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Query: UNIPROT:P06889 (Mol)
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The objective of this study was to examine the mechanisms of estrogen receptor (ER) processing and replenishment in the uterus of ovariectomized rats after estradiol and progesterone treatment. Uterine ER binding activity, ER protein and ER mRNA were measured by receptor binding exchange assay, Western blot and slot blot, respectively. The regulation of ER levels in rat uterus by estradiol and progesterone was very dramatic. Changes in ER protein were faithfully reflected by changes in binding activity. Estradiol caused receptor "processing" within 4 h of administration followed by recovery or "replenishment" of ER levels to the initial level by 20 h. The term "processing" has previously been used to describe the loss of ER binding activity in the early phase of estradiol-action, but it was never clear whether the ligand binding site was inactivated by processing or if the receptor molecule actually disappeared. This study shows that receptor "processing" constitutes disappearance of receptor protein and the later "replenishment" phase represents new ER protein rather than recycling of "processed" receptor. Progesterone-action, on the other hand, influenced only the "replenishment" phase by blocking recovery of ER protein. ER mRNA was suppressed by estradiol at 8 h, after the receptor was "processed" and "replenishment" already initiated. Progesterone, on the other hand, did not alter the steady state level of the message. Other mechanisms, such as regulation of translation rate of existing mRNA and changes in the rate of degradation of ER proteins are more likely involved in acute regulation of ER by these ovarian steroid hormones.
J Steroid Biochem Mol Biol 1993 Dec
PMID:Regulation of estrogen receptor protein and messenger ribonucleic acid by estradiol and progesterone in rat uterus. 827 3

Progesterone, acting at the amphibian oocyte plasma membrane, triggers the progression of the prophase oocyte nucleus through the first meiotic metaphase. We previously reported a transient increase in 1,2-diacylglycerol (1,2-DG) within the first 1-2 min after exposure of Rana pipiens oocytes to progesterone. We have now investigated the source of the 1,2-DG, using this highly synchronous oocyte population. Phospholipid pools of intact prophase-arrested oocytes were labeled with [3H]glycerol, [methyl-3H]choline chloride or 1-O-[3H]octadecyl-sn-glycero-3-phosphocholine (lyso platelet activating factor, lysoPAF). [3H]LysoPAF is selectively taken up into the plasma membrane of the intact oocyte and esterified to form the [3H]alkyl-analogue of phosphatidylcholine (PC). Intact oocytes and/or isolated plasma membranes were then stimulated with progesterone and the changes in [3H]DG, [methyl-3H]phosphocholine and [3H]phospholipids were monitored as a function of time. Progesterone induced a transient increase in [3H]glycerol-derived DG, [methyl-3H]phosphocholine and [3H]alkyl-2-acylglycerol from [3H]alkyl-PC within the first 2 min, indicating activation of a PC-specific phospholipase C. Different pulse-labeling conditions indicate a biphasic rise in [3H]DG from [3H]glycerol-labeled oocytes; the first rise (1-2 min) when phospholipid labeling in the plasma membrane is enriched followed by an approximately 3-fold larger rise at 5-15 min when phospholipids of intracellular membranes are preferentially labeled. An early transient increase in [3H]DG or [3H]alkyl-2-acylglycerol was also seen when progesterone and/or guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) were added to isolated plasma-vitelline membranes prepared from oocytes prelabeled with either [3H]glycerol or [3H]lysoPAF. Progesterone thus appears to activate a G-protein-linked PC-specific phospholipase C in the oocyte plasma membrane which is followed by much larger DG release from intracellular membranes. The transient character of the hydrolysis suggests that this may represent a mechanism for transducing a membrane event into a meiotic signal.
Mol Cell Endocrinol 1993 Mar
PMID:Steroid action at the plasma membrane: progesterone stimulation of phosphatidylcholine-specific phospholipase C following release of the prophase block in amphibian oocytes. 838 17

Progesterone receptors (PRs) recognize and bind to DNA in a sequence-specific manner. To define the sequence-specific determinants of PR binding to DNA, we employed a detailed series of target elements and analyzed both PR binding in vitro and PR-mediated activation of a reporter gene in vivo. These elements represent point substitution or insertion mutants of a progesterone response element derived from the mouse mammary tumor virus (MMTV). Substitution of a G for the first T in the 15-base pair (bp) MMTV progesterone response element core sequence, GTTACAAACTGTTCT, increases PR-DNA binding in vitro. All other tested mutations within this sequence either had no effect or decreased PR binding. From these analyses, we infer an optimal PR recognition sequence, -7RGNACANRNTGTNCY+7, composed of hexameric half-sites separated by precisely 3 bp and exhibiting dyad symmetry. Limited substitution of a suboptimal base for an optimal base, as in the wild type MMTV element, can be tolerated, but further suboptimal substitutions significantly decrease binding by PR. The identity of 1 bp within the hexameric half-site, position +/- 5, is unconstrained. Transition mutations, but not transversions, are permitted at position +/- 7. Here the hydrogen bond acceptor of the N-7 position of the purine ring may be involved in receptor recognition, since this feature is shared by the permitted substitutions. Insertion of a single base pair between the half-sites abolishes detectable binding, suggesting that the spatial orientation of the DNA binding domains of the monomeric receptor subunits are fixed by dimerization of the receptor. This pattern of sequence-specific recognition parallels that previously inferred for the glucocorticoid receptor, indicating that the two receptors may be unable to distinguish individual target sites. Each of the mutant response elements was also assessed for its ability to confer progestin responsiveness to a truncated MMTV promoter when introduced into a PR-containing cell line. Elements exhibiting strong receptor binding in vitro were fully inducible, whereas poorly inducible or uninducible elements displayed little or no recognition by receptor in vitro. However, some elements, though poorly bound in vitro, still activated transcription in vivo in response to hormone. In certain cases activation was as good as that seen with the wild type element. Further examination of in vitro receptor binding by this class of mutant elements using higher levels of baculovirus-expressed receptor revealed that many were indeed recognized by receptor, albeit with a lower affinity than the wild type sequence.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Endocrinol 1993 Apr
PMID:The constitution of a progesterone response element. 838 96

The ability of the sex hormones progesterone, testosterone and estradiol-17 beta and the glucocorticoid dexamethasone to modulate expression of the interleukin-5 (IL-5) gene in T cell lines has been investigated. The T cell lines used show analogous regulation of IL-5 gene expression to that occurring in T-lymphocytes, in that IL-5 mRNA levels are undetectable unless the cells are induced with phorbol myristate acetate (PMA). Progesterone and testosterone were as effective as PMA in inducing IL-5 mRNA levels in the T cell hybrid NIMP-TH1 and induced IL-5, -3 and -2 mRNA accumulation in the T cell lymphoma EL-4. Estradiol-17 beta also induced IL-5 mRNA accumulation but less effectively than testosterone. Nuclear run-on experiments suggested that the effects of progesterone, testosterone and PMA on IL-5 gene expression were mediated at the level of transcription. The presence of the protein synthesis inhibitor cycloheximide completely prevented PMA-induced synthesis of IL-5 mRNA by both NIMP-TH1 and EL-4 cells, indicating that induction of IL-5 mRNA via PMA stimulation requires de novo synthesis of a presumptive trans-acting factor(s). PMA-, testosterone- and progesterone-induced expression of the IL-5 gene was completely blocked by the anti-inflammatory steroid dexamethasone. Stimulation of IL-5 expression by PMA was relatively resistant to the immuno- suppressive drug cyclosporin A although inhibition did occur at very high levels. Testosterone- and progesterone-induced IL-5 gene expression was not inhibited by cyclosporin A. The in vivo significance of these findings are not yet clear but the results show that sex hormones have the potential to regulate cytokine gene expression in cells possessing the appropriate steroid receptors.
J Steroid Biochem Mol Biol 1993 Mar
PMID:Sex hormones and dexamethasone modulate interleukin-5 gene expression in T lymphocytes. 846 Dec 54

Progesterone 5 alpha-reductase activity and 5 alpha-dihydroprogesterone 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSOR) activities (NADH- and NADPH-linked) were measured in anterior pituitaries, hypothalami and brains from lactating rats (8 and 21 days postpartum) and non-lactating (60-day-old cycling) rats. Tissue levels of these three enzyme activities varied significantly among the three groups examined. In terms of pituitary, mean levels of both of its 3 alpha-HSOR activities were 40-140% higher in actively lactating rats (8 days postpartum) relative to mean levels in lactating rats at weaning (21 days postpartum) or in non-lactating rats. There were no differences in pituitary progesterone 5 alpha-reductase activity among the three experimental groups. In the hypothalamus, the NADPH-linked 3 alpha-HSOR was elevated (50%) at 8 days of lactation compared to the group at 21 days. Hypothalamic NADH-linked 3 alpha-HSOR levels did not vary among the 3 groups. Hypothalamic progesterone 5 alpha-reductase levels in the actively lactating and weaning groups were 30% lower than those of the non-lactating group. Brain levels of progesterone 5 alpha-reductase were also lower in these two lactating groups (35-55%) as compared to the non-lactating control group. In brain, NADPH 3 alpha-HSOR activity did not vary among the three groups, but levels of NADH 3 alpha-HSOR activity were lower (40-50%) in the weaning group as compared to the actively lactating and control groups. These findings suggest the possibility that tissue changes in these progesterone-metabolizing enzyme activities during lactation and at weaning are influencing the in situ supply of 3 alpha,5 alpha-tetrahydroprogesterone and 5 alpha-dihydroprogesterone and their derivative effects on GABAA receptor activity and prolactin and gonadotropin release. The decreased activity of progesterone 5 alpha-reductase in hypothalamus and brain would presumably reduce in situ 5 alpha-dihydroprogesterone formation while increases in 3 alpha-HSOR activity would suggest higher in situ 3 alpha,5 alpha-tetrahydroprogesterone formation, especially in the pituitary.
J Steroid Biochem Mol Biol 1993 Mar
PMID:Changes in pituitary, hypothalamic and brain progestin-metabolizing enzyme activities during lactation. 846 Dec 62

This laboratory has previously reported that progesterone can initiate a rapid transient increase in the concentration of intracellular free Ca2+ ([Ca2+]i) and an increase in a Ca(2+)-requiring exocytotic event, the acrosome reaction (AR) in human sperm. Rapid increases in Ca2+ fluxes of some mammalian cells caused by another steroid, testosterone, require polyamine biosynthesis. Herein, we tested two polyamine biosynthesis suicide inhibitors for their effects on the progesterone-initiated increase in [Ca2+]i and AR in capacitated human sperm in vitro: DL-alpha-(difluoromethyl)ornithine hydrochloride (DFMO), an inhibitor of putrescine synthesis by ornithine decarboxylase and (5'[[(Z)-4-amino-2-butenyl]methylamino]-5'-deoxyadenosine (MDL 73811), an inhibitor of S-adenosylmethionine decarboxylase (required for spermidine and spermine synthesis). Sperm were capacitated in vitro and preincubated 10 min with 4.9 mM DFMO or 9.8 microM MDL 73811 with or without various polyamines (245 microM). Progesterone (3.09 microM final concentration) or progesterone solvent (ethanol, 0.1% final concentration) was then added, sperm fixed 1 min after additions and AR assayed by indirect immunofluorescence or with fluorescein-labeled Con A lectin. DFMO strongly inhibited the AR, but putrescine (product of ornithine decarboxylase and precursor of spermidine and spermine) reversed that inhibition. Preincubation for 25 min with DMFO + spermidine also reversed DFMO inhibition. MDL 73811 inhibited the progesterone-initiated AR, and a 10 min preincubation with spermidine, but not putrescine or spermine, reversed that inhibition. Preincubations with putrescine alone or with spermidine alone followed by addition of the progesterone solvent did not initiate the AR, and such preincubations followed by progesterone addition did not increase the AR more than progesterone alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Reprod Dev 1993 Apr
PMID:Effects of polyamine biosynthesis inhibitors on the progesterone-initiated increase in intracellular free Ca2+ and acrosome reactions in human sperm. 847 Dec 65

Estradiol-treated, rat pituitary cells were studied to examine the effects of progesterone (P) on follicle-stimulating hormone (FSH) synthesis and secretion. Progesterone was administered prior to or concurrent with 3 h secretory challenges with either gonadotropin-releasing hormone (GnRH), the iontophore A23187, the protein kinase C activator phorbol 12,13-myristate (PMA), or no secretagogue. Medium FSH levels and cell FSH stores were quantified by radioimmunoassay and bioassay. Acute (< 6 h) exposures to P increased medium levels of immunoreactive and bioactive FSH following GnRH challenge without influencing total (cell + medium) values whereas chronic (9-24 h) treatments increased both parameters. Chronic P elevated total FSH levels even when no secretagogue was present. Studies with antiprogestins, 5 alpha-dihydroprogesterone and 5 alpha-reductase inhibitors revealed that this direct action of P depended on progestin receptor occupation but not on 5 alpha-reduction. These studies indicate that P selectively increases bioactive and immunoactive FSH levels, presumably by increasing FSH synthesis, and characterize the time course and cellular mechanisms of this response. To accommodate for P modulation of total FSH levels, FSH secretion was standardized as the percentage of cellular stores available for release. Progesterone modulation of GnRH-stimulated FSH secretion was multiphasic, i.e. increased at 0-6 h, unchanged at 9 h and suppressed at 24 h. Acute and chronic exposures to P similarly modulated A23187-stimulated FSH release, whereas both P treatments increased PMA-stimulated FSH secretion. In these experiments P modulated luteinizing hormone secretion in parallel fashion, suggesting that common cellular mechanisms underlie peptidergic and steroidal regulation of the secretion of both gonadotropins.
Mol Cell Endocrinol 1993 Feb
PMID:Progesterone modulation of gonadotropin secretion by dispersed rat pituitary cells in culture. IV. Follicle-stimulating hormone synthesis and release. 847 44

The monoclonal anti-progesterone antibody DB3 binds progesterone with nanomolar affinity (Ka approximately 10(9) M-1), suggesting high specificity. However, DB3 also cross-reacts with similar affinity with a subgroup of structurally distinct, progesterone-like steroids. Crystals of the unliganded Fab' and various steroid-Fab' complexes are isomorphous and belong to the hexagonal space group, P6(4)22, with unit cell dimensions of a = b = 135 A, c = 124 A. Structures of free and progesterone-bound Fab' have been determined by X-ray crystallography at 2.7 A resolution using molecular replacement techniques. Progesterone is bound in a hydrophobic pocket formed mainly by the interaction of three complementarity determining regions L1, H2 and H3. The orientation of the ligand in the binding site was aided by both crystallographic and biochemical analyses of substituted steroids. The indole side-chain of TrpH100 of the DB3 has two different conformations, inter-converting "open" and "closed" forms of the antibody combining site. The TrpH100 indole thus appears to be acting as an antibody-derived surrogate ligand for its own hydrophobic binding pocket. These structures provide the first atomic view of how a steroid interacts with a protein and offer a structural explanation for the restriction of the anti-progesterone response to the VGAM3.8 family of VH genes.
J Mol Biol 1993 May 05
PMID:Three-dimensional structure of an anti-steroid Fab' and progesterone-Fab' complex. 849 56

To evaluate the possibility that 5 alpha-dihydro-11-deoxycorticosterone (5 alpha-DH-DOC), a weak mineralocorticoid, is an antagonist of a more potent mineralocorticoid, aldosterone, 0.25 microgram aldosterone was injected into adrenalectomized rats simultaneously with 200-800 micrograms 5 alpha-DH-DOC and urinary Na/K ratio and Na and K excretion were evaluated. Urinary Na/K ratio and Na excretion were significantly lower than those of control rats regardless of whether rats were treated with 0.25 microgram aldosterone alone or 400-800 micrograms 5 alpha-DH-DOC alone. Urinary Na/K ratio and Na excretion of rats given a combination of 0.25 microgram aldosterone plus 400-800 micrograms 5 alpha-DH-DOC were significantly higher than those of rats given 0.25 microgram aldosterone alone. None of the treatment caused significant changes in urinary K excretion. The results demonstrate that 5 alpha-DH-DOC, a weak mineralocorticoid, is an antagonist of the sodium-retaining action of a more potent mineralocorticoid, aldosterone. Progesterone which has weak mineralocorticoid activity is also known as an antagonist of more potent mineralocorticoids. The results of the present study demonstrate further evidence that weak mineralocorticoids may work as antagonists of more potent mineralocorticoids.
J Steroid Biochem Mol Biol 1993 Apr
PMID:5 alpha-Dihydro-11-deoxycorticosterone as a mineralocorticoid agonist and antagonist: evidence for a weak mineralocorticoid as an antagonist of potent mineralocorticoids. 849 32

When the mouse Y chromosome of Mus musculus domesticus is placed onto the C57BL/6J genetic background, half of the XY progeny develop bilateral ovaries and the female phenotype, but lack regular estrous cyclicity and lose embryos after fertilization. In the present study, we compared the endocrinological activity of XY ovaries with XX ovaries during postnatal development by measuring steroids in the incubation medium by radioimmunoassay. At 1 day postpartum (d.p.p.), production of progesterone and estradiol was significant while testosterone was undetectable in both ovaries. At 14 and 35 d.p.p., amounts of testosterone and estradiol produced by XY ovaries were half of those by XX ovaries. Production of progesterone by XY ovaries was slightly higher than XX ovaries at 14 d.p.p., but only half of that at 35 d.p.p. Addition of gonadotropins increased testosterone production by XX ovaries but not by XY ovaries at either 14 or 35 d.p.p. Progesterone production in XY ovaries at 35 d.p.p. was increased by gonadotropins to a much lesser extent than in XX ovaries. Gonadotropins increased estradiol production similarly in both ovaries at 35 d.p.p. Striking differences were found in the histochemical distribution of 3 beta-hydroxysteroid dehydrogenase between XY and XX ovaries at 14, but not at 35 d.p.p. In conclusion, the XY ovary develops abnormal endocrine features during the postnatal period, which likely lead to the fertility problems at puberty.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Endocrine differentiation of the XY sex-reversed mouse ovary during postnatal development. 849 34


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