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)

Norethisterone (NET) has been used as a contragestational postcoital agent. It is biotransformed to 5 alpha dihydro-NET (5 alpha-NET) and 3 beta,5 alpha tetrahydro-NET (3 beta,5 alpha-NET) in target tissues. The participation of these metabolites in NET effects is unknown. We have examined the antiimplantation and antiprogestational effects of NET and its metabolites, in adult mated female rabbits, by assessing the number of implantation sites and the expression products of the uteroglobin (UTG) gene in the uterus, and by comparing them with those of RU-486 and estradiol. Steroids were daily administered s.c. at several doses for 7 consecutive days, starting 24 hr after coitus. To assure that fertilization occurred in all animals, the presence of early pregnancy factor was determined. The results demonstrated that high doses (5 mg/kg) of NET reduced both implantation and the expression of the UTG gene. On the other hand, lower doses (1.5 mg/kg) of 5 alpha-NET produced an antiimplantation effect and suppressed UTG synthesis and its mRNA. These effects were similar to those of RU-486. At lower doses (1 mg/kg), both estradiol and the estrogenic metabolite 3 beta,5 alpha-NET were also effective in inhibiting implantation and UTG gene expression. The overall results suggest that NET metabolites exert antiimplantation and antiprogestational effects through their interaction with progesterone and estrogen receptors, and provide an explanation for the molecular mechanisms involved in the postcoital contraceptive action of NET.
Mol Reprod Dev 1995 Feb
PMID:Molecular mechanisms of the antihormonal and antiimplantation effects of norethisterone and its A-ring reduced metabolites. 776 8

The ability of breast tumours to synthesize hormones is well recognized, and local production of sex steroids is thought to play a role in breast cancer growth. We measured the intratumour and circulating levels of testosterone, dihydrotestosterone (DHT) and oestradiol in 35 histologically confirmed carcinomatous mammary tissues obtained at breast surgery from 34 postmenopausal patients, age 50-85 years. Intra-tissue steroids were extracted with ethanol:acetone (1:1; v/v), defatted with 70% methanol in water, and extracted with ether. Steroids, from tissue and serum, were separated by partition chromatography on celite columns and were measured by RIA. Intratumour testosterone and DHT concentrations were significantly correlated, after the exclusion of an outlier (rs = 0.71; P = 0.0001). No association was found between oestradiol and either of the two androgens. Mean oestradiol and DHT concentrations were significantly higher in tissue than in blood (P = 0.0001). Mean testosterone levels in tissues did not significantly differ from those measured in blood. Our data suggest that at least a part of intratissue DHT is produced locally from testosterone. The meaning of high oestradiol and DHT levels in cancer tissue still needs to be defined.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Testosterone, dihydrotestosterone and oestradiol levels in postmenopausal breast cancer tissues. 777 58

We have previously shown that progesterone, but not estradiol or testosterone, can compete with [3H]N-methyl scopolamine (NMS) for the cardiac M2 muscarinic binding site. Experiments have been carried out to investigate the inhibitory effects of a large variety of progesterone-like steroids on the M2 muscarinic receptor. These studies were performed with the aid of a new binding assay which uses intact tissue in the form of ventricular micropunches. Our data show that synthetic, clinically-used progestins such as Provera, norgesterel and cyproterone are largely ineffective at the M2 binding site whereas the naturally occurring progesterone derivatives 17 alpha hydroxy progesterone and Reichstein's Substance S are highly active. (Ki values 5 x 10(-6)M and 1 x 10(-6)M, respectively). Minor structural modifications such as acetylation of the 17 alpha hydroxy group abolishes activity. Steroids known to exert cell membrane effects, such as alfaxalone and pregnenolone sulfate, had no influence on [3H] NMS binding. The progesterone antagonist RU-486 did not block the inhibitory effect of progesterone. Moreover, this putative receptor may be located in the cardiomyocyte membrane since 17 alpha hydroxy progesterone induces rapid dissociation of [3H] NMS from its binding site (30% reduction in 5 min). We attempted to further localize the inhibitory locus to the M2 receptor itself by means of the irreversible antagonist propylbenzilylcholine mustard (PrBCM). Ninety percent of the M2 receptor could be blocked by PrBCM (10(-6) M), an effect reversible by the specific muscarinic antagonist scopolamine methyl bromide but not by progesterone. These results suggested that progesterone does not interact directly with the [3H] NMS labelled M2 binding site.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1995 Sep
PMID:Modulation of cardiac M2 muscarinic receptor binding by progesterone-related steroids. 852 44

1. Some progesterone is synthesized within both the central and the peripheral nervous systems, where it regulates neurotransmission and important glial functions, such as the formation of myelin. Progesterone can thus be designated a "neurosteroid." 2. Steroids act not only on the brain, but also on peripheral nerves, which offer many advantages to study the biological significance of locally produced neurosteroids: their remarkable plasticity and regenerative capacity and their relatively simple structure. 3. By using the regenerating mouse sciatic nerve as a model, we have shown that progesterone synthesized by rat Schwann cells promotes the formation of new myelin sheaths. Progesterone also increases the number of myelinated axons when added at a low concentration to cocultures of Schwann cells and sensory neurons. 4. These findings show a function on myelination for locally produced progesterone and suggest a new pharmacological approach of myelin repair.
Cell Mol Neurobiol 1996 Apr
PMID:Progesterone as a neurosteroid: actions within the nervous system. 874 66

Neuroactive steroids have been postulated to cause anesthesia by binding to unique steroid recognition sites on gamma-aminobutyric acid (GABA) receptors and modulating GABA receptor function. Steroids interact with these sites diastereoselectively, but it is unknown whether steroid sites show enantioselectivity. To address this issue, we synthesized enantiomers to (+)-3alpha-hydroxy-5alpha-androstane-17beta-carbonitrile and (+)-3alpha-hydroxy-5alpha-pregnan-20-one. In this study, we show that potentiation of GABA-mediated currents and gating of the GABA(A) channel by steroids, as well as steroid-induced anesthesia in tadpoles and mice, is enantioselective, with the (+)-enantiomers exhibiting significantly greater potency in all assays. The correlation between the effects of steroid enantiomers on channel behavior and their effects as anesthetics provides strong evidence that GABA(A) receptors play a predominant role in steroid-induced anesthesia. The enantiomers also provide a tool to probe the relative contributions of direct chloride channel activation versus potentiation of GABA-elicited currents to the induction of anesthesia. Studies examining the effects of combinations of (+)- and (-)-3alpha-hydroxy-5alpha-androstane-17beta-carbonitrile were consistent with the hypothesis that potentiation of GABA-activated currents contributes to steroid-induced anesthesia but indicated that direct steroid activation of GABA(A) receptors is not mechanistically important in producing anesthesia.
Mol Pharmacol 1996 Dec
PMID:Enantioselectivity of steroid-induced gamma-aminobutyric acidA receptor modulation and anesthesia. 896 80

Calcitrol, 1,25 dihydroxyvitamin D3 (1,25-D3) has an important role in the antiproliferative and growth regulatory effects on normal and neoplastic cells (e.g. prostate cancer cells). 1,25-D3 binds to the vitamin D receptor (VDR), a member of the steroid receptor superfamily. Steroids, via intranuclear receptors, have been demonstrated to have high affinity binding to the nuclear matrix, the tissue specific scaffolding of the nucleus that is involved in the organization of DNA, replication and transcription. We hypothesized that the VDR interacts closely with the nuclear matrix in both human and rat tissues. In the studies described here, nuclear matrix proteins (NMP) were extracted from a number of rat and human tissues and immunoblot analysis performed using a rat anti-VDR antibody. The results from these studies reveal that the anti-VDR antibody detects six forms of the VDR in the NMP preparations: human testis demonstrated a protein of 57 and 52 kDa molecular weight compared with 57 and 37 kDa in the rat testis. Human prostate demonstrated proteins of 52 kDa compared to rat ventral (57 and 37 kDa) and dorsal prostate (52 and 26 kDa). Human and rat bladder NMP demonstrated a protein binding at 55 kDa and rat seminal vesicle NMP binding at 48 kDa. This is the first report of VDRs associated with the nuclear matrix. The varying molecular weight proteins reactive with the anti-VDR antibody within these tissues may represent different isoforms, proteolytic cleavage of a larger VDR or post-translational modification. The VDR-NMP interaction may be involved in the tissue specific actions of 1,25-D3 especially growth regulatory and antiproliferative effects.
J Steroid Biochem Mol Biol 1998 Aug
PMID:Association of vitamin D receptors with the nuclear matrix of human and rat genitourinary tissues. 974 21

Spawnings of scleractinian corals are affected by light, temperature, and other environmental cues, but no studies elucidate physiological mechanisms that regulate coral gametogenesis. We hypothesized that estrogens may act as bioregulators of coral reproduction. Estrone (E1) and estradiol-17 beta (E2) concentrations were measured in homogenates of tissue and skeleton from M. verrucosa. Tissue samples were collected monthly throughout the year, and more frequently in July and August around spawning. Steroids were extracted with diethyl ether, purified via celite chromatography and assayed with radioimmunoassay. Non-specific binding in coral tissue varied with sample weight and was elevated relative to standards. Monthly mean E1 ranged from 20-70 ng E1 g ash-free dry weight (AFDW)-1, with highest values in April. Smaller asynchronous peaks occurred in early July, prior to spawning. Monthly mean E2 ranged from 8-25 ng E2 g AFDW-1, with highest values in February and March. Peaks in E2 preceded peaks in E1, indicating metabolism of a pool of estrogen. E1 was positively correlated with protein concentration, which is consistent with a bioregulatory role of estrogens. Estrogen peaks in spring and prior to the July spawn corroborate our hypothesis that estrogens regulate coral gametogenesis and spawning.
Comp Biochem Physiol A Mol Integr Physiol 1999 Jan
PMID:Estrone and estradiol-17 beta concentration in tissue of the scleractinian coral, Montipora verrucosa. 1021 33

Sulfation is an important conjugation reaction in the metabolism of steroids. Steroids sulfates do not interact with the appropriate hormone receptors; additionally, the presence of the charged sulfate moiety increases the aqueous solubility and excretion of most steroids. Estrogen sulfotransferase (EST) is the major form of human cytosolic ST involved in the conjugation of estrogens. EST is important in the inactivation of beta-estradiol (E2) during the luteal phase of the menstrual cycle. EST has a significantly higher affinity for the sulfation of E2 and 17alpha-ethinylestradiol (EE2) than for other potent estrogens such as diethylstilbestrol (DES) and equine estrogens. The ability of EST to sulfate these estrogenic compounds at physiologic concentrations is important in regulating their activation of the ER in estrogen responsive cells. Human Ishikawa endometrial adenocarcinoma (ISH) cells possess an estrogen receptor (ER)-regulated alkaline phosphatase (AlkPhos) which is used to assay ER activation. To study the effects of EST activity on the ER activation of different estrogenic compounds, ISH cells were stably transformed with an EST expression vector. Dose-response curves for the induction of AlkPhos activity by the different estrogenic compounds were generated with EST/ISH and control pcDNA/ISH cells. EST/ISH cells were 200-fold less sensitive to E2 and EE2 than were control cells. No differences were observed in the dose response curves for DES between EST/ISH and pcDNA/ISH cells. EST/ISH cells were approximately 3-10-fold less sensitive to the equine estrogens equilin and 17-equilin as compared to control cells. The ability of EST to decrease the ER activation of an estrogen correlates with the sulfation of these compounds at nanomolar concentrations by EST/ISH and pcDNA/ISH ISH cells. These results indicate that EST is capable of efficiently inactivating E2 and EE2 but is significantly less effective in inhibiting the ER binding of other potent estrogenic compounds.
J Steroid Biochem Mol Biol 1999 Feb
PMID:Regulation of estrogen activity by sulfation in human Ishikawa endometrial adenocarcinoma cells. 1036 11

Steroids and retinoids are important regulators of development in invertebrates and vertebrates. The central mediators of action of these compounds are their cognate receptors, which together form a family of proteins known as the nuclear receptor family. Previous studies have demonstrated that the genome of Onchocerca volvulus encodes at least three members of the nuclear receptor family. Here, the characterization of one member of this family from O. volvulus, designated OvNR-2, is described. OvNR-2 was found to be most similar to a number of vertebrate retinoic acid receptors and to the Drosophila melanogaster EiP78c protein. Modeling studies suggest that OvNR-2 forms a boot shaped ligand-binding cavity of a shape and size that can bind steroids. Expression of the mRNA corresponding to OvNR-2 is tightly regulated in adult parasites, appearing only in the extended intrauterine microfilariae. The protein derived from expression of the OvNR-2 cDNA in a bacterial system is recognized by serum antibodies in a majority of individuals infected with O. volvulus.
Mol Biochem Parasitol 1999 Nov 30
PMID:Characterization of a putative nuclear receptor from Onchocerca volvulus. 1059 80

The genus Morus consists of trees and shrubs, which are distributed in temperate and subtropical regions. Commonly known as mulberry, a few of the Morus species are valued for their foliage, which constitutes the chief feed for mulberry silkworms. Steroids and isoprenoid compounds present in the foliage not only add nutritive factors to the feed but also contribute greatly to silkworm health and silk production. Mevalonate synthesis, which is the first step in isoprenoid biosynthesis, is catalyzed by the enzyme hydroxymethylglutaryl-CoAreductase (HMGR). A genomic clone, Mahmg1, was isolated from Morus alba and its expression characterized in mulberry and transgenic tobacco. In mulberry, Mahmg1 transcripts were highest in young leaves and flowers. The promoter region of the Mahmg1 gene was fused to the beta-glucuronidase (GUS) reporter gene and the fusion introduced into tobacco. In imbibed embryos, GUS expression was limited to the cotyledons, epicotyl, and root elongation zone. Later, GUS staining was observed in floral tissues, guard cells, and the heads of trichomes on the stem and petioles. Mahmg1::GUS activity increased 3-4-fold by treatment with 100 microM abscisic acid and 15-80-fold in dark-grown versus light-grown seedlings. These results show that expression of the Mahmg1 gene is differentially regulated by developmental and environmental cues, suggesting that its HMGR isozyme a may provide a precursor for synthesis of specific isoprenoids during mulberry growth and development.
Plant Mol Biol 2000 Mar
PMID:Molecular characterization of a hydroxymethylglutaryl-CoA reductase gene from mulberry (Morus alba L.). 1080 2


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