Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00627 (MAP)
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Uteroglobin was obtained from 5 day pregnant rabbits and purified to homogeneity by Sephadex G 75 and DEAE-cellulose chromatographies. Progesterone binding to uteroglobin was decreased by lyophilization and enhanced by SH-reducing agents. Dithiothreitol was more effective than dithioerythritol, and beta-mercaptoethanol was only active at 25 to 100 mM concentrations. SH-blocking agents (iodoacetate, iodoacetamide, phydroxymercuribenzoate and, dithiobisnitrobenzoic acid) inhibited binding. In the absence of SH-reducing agents only one in every 500 uteroglobin molecules bound the hormone, whereas under optimal conditions (20 mM dithiothreitol) one in every two molecules bound progesterone. There was no significant difference in equilibrium dissociation constants under these two conditions. Uteroglobin had a relatively high affinity for progesterone (KD=4.1 X 10(-7)M) but a threefold higher affinity for 5alpha-pregnane-3,20-dione (KD=1.3 X 10(-7)M). Estradiol was bound but non-specifically with a very low affinity, and its binding was not enhanced by SH-reducing agents. Hormonal specificity of binding to uteroglobin was different from that of binding to rabbit uterine progesterone receptor. Various synthetic progestagens (chlormadinone acetate, norethisterone, R5020) were bound to the latter but not to the former protein. Diethylstilbestrol had some affinity (15% of that of progesterone) for uteroglobin and no affinity for the progesterone receptor. Uteroglobin incubated in the presence or absence of cofactors (NADH and NADPH) with or without dithiothreitol did not metabolize progesterone.
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PMID:Interaction of uteroglobin with progesterone, 5alphapregnane-3,20-dione and estrogens. 1 Oct 93

The mechanism of action of the copper IUD was investigated in the rabbit uteri. The effects of copper on steroid-hormone-receptor interaction and the morphologic effects of copper were studied, and the uterine copper content was measured. In vivo and in vitro results were compared. Uterine cytosol was produced by daily sc injections of 50 mcg 17beta-estradiol for 8 days into immature female rabbits. 2 days later the rabbits were decapitated and the cytosol prepared from homogenized uteri. Radioactive steroids were purchased. Radioactivity was counted with a Packard 3390 liquid scintillation spectrometer. Progesterone binding to uterine cytosol was measured. Techniques used are described. On Day 8 of priming of female immature rabbits, a copper IUD was inserted into the right uterine horn. Progesterone (1 mg) or 17beta-estradiol (50 mcg) was injected sc for another 7 days. The rabbits were decapitated on Day 8 and their uteri excised. Sections were prepared and studied histologically. Each horn was minced and homogenized. The supernatant was used as cytoplasm and the copper content of each uterine horn measured. The binding capacity of the estrogen receptor was less affected by copper than was that of the progesterone receptor. Copper was a competitive inhibitor of steroid-ho rmone-receptor binding. Results indicate that copper acts through direct interference at the steroid-binding site of the receptor resulting in the increased contraceptive effect of the copper IUD. A 5-20% sucrose linear gradient centrifugation showed that estrogen and progeste rone receptors, which both sedimented at 8S, were changed to more sedimentary forms in the presence of 10-4 M Cu ++ and were dissociated to a 6.5S form with (some loss of steroid hormone binding affinity at 10-2 Cu ++. This dissociation and aggregation of the receptor macromolecules may cause biologic inactivation of the receptors. Histological study of the uteri of rabbits bearing the copper 7 IUD showed that progestational proliferation and estrogenic activity were inhibited. The copper content of the cytoplasm was increased in the presence of a copper IUD. The greater stability of the estrogen receptor in the presence of copper suggests an increased estradiol uptake in rat uteri bearing a copper IUD. The concentration of 1.4 X 10 -6 M Cu ++ appears to be effective in the steroid-hormone-receptor interaction. However, this effect by copper cannot exclude the coexistence of some other mechanism in these phenomena.
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PMID:The mechanism of action of the copper intrauterine device. 18 Dec 76

Estrogen priming increases uterine 8S macromolecule which binds progesterone specifically. Progesterone-8S complex in the cytoplasm enters into nucleus and is bound to chromatin finally. In this paper, the mode of nuclear translocation of steroid in exchange assay of receptor introduced by Anderson et al., and the mode of binding to chromatin were studied on the progesterone-receptor complex in the uterus of estrogen primed female rabbit. 1. After intravenous administration of 200 mug progesterone into the estrogen primed immature rabbit, uterine nuclei were prepared by the method in Table 1. These nuclei were incubated with 3H-progesterone and cold steroids at 4 degrees C for 30 minutes, and then washed with buffer A. The radioactivity of the nuclei was counted. This experiment was performed at 4 degrees C because progesterone receptor and chromatin were observed to be degraded at 37 degrees C for 20 minutes. The effect of cold steroids in vitro on the incorporation of 3H-progesterone into the uterine nuclei of rabbit pretreated with progesterone was found to be similar to their effect on progesterone-receptor binding in cytosol or chromatin (Fig. 1). 2. The effect of cold steroids on 3H-progesterone-receptor-chromatin triplex (Table 2 and Fig. 2) was examined. Once 3H-progesterone-receptor-chromatin triplex was formed, it was difficult to exchange 3H-progesterone to other steroids at 4 degrees C. These results (1 & 2) indicate that progesterone-receptor complex enters into nucleus and is bound to chromatin. Exchange of steroid may occur in the nuclear progesterone-receptor complex, which is free from the binding with chromatin. And thus exchange assay cannot represent quantitative data on receptor content. 3. 3H-progesterone-8S or 5S complexes were obtained by 5 approximately 20% sucrose linear gradient centrifugation (Fig. 3). The same molar concentration of these complexes from estrogen primed or castrated rabbit uterus were incubated with primed uterine chromatin for 30 minutes. Then the chromatin was washed with buffer A and the radioactivity was counted. It was shown in Fig. 4 that 3H-progesterone-8S complex was bound to chromatin much more tightly than 3H-progesterone 5-S complex in preparations obtained from both castrated or primed uterine cytosols. All these results indicate that 8S may be the biologically active form of the receptor. 4.3H-progesterone uptake into uterine nuclei was observed in very limited amount following the injection into uterine artery. The radioactivity in nuclei decreased easily by washing with buffer A as in Fig. 5. The small amount of residual radioactivity after washing, that is, very limited number of binding sites with high affinity is considered to be indicative of biologically active binding.
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PMID:[Studies on progesterone receptor in rabbit uterine cytosol -- nuclear translocation and chromatin binding-- (author's transl)]. 18 91

MPA (medroxyprogeste)rone acetate) has been shown to be te)ratogenic in rabbits but not in rats or mice (Andrew and Staples 1977). Since normal steroid action appears to be mediated, in large part, through interaction with specific steroid receptors, it was postulated that the species difference in teratogenicity might be due to a difference in the interaction of MPA with target cells. A primary event in steroid-cell interaction is the binding of a steroid to intracellular receptors. Studies were initiated to measure the specific nature of MPA binding to glucocorticoid and progestin receptors in appropriate rat and rabbit target tissues. The competition of MPA with 3H-dexamethasone binding in liver cytosol (glucocorticoid receptor) and with 3H-progesterone binding in uterine cytosol (progesterone receptor) was determined. In rabbit liver cytosol, MPA was as effective at competing for specific dexamethasone binding as the natural glucocorticoids and considerably more effective than the nonspecific steroids. In rat liver cytosol MPA was only 10% as effective as the natural glucocorticoids and the competition could not be distinguished from that of nonspecific steroids. A similar species difference was not seen in uterine cytosol; MPA competed with progesterone in a similar fashion in both rat and rabbit. These data demonstrate a distinct species difference in the competitive nature of MPA for the glucocorticoid receptor but not for the progestin receptor. The results suggest that MPA, or possibly a metabolite, may be teratogenic in rabbits by binding with specific glucocorticoid receptors to inhibit or alter normal steroidal function in embryo-fetal development.
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PMID:A potential mechanism in medroxyprogesterone acetate teratogenesis. 47 71

We examined the effects of progesterone and some synthetic progestins and other steroids on the physical properties of the progesterone receptor of guinea pig uterine cytosol and on the binding of the receptor by nuclei. Progestational potency seemed to correlate with the ability to keep the receptor in the 7S form and to prevent dissociation into smaller subunits. The rate of activation prior to nuclear binding was slower with steroids of increasing progestational activity. Therefore activation in vitro may be unrelated to biological activity. Concentration of the cytosol led to a decrease in the equilibrium association constant. The extent of the decrease was less with progesterone than with its metabolite, 5 alpha-pregnanedione. When cytosol and nuclei were incubated in the absence of ligand measureable progesterone receptor was bound by the nuclei. The uncomplexed nuclear receptor bound [3H]-progesterone of [3H]-R5020 rapidly at 0 degrees, but progesterone-receptor complexes exchanged [3H]-progestin slowly at 0 degrees. Progesterone increased the amount of nuclear receptor at concentrations of 10(-9) and 10(-8)M, but decreased binding at higher concentrations. 5 alpha-Pregnanedione had the same effect as progesterone, but other metabolites of progesterone that had little affinity for the 7S progesterone receptor in cytosol had no effect on nuclear binding at any concentration. Glucocorticoids, testosterone and estradiol-17 beta increased the nuclear binding of the progesterone receptor when present at concentration of 10(-8)M and greater.
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PMID:Effects of progestins on the progesterone receptor in guinea pig uterus. 47 78

The molecular conformation of 17-hydroxy-6 alpha-methylprogesterone has been determined crystallographically and is compared with 17-hydroxy-progesterone, 17-acetoxyprogesterone and 17-acetoxy-6 alpha-methylprogesterone (MPA). The analysis demonstrates that the 6 alpha-methyl substituent is not sufficient by itself to induce inversion of the A-ring. Consequently, the inverted form observed in MPA and proposed to be responsible for high affinity binding to the progesterone receptor appears to be induced by the combined long range influence of 17 alpha-acetoxy substituent and the direct interaction of the 6 alpha-methyl group with the flexible A-ring.
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PMID:Steroid structure and function V. A-ring conformation in 17-hydroxy-6 alpha-methylprogesterone. 51 15

This study was designed to examine whether 8S protein as progesterone receptor exists in the human endometrium which has been primed with estrogen. The kinetic study showed that 8S-progesterone binding was specific with Kd of 2.0 X 10(-9) M. 5S-progesterone binding was inhibited competitively by cortisol. The study of ligand specificity also showed that progesterone and its related steroids had much stronger affinity for 8S component than for 5S component. Therefore, 5S protein may be CBG. Progesterone-8S protein binding was easily dissociated during the 5-20% sucrose gradient centrifugation, but such a protein from which progesterone had been dissociated could be sedimented at 8S region. Glycerol could stabilize progesterone-8S protein binding. These results indicate the existence of 8S protein as a progesterone receptor under the low salt medium in the estrogen primed human endometrium.
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PMID:Progesterone receptor in human endometrium of leiomyoma uteri. 60 43

Norethindrone (17beta-hydroxy-19-nor-17alpha-pregn-4-en-20-yn-3-one) and norethindrone acetate (17beta-acetoxy-19-nor-17alpha-pregn-4-en-20-yn-3-one) interfered to a varying degree, by competitive inhibition, with the binding of progesterone and oestradiol to respective cytoplasmic receptors in the human uterus. Progesterone binding to 4S macromolecule was saturable and co-specific for progestins. Competitors like norgestrel (17beta-hydroxy-18-methyl-19-nor-17alpha-pregn-4-en-20-yn-3-one), 19-norprogesterone, medroxyprogesterone acetate (17alpha-acetoxy-6alpha-methylpregn-4-ene-3,20-dione) and compound R(5020) (17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione) possessed higher binding affinities for the progestin receptor. The dissociation constant (K(d)) for the progesterone-receptor interaction was 0.6-1.6nm and the receptor concentration ranged between 6600 and 8200 sites/cell. Norethindrone and norethindrone acetate competed for the progesterone receptor with inhibition constants (K(i)) of 6.8 and 72nm respectively. Gradient displacement and competitive-receptor assays indicated that norethindrone acetate-binding affinity for progestin receptor was approximately one-tenth that of norethindrone and progesterone. The progestins also inhibited oestradiol binding to 4.6S oestrogenic receptor by 8-12%, involving interaction at the oestradiol-binding site with a calculated K(i) value of 0.5-0.8mum. The competitive interaction of progestins with steroid receptors may be of putative importance in explaining the progestin action at the target site.
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PMID:Interaction of progestins with steroid receptors in human uterus. 74 57

A simple method for the assay of specific progesterone receptors in breast cancer tissue is described. Progesterone receptors were detected in 63 of 74 breast cancer specimens (85%). Estrogen receptor positive tumors had a wide range of progesterone receptor concentrations, but in 77% of cases the level was above 3 fmol/mg protein. The progesterone receptor level was generally low in tumors lacking estrogen receptors, 75% of the samples having concentrations between 0 and 3 fmol/mg protein. Unlike estrogen receptors, age had no influence on the number of progesterone receptors in breast cancer tissue.
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PMID:The determination of progesterone receptors in breast cancer and their relationship to estrogen receptors. 96 95

Recently, it was shown that lipoprotein lipase (LPL) was produced in neonatal but not in adult rat liver. In an attempt to further define the mechanism involved in liver LPL expression, we identified a neonatal mouse hepatoma cell line, BWTG3, capable of producing LPL. The regulation of LPL expression by various extracellular stimuli was investigated in this cell line. Progesterone caused a rise in LPL production by BWTG3 cells. Other hormones tested, such as insulin, glucagon, adrenalin, testosterone, and thyroid hormone, had no effect on LPL production. The effects of progesterone on LPL production showed slow kinetics reaching a maximum 24 h after addition. Cotransfection of a progesterone receptor expression vector with a 5'-LPL-CAT reporter construct resulted in an induction of CAT activity, suggesting that the increase in LPL accumulation after progesterone was linked to transcriptional induction of the LPL gene. Stimuli causing an elevation of protein kinase A activity in the cells also increased LPL production. Three agents capable of elevating intracellular cAMP levels, i.e., forskolin, dBcAMP, and choleratoxin, caused an elevation of LPL production. The increase in LPL activity caused by forskolin and choleratoxin was paralleled by an elevation of LPL mRNA levels, while dBcAMP only induced a small elevation of LPL mRNA levels. The increase in LPL production was shown to be linked to the stimulation of the PKA signal transduction pathway and was apparently transmitted via the transcription factor CREB. No effect of the stimulation of protein kinase C or calcium/calmodulin-dependent kinase on LPL production was detected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipoprotein lipase expression in undifferentiated hepatoma cells is regulated by progesterone and protein kinase A. 132 33


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