Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We have used monoclonal antibodies against the estrogen (E), progestin (P) and androgen (A) receptors (R) to study receptor localization and regulation in the seminal vesicles of rhesus monkeys under different hormonal conditions. The antibodies caused substantial shifts of the appropriately labeled receptors on sucrose gradients. ER levels were lower in intact males than in immature, castrate, and estrogen-treated castrates. With immunocytochemistry, ER were detectable only in stromal and smooth muscle cells, not the epithelium. The number of ER-positive stromal cells was significantly lower in intact males than in immature, castrate, and estrogen-treated castrates, and low in a DHT-treated castrate animal. Androgen receptors were localized in epithelial as well as stromal and smooth muscle cells, and the number of AR-positive stromal cells was highest in intact adults and lowest in castrated and immature animals. Estrogen treatment at the time of castration induced PR in the ER-positive stromal cells, prevented a decline in the number of AR-positive stromal cells, and caused stromal hypertrophy. In summary, in the seminal vesicle, as in the prostate, ER is restricted to the fibromuscular stroma, is suppressed by androgens, and can mediate induction of PR on estrogen treatment. Androgen receptors are present in epithelial as well as stromal and smooth muscle cells, but variations in hormonal state appear to affect regulation of AR more in the stroma than the epithelium.
J Steroid Biochem Mol Biol 1990 Sep
PMID:Localization and regulation of estrogen, progestin and androgen receptors in the seminal vesicle of the rhesus monkey. 224 43

FCE 24928 (4-aminoandrosta-1,4,6-triene-3,17-dione) was selected among a series of 4-aminoandrostenedione derivatives as a novel irreversible aromatase inhibitor. Its in vitro and in vivo properties have been studied and compared to FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione) and 4-OHA (4-hydroxyandrostenedione). FCE 24928 caused time-dependent inhibition of human placental aromatase with a t1/2 of 4 min and Ki of 59 nM. Enzyme inactivation by FCE 24928 was faster than by FCE 24304 (t1/2 13.9 min). In PMSG-treated rats, microsomal ovarian aromatase activity was reduced 24 h after FCE 24928 dosing by both the s.c. (ED50 1.2 mg/kg) and the oral (ED50 14.1 mg/kg) routes. The compound was more potent than FCE 24304 and 4-OHA (ED50 1.8 and 3.1 mg/kg s.c.). FCE 24928 did not show any interference with 5 alpha-reductase and desmolase activity nor any significant binding affinity for androgen and estrogen receptors. Slight binding affinity for androgen receptor was observed with FCE 24304 and 4-OHA (0.21 and 0.25% of DHT). In immature, castrated rats, FCE 24928 did not show any intrinsic androgenic activity, up to 100 mg/kg/day s.c., in contrast to a slight androgenic activity observed with FCE 24304 at 10 mg/kg s.c.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:4-Aminoandrostenedione derivatives: a novel class of irreversible aromatase inhibitors. Comparison with FCE 24304 and 4-hydroxyandrostenedione. 225 40

The highest molecular weight form of the calf uterine androgen receptor separates as an 11S form in glycerol gradients. This "cytosolic" receptor, prepared in the presence of molybdate, polyethyleneimide and low ionic strength, dissociates into 9S and 7.2S forms with increasing KCl concentration. A 4.5S androgen binding component appears as the predominant form of the receptor in the absence of polyethyleneimide and this unit quantitatively converts to a stable 3.5S form in the absence of molybdate. Renaturation of partially purified protein, separated by SDS-PAGE electrophoresis, demonstrates the presence of an androgen binding component in the 110 kDa region of the gel. This renatured protein separates as a 4.5S component in glycerol gradients and has a Stokes radius of 6 nm. Photoaffinity labelling of partially purified receptor preparations, followed by SDS-PAGE electrophoresis, reveals the presence of an androgen binding component having a molecular weight of 115 kDa. The binding characteristics and specificity of the receptor binding to R1881 have been studied and a DHT-affinity chromatography resin used to purify the receptor.
J Steroid Biochem Mol Biol 1990 Nov 30
PMID:Characteristics of the calf uterine androgen receptor. 227 33

The purified cytosolic 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSOR) from female rat pituitary which catalyzes the reversible conversion of 5 alpha-dihydroprogesterone (5 alpha-DHP) to 3 alpha, 5 alpha-tetrahydroprogesterone (3 alpha, 5 alpha-THP) has been characterized in terms of its steroid substrate specificity, dihydrodiol dehydrogenase activity and inhibition by drugs such as medroxyprogesterone and indomethacin. The purified enzyme has a strong preference for the C21 progestin steroid substrates, 5 alpha-DHP and 3 alpha, 5 alpha-THP, over the corresponding C19 androgenic steroid substrates, 5 alpha-dihydrotesterone (5 alpha-DHT) and 3 alpha, 5 alpha-tetrahydrotestosterone (3 alpha, 5 alpha-THT). The apparent Km for 5 alpha-DHP (80 nM) is about 250 times lower than the Km for the androgenic steroid, 5 alpha-DHT (21 microM). In the oxidative direction, the apparent Km for 3 alpha, 5 alpha-TP (1.4 microM) is about 3-fold lower than the Km for the androgenic steroid, 3 alpha, 5 alpha-THT (4.2 microM). A number of other naturally occurring 3-keto- and 3 alpha(beta)-hydroxy-steroids were assessed for their ability to act as inhibitors (alternate substrates) of the 3 alpha-reduction of 5 alpha-DHP catalyzed by the purified 3 alpha-HSOR. None of the 3 beta- or 5 beta-isomers had any effect. Of the other 3-keto and 3 alpha- steroids tested, only deoxycorticosterone and the ovarian progestins showed any significant inhibition. These may be acting as inhibitors since there was little, if any, direct 3 alpha-reduction of progesterone to 3 alpha-hydroxy-4-pregnen-20-one. Unlike the liver cytosolic 3 alpha-HSOR, the pituitary enzyme has no associated dihydrodiol (quinone) dehydrogenase activity. This enzyme is similar to other cytosolic 3 alpha-HSORs from liver and brain in that it is potentially inhibited by indomethacin and by medroxyprogesterone.
J Steroid Biochem Mol Biol 1990 Nov 30
PMID:Characterization of the purified pituitary cytosolic NADPH:5 alpha-dihydroprogesterone 3 alpha-hydroxysteroid oxidoreductase. 227 37

Complementary DNA (cDNA) clones encoding human-androgen receptors (haR) were isolated using synthetic oligonucleotides homologous to the human glucocorticoid, estradiol, progesterone, and aldosterone receptors as probes to screen a human testis lambda gt11 cDNA library. One of the receptor proteins (hARa) produced in vitro bound the [3H]dehydrotestosterone ([3H]DHT) with high affinity and selectivity similar to the human androgen receptor present in target tissues and cells. A second cDNA clone (hARb) encoding an identical amino terminal and DNA binding domains, but differing by four amino acids at the hormone binding domain, did not bind [3H]DHT with high affinity when incubated with protein expressed by in vitro transcription-translation. Cotransfection of hARa in an expression vector with mouse mammary tumor virus (MMTV)-bacterial chloramphenicol acetyltransferase chimeric plasmids, followed a hormone-dependent trans-activation, defining the binding affinity of hARa between 5 x 10(-10) and 1 x 10(-9) M for [3H]DHT. A similar cotransfection experiment with hARb indicated a KD of hARb for [3H]DHT to be above approximately 10(-8) M. The deduced primary structures of hARa and hARb contain the viral erbA homologous region found in other steroid, thyroid, and vitamin receptors and is identical to the hAR sequences reported by others. The amino acid sequence differs at the Gly stretch (16 Gly instead of 27, 24 or 23) of the N-terminal domain and in hARb, the sequence reads I.F.F.F.F.L.L (816-822) instead of K.F.F.D.E-L (816-821) in the hARa and other reported hAR sequences. The difference of four amino acids in the steroid binding domain of hARb is associated with altered DHT binding and thus a lack of trans-activation by way of AR responsive elements in MMTV-long terminal repeat. The interaction of hARa and hARb with synthetic responsive elements by gel-retardation assay and their responsiveness in trans-activation by calcium phosphate coprecipitation demonstrates that hARb can inhibit trans-activation by hARa in this system.
Mol Endocrinol 1990 Mar
PMID:Specific region in hormone binding domain is essential for hormone binding and trans-activation by human androgen receptor. 234 76

The nucleocytoplasmic RNA transport in rat ventral prostate was studied by electron microscope autoradiography. Isolated prostate acini from normal, castrated, and DHT-treated animals were labeled in vitro with [3H]uridine for 5 min and chased for 0, 15, 30 min and 4 hr. The results show that DHT induces a significant nucleolar enlargement but intranuclear migration of rRNA is not apparently affected by androgens; migration of RNA through euchromatin is delayed by castration and stimulated by DHT; migration through the nuclear envelope is androgen-dependent. In addition prostate acini were maintained for 24 hr in suspension culture in order to study the in vitro effects of DHT. The result show that DHT stimulates uridine uptake and/or incorporation but induces no nucleolar enlargement; DHT has no clear effects on RNA migration kinetics; cytoplasmic transport of RNA in cells cultured in medium with or without DHT is severely impaired but is restored after supplementation of medium with insulin and dexamethasone.
J Ultrastruct Mol Struct Res 1986 Jan
PMID:Quantitative ultrastructural autoradiographic study of RNA transport in rat ventral prostate. 243 32

The fine modulation of gonadotropin gene expression and secretion is well recognized to be regulated by sex steroids through their direct action both at the anterior pituitary level and on the pulsatile pattern of GnRH secretion at the hypothalamic level. Since the influence of sex steroids on hypothalamic GnRH mRNA levels remains to be elucidated, quantitative in situ hybridization was used to study the effect of sex steroids on cellular levels of pro-GnRH mRNA in adult rats of both sexes. The effects of 14-day gonadectomy as well as administration of 17 beta-estradiol (E2, 0.25 micrograms) or dihydrotestosterone (DHT, 100 micrograms) twice a day during 14 days to gonadectomized animals were evaluated. In addition, the effect of progesterone (P, 2 mg, twice daily) alone or in the presence of E2 was also studied in ovariectomized animals. Hybridization was performed using a 35S-labeled cDNA probe encoding rat pro-GnRH and the corresponding mRNA levels were assessed by counting the number of silver grains overlying labeled neurons. In male rats, castration induced a highly significant 65% increase (compared to intact rats) in the mean number of grains per neuron. Administration of E2 or DHT to castrated animals completely prevented the post castration rise in pro-GnRH mRNA levels. In female animals, the effect of ovariectomy was less striking than in the male, a 25% increase (P less than 0.001) being observed. Treatment with E2 or DHT also completely prevented the increase in pro-GnRH mRNA levels induced by ovariectomy. Moreover, treatment with P in ovariectomized animals markedly potentiated the inhibitory effect of E2 on pro-GnRH mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1989 Nov
PMID:Regulation of pro-gonadotropin-releasing hormone gene expression by sex steroids in the brain of male and female rats. 251 47

Since there is convincing evidence for a role of adrenal steroids as precursors of active sex steroids in peripheral tissues, especially prostate cancer, we have studied the effect of the four main adrenal steroids, namely dehydroepiandrosterone sulfate (DHEA-S), DHEA, 5-androstene-3 beta,17 beta-diol (delta 5-diol) and 4-androstene-3,17-dione (delta 4-dione) on the growth of an androgen-sensitive clone (SEM-1) of the mouse mammary carcinoma Shionogi. From a control doubling time of 6.69 +/- 0.03 days, 0.1 microM DHT, 1.0 microM delta 4-dione, 10 microM delta 5-diol, 10 microM DHEA-S and 10 microM DHEA decreased generation time to 1.60 +/- 0.01, 1.69 +/- 0.01, 1.95 +/- 0.01, 4.37 +/- 0.02 and 5.66 +/- 0.03 days, respectively (P less than 0.01 vs. control). The same compounds exerted their stimulatory effects on cell growth at the following ED50 values: 0.06 nM, 16 nM, 90 nM, 150 nM and 16 microM for DHT, delta 4-dione, DHEA, delta 5-diol and DHEA-S, respectively. The stimulatory effect of all compounds was inhibited in a competitive manner by the pure antiandrogen hydroxyflutamide. Further evidence for an action of the adrenal steroids through the androgen receptor is indicated by competition of [3H]testosterone uptake in the tumor cells at the following IC50 values: 0.21 nM, 0.63 nM, 50 nM, 75 nM and 680 nM for DHT, testosterone, delta 4-dione, delta 5-diol and DHEA, respectively. The present data show that the four main adrenal steroids present in the serum of adult men can exert potent stimulatory effects on the growth of an androgen-sensitive cancer cell line through an androgen receptor-mediated mechanism.
Mol Cell Endocrinol 1988 Aug
PMID:Adrenal precursor C19 steroids are potent stimulators of growth of androgen-sensitive mouse mammary carcinoma Shionogi cells in vitro. 297 15

Two specific androgen binding sites were characterized in the ovine follicle with [3H]DHT, [3H]T and [3H]R-1881 as ligands, different incubation times and a charcoal separation step: the first, with characteristics very similar to testicular ABP in terms of its capacity, affinity, association and dissociation rates and specificity for natural and synthetic androgens, was found in serum, follicular fluid and the 27000 X g particulate and cytosol fractions of granulosa cells; the second, classic androgen receptors, were found in the cytosol with high affinity and low capacity for the synthetic androgen R-1881 and a very slow steroid-protein rate of dissociation. Saturation analysis on purified nuclei showed only the presence of the androgen receptor binding R-1881 with capacity similar to cytosol receptor. Isolated follicles showed a direct correlation between the total concentrations of androgen ([3H]-[3H]R-1881) binding sites and the follicular diameter. The complex actions which androgens exert on granulosa cell function may be mediated by interactions in vivo between these extra- and intracellular specific androgen binding proteins.
Mol Cell Endocrinol 1985 Mar
PMID:Distribution of specific androgen binding sites within the ovine ovarian follicle. 387 36

Adult male rats were injected into the lateral brain ventricle with 5,7-dihydroxytryptamine (5,7-DHT). They were adrenalectomized 5-7 days later and, following an additional 24 h, the specific in vitro [3H]corticosterone binding capacity of dorsal hippocampal slices was determined by estimation of uptake of radioactivity by the nuclear fraction. Specific corticosterone (CS) binding was reduced by 50-70% in the neurotoxin-treated as compared to vehicle-injected animals. Brain serotonin and 5-hydroxyindoleacetic acid concentrations were depleted by 50-70% in the 5,7-DHT-injected rats. These results suggest that the maintenance of normal dorsal hippocampal CS binding capacity is dependent upon the integrity of endogenous brain serotoninergic neuronal systems.
Mol Cell Endocrinol 1983 Aug
PMID:Hippocampal cell nuclear binding of corticosterone following 5,7-dihydroxytryptamine. 619 32


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