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Query: UNIPROT:P06889 (Mol)
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We were previously investigating the expression of the extracellular matrix glycoprotein tenascin in normal and malignant endometrial tissues of humans and rodents. These studies suggested that the expression of tenascin was induced by proliferating epithelia (normal and particularly malignant) and was downregulated with their differentiation. The aim of this study was to investigate the hormone dependency of tenascin expression in (a) the transplantable EnDA endometrial tumor model with or without estrogen deprivation (ovariectomy) of the animals, (b) DMBA-induced rat mammary tumors with or without a hormonal treatment of the animals [ovariectomy, antiestrogen (tamoxifen) or antiprogestin (ZK 98299) treatment] and (c) in the rat prostate of untreated or androgen deprived animals (orchiectomy, flutamide-, casodex- or cyproterone acetate (CPA)-treatment). 1. Estrogen withdrawal by ovariectomy did not affect tenascin expression in transplantable EnDA endometrial adenocarcinoma, meaning the entire extracellular space of the stromal mesenchyme was decorated by tenascin immunoreactivity. 2. In untreated DMBA-induced rat mammary tumors almost the entire extracellular space of the stroma was stained by tenascin immunoreactivity. Ovariectomy and antiestrogen treatment did not affect tenascin expression. In contrast, antiprogestin treatment induced terminal differentiation of mammary tumor cells and in parallel downregulated tenascin expression. 3. In the normal rat prostate no tenascin was detectable by immunocytochemistry. However, following androgen deprivation we found tenascin expression in the stroma of the prostate. The most prominent expression was observable after CPA-treatment, possibly due to its progestagenic potency. In conclusion, the hormones and antihormones tested show no direct effect on the stromal expression of tenascin. However, proliferative activity and a low degree of differentiation of the epithelium induces tenascin expression, whereas epithelial differentiation apparently shuts down tenascin expression. Preliminary in vitro studies suggest that paracrine acting growth factors trigger the hormonal regulation of tenascin expression.
J Steroid Biochem Mol Biol 1994 Apr
PMID:Stromal expression of tenascin is inversely correlated to epithelial differentiation of hormone dependent tissues. 751 33

Antagonists of steroid hormones are clinically important in the management of breast cancer. However, the duration of response is limited due to the development of hormone-independent tumors in virtually all cases. In an attempt to obtain insight into the mechanisms underlying antiestrogen resistance, the consequences of epigenetic changes in gene expression were studied in vitro. Estrogen-dependent ZR-75-1 human breast cancer cells were treated with 5-azacytidine, an inhibitor of DNA methylation, and cultured in the absence of estradiol or in the presence of antiestrogens. Estrogen-independent cell colonies developed within 3 weeks at high frequency in 5-azacytidine-treated cultures (0.7 x 10(-3), in contrast to control cultures (< or = 10(-8). The derived cells (ZR/AZA) were resistant to 4-hydroxytamoxifen and ICI 164,384, independent of the selection protocol, but had lost the ability to grow anchorage-independent. Whereas expression of estrogen receptor, progesterone receptor, and pS2 were down-regulated, expression of epidermal growth factor (EGF) receptor and HER2/neu were increased in ZR/AZA cells. In contrast to the stable altered expression patterns of estrogen receptor and EGF receptor, transient keratin 7 expression was observed. Transforming growth factor-alpha mRNA was identified in ZR-75-1 cells and ZR/AZA cells and EGF-like peptides were secreted in the culture medium. Proliferation of ZR/AZA cells could be partially inhibited with an EGF receptor-blocking antibody. Presence of both growth factor receptors and possible ligands suggests the development of an autocrine growth mechanism. Our data show that epigenetic alterations of gene expression result in rapid progression of breast cancer cells to hormone independence.
Mol Endocrinol 1994 Nov
PMID:Induction of estrogen independence of ZR-75-1 human breast cancer cells by epigenetic alterations. 753 60

The measurement of the urinary excretion ratio of 6 beta-hydroxycortisol (6 beta-OHC)/cortisol was used as a non-invasive method to investigate possible changes in the activity of drug-metabolizing enzymes in women receiving different oral contraceptive formulations for 1 up to 3 treatment cycles. The contraceptive preparations were either levonorgestrel, gestodene or cyproterone acetate, each in combination with ethinyl estradiol, or only the progestogens levonorgestrel or gestodene. There was either no or only a small decrease in the 6 beta-OHC/cortisol ratio. Thus, only a minor inhibitory effect, if any, can be ascribed to the investigated contraceptive steroids in vivo. Previously observed differences between selected contraceptive steroids in vitro were not observed in the same way in vivo. This may be due either to the absence of a marked inhibitory activity in vivo or to the insufficient sensitivity of the marker 6 beta-OHC/cortisol to detect these changes. Another possible reason may be the considerably higher drug concentrations used in the in vitro studies as compared to those present in the serum of women under oral contraceptive therapy.
J Steroid Biochem Mol Biol 1995 Oct
PMID:Urinary excretion of 6 beta-hydroxycortisol in women during treatment with different oral contraceptive formulations. 757 16

Endometrial fibroblasts derived from uterine endometrium as controls and endometrial cancer cells (Ishikawa and HHUA cells) were used to analyze the manner of induction of c-Ha-ras transcripts in endometrial cancers, some of which are estrogen-dependent in growth. Estrogen increased c-Ha-ras expression and tyrosine kinase (TK) activity in fibroblast and Ishikawa cells, but not in HHUA cells. Progesterone diminished c-Ha-ras expression and tyrosine kinase (TK) activity induced by estradiol in the fibroblasts, but not in Ishikawa cells, which persistently overexpressed c-Ha-ras. In these cells, epidermal growth factor (EGF) increased c-Ha-ras expression as did estradiol. Pretreatment with tyrphostin, an inhibitor of TK, abolished estrogen-inducible overexpression of c-Ha-ras. The combination of both estradiol and EGF at maximum effective concentration exerted no additive or synergistic effect on induction of c-Ha-ras expression. In conclusion, persistent activation of TK might lead to overexpression of c-Ha-ras in some endometrial cancer cells under estrogen predominant milieu, which might be associated with the transformation or growth potential.
J Steroid Biochem Mol Biol 1995 Oct
PMID:Estrogen induces c-Ha-ras expression via activation of tyrosine kinase in uterine endometrial fibroblasts and cancer cells. 757 18

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

Sturgeon are an ancient family (Acipenseridae) of fishes that lie close to the divergence of fish that eventually evolved into terrestrial animals and those that evolved into modern teleost species. Therefore, white sturgeon vitellogenin sequences fill a gap in the current understanding of the functional domains of this protein family. Vitellogenin cDNA was sequenced and used to investigate gene expression in white sturgeon, Acipenser transmontanus. Estrogen-induced vitellogenin mRNA was detected in the livers of both males and females and was also detected in undifferentiated gonads of estrogen-treated fish. Low levels of vitellogenin mRNA were also detected in the testis of both control and estrogen-treated males. The cDNA encoded a 186-kDa protein that was missing only six to seven of the amino-terminal amino acids. Comparisons to silver lamprey, Xenopus, and chicken vitellogenin sequences indicate that the overall structure of the yolk protein domains were highly conserved. There was considerable homology in three regions of the lipovitellin I domain. These conserved sequences are likely to be involved in vitellogenin receptor binding. The phosvitin domain of white sturgeon vitellogenin contained fewer and shorter serine repeats as predicted from yolk protein phosphate content of fish compared to Xenopus and chicken. However, the vitellogenin of white sturgeon had a lower serine content as compared with silver lamprey, indicating that an increased serine content is not strictly a function of evolutionary age.
J Mol Evol 1995 Jul
PMID:Characterization of vitellogenin from white sturgeon, Acipenser transmontanus. 760 84

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


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