direct effect of estrogens and antiestrogens. It is therefore of interest to determine whether the re-expression of the ER will be sufficient to make ER-negative cells sensitive to the growth effect of estrogen. Transfection experiments with wild type and mutant ER cDNAs into different mammalian cell lines have been performed to re-establish hormonal control over hormone-independent cells. Paradoxically, introduction of exogenous ER into ER-negative cells and treatment with estrogen leads to growth inhibition rather than growth promotion. The activation of a number of estrogen-regulated genes has been examined in ER-transfectants but gene regulation is often variable. It is clear that the transfection of the ER gene into cells lacking this protein does not simply re-create the native ER-positive phenotype. Studies need to be extended to identify either the transcription factors that interact with ER to cause the negative effects of estrogen indirectly ("squelching") or the precise target genes that cause growth inhibition directly.
J Steroid Biochem Mol Biol 1994 Dec
PMID:Transfection of human estrogen receptor (ER) cDNA into ER-negative mammalian cell lines. 782 84

Although estrogen receptor (ER) and progestin receptor (PR) are members of different steroid hormone receptor subfamilies, there is considerable biological evidence for cross-talk between the estrogen and progestin hormone-receptor signaling pathways. We have developed a model system to analyze the mechanisms underlying this cross-talk, specifically the repression of ER-mediated transcriptional activity by PR complexed with agonistic or antagonistic ligands. Estrogen- and progestin-responsive reporter vectors containing a variety of promoters were transfected into primary cultures of rat uterine cells and 3T3 mouse fibroblasts with expression vectors for PR (the A and/or B isoforms) as well as ER. Our results demonstrate that both PR isoforms can act as potent ligand-dependent repressors of ER activity. The magnitude of the repression was dependent on the PR isoform (i.e., PR A or PR B), ligand type (i.e., agonist or antagonist), PR levels, and ligand concentration but was unaffected by the ER levels. The promoter context was important in determining both the magnitude and PR isoform specificity of the repression for agonist-occupied PR but not for antagonist-occupied PR. Ligand-occupied PR A was a stronger repressor of ER-mediated transcriptional activity than was ligand-occupied PR B, and antagonist-occupied PR was a more effective repressor than agonist-occupied PR. Mechanistic studies suggest that liganded PR represses ER activity by interfering with its ability to interact productively with the transcriptional machinery, a process known as quenching. The data do not support competitive repression, direct repression, or squelching as the mechanism of PR's inhibitory effect. Experiments with ER mutants demonstrated that the N-terminal portion of ER was required for repression by agonist-occupied PR but not by antagonist-occupied PR. These results, as well as other differences between the two PR-ligand complexes, suggest that they differentially target ER when repressing ER transcriptional activity. These findings underscore the mounting evidence for the importance of interactions between members of the steroid hormone receptor family.
Mol Cell Biol 1995 Apr
PMID:Inhibitory cross-talk between steroid hormone receptors: differential targeting of estrogen receptor in the repression of its transcriptional activity by agonist- and antagonist-occupied progestin receptors. 789 78

Estrogen regulates the hepatic synthesis of a variety of proteins required for egg yolk production in oviparous vertebrates. In chickens, two of these proteins, apolipoprotein (apo) B and apoII, comprise the major protein components of specialized very low density lipoprotein particles that transport triacylglycerols and cholesterol to the developing egg yolk. In the adult, apoB is synthesized constitutively in liver, small intestine, and kidney but is estrogen-responsive only in the liver. In this work we have examined the embryonic expression of the apoB and apoII genes in yolk sac, liver, kidney, and small intestine. The 14 kb apoB mRNA was first detected at day 3 of development in vascular yolk sac, a tissue involved in the transfer of yolk lipids into the embryonic circulation. Constitutive apoB mRNA expression was detectable in liver at day 6.5 and in kidney at day 7.5, but in intestine was barely detectable before hatching. The hepatic apoB gene acquired estrogen-responsiveness at day 6.5 and its hormone-dependent expression increased throughout development in concert with the estrogen-responsive expression of the apoII gene. In contrast, the constitutively expressed apoB gene in kidney remained unresponsive to estrogen. Surprisingly, the apoII gene was found to be responsive to estrogen in both the embryonic kidney and small intestine. ApoII mRNA induction by estrogen in kidney at day 11 was at 10% of the level in the liver but estrogen-responsiveness decreased later in development and was low in the adult.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1994 Dec
PMID:Apolipoprotein (apo) B and apoII gene expression are both estrogen-responsive in chick embryo liver but only apoII is estrogen-responsive in kidney. 789 7

The estrogen receptor (ER) typically activates gene transcription by binding to estrogen-responsive elements (EREs). The brain creatine kinase (BCK) promoter is responsive to estrogen but contains no ERE-related sequence. To investigate the mechanism of estrogen induction, we have introduced the estrogen receptor into HeLa cells and primary rat cardiomyocytes and fibroblasts along with 195 bp of BCK promoter linked to a chloramphenicol acetyltransferase (CAT) reporter gene. A 10-fold stimulation of CAT activity was observed in the presence of beta-estradiol in both HeLa and rat primary fibroblasts, but no induction was observed in primary rat cardiomyocytes. In contrast, a control vitellogenin gene construct which contains a typical ERE was induced in an ER-dependent manner in all cell types studied. Estrogen induction in HeLa was not sensitive to cycloheximide and was blocked by the ER antagonists tamoxifen and ICI 164,384. Analysis of 5' deletion and linker-scanning mutations indicates sequences between bp -45 and -75 including a TA-rich sequence and a CCAAT sequence to be crucial for stimulation of the BCK promoter by the ER. BCK estrogen induction is dependent on the DNA-binding domain and transactivation domain TAF2 of the ER. However, direct DNA binding is probably not required. Taken together, these results suggest a novel mechanism for ER-mediated gene activation. This mechanism is consensus ERE independent and cell type specific and requires interactions between the ER and molecules capable of interacting with the BCK promoter TA-rich region.
Mol Cell Biol 1994 Nov
PMID:A novel, cell-type-specific mechanism for estrogen receptor-mediated gene activation in the absence of an estrogen-responsive element. 793 28


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