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Query: UNIPROT:P06889 (Mol)
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We have analyzed the dimerization of two forms of the chicken progesterone receptor (cPRA and cPRB) by nondenaturing gradient gel electrophoresis and chemical cross-linking with dimethylpimelimidate (DMP). We demonstrate by these two methods that the PRs assemble in vitro into dimers in the absence of DNA, and that dimerization does not require hormone. The cPRA homodimer binds quantitatively to its cognate DNA response element in our nondenaturing gradient gel assay. DMP cross-linking confirms that both forms of the receptor (cPRA and cPRB) assemble into dimers in solution. Finally, in a standard mobility shift assay, chemically cross-linked receptors bind to the progesterone DNA response element with high affinity. We conclude that the PR contains a dimerization motif, which can promote stable subunit-subunit contacts without the presence of hormone in vitro. The complex thus formed expresses sequence-specific DNA-binding activity indistinguishable from that observed in the presence of hormone.
Mol Endocrinol 1990 Dec
PMID:Dimerization of the chicken progesterone receptor in vitro can occur in the absence of hormone and DNA. 208 81

The role of growth factor signal transducers in the induction of the progesterone receptor by epidermal growth factor (EGF) and the potential sites of EGF antagonism by an antiestrogen were studied in fetal uterine cells in culture. The effects of EGF and estradiol were not additive, suggesting that EGF and estradiol are acting through common mechanisms where antiestrogens could possibly intervene. Fetal uterine cells in culture were found to contain specific, high affinity binding sites for [125I]EGF. Estradiol treatment of the cells led to a higher number of binding sites, but the site of action of 4-hydroxytamoxifen is not the EGF receptor because this antiestrogen had no effect on EGF binding. Activation of protein kinase C by a phorbol ester (12-O-tetradecanoylphorbol 13-acetate) increased progesterone receptor levels to a similar extent as EGF or estradiol. Increasing the intracellular cAMP concentrations by either adding dibutyryl cyclic AMP or activating adenylate cyclase with forskolin also raised progesterone receptor concentrations. Neither the phorbol ester nor dibutyryl cAMP had any effect on cell proliferation. 4-Hydroxytamoxifen completely abolished the effects of the phorbol ester and cAMP. In conclusion, the levels of an estrogen-induced steroid hormone receptor can be regulated by molecules involved in the signal transduction pathway of peptide factors. Moreover, in fetal uterine cells, a potent antiestrogen appears to act as a multiple antagonist but only on an estrogen-inducible response.
Mol Cell Endocrinol 1990 Mar 05
PMID:Stimulation of progesterone receptors by phorbol ester and cyclic AMP in fetal uterine cells in culture. 215 66

Using biochemical methods we established that estrogen receptor content and distribution and progesterone receptor content in female and male baboon myocardium did not differ between sexes. In contrast, myocardial androgen receptor distribution between cytosolic and nuclear compartments was sexually dimorphic. Female baboon myocardial androgen receptors were restricted to the cytosolic compartment, whereas male myocardial androgen receptors were distributed between the cytosolic and nuclear compartments. Using human estrogen receptor cDNA we showed that baboon aorta, myocardium and uterus contain a 6.3 kb estrogen receptor transcript. Analyses performed with human progesterone receptor cDNA established that baboon aorta and uterus contain an 8 kb progesterone receptor transcript; however, progesterone receptor transcripts were not demonstrable in baboon myocardial RNA preparations. Because relative hybridization signal intensity reflected known uterine and aortic progesterone receptor content, failure to detect progesterone receptor transcripts in myocardial preparations may reflect sensitivity limitations and the fact that aortic progesterone receptor content is 5-fold greater than that of myocardium. Immunocytochemical analyses demonstrated that baboon myocardial progesterone receptors were present in greater than 25% of myocytes and generally absent from other myocardial cells. Our studies establish that: (1) gonadal steroid hormone receptor gene transcription occurs in cells of the baboon cardiovasculature, (2) these steroid hormone receptors may be physiologically functional, and (3) gonadal steroid hormone receptors may be restricted to specialized cells of the cardiovasculature.
J Steroid Biochem Mol Biol 1990 Sep
PMID:Sexual dimorphism characterizes baboon myocardial androgen receptors but not myocardial estrogen and progesterone receptors. 224 55

Aromatase (estrogen synthetase) occurs in a variety of tissues. Using immunocytochemistry, we have recently located this enzyme in cellular compartments of several types of human tissue. Furthermore, we found the mRNA was located in the same structures where tested. As both gonadal and peripherally formed estrogen contribute to growth of hormone sensitive cancers, we have developed aromatase inhibitors to block synthesis of this hormone. We have determined that 4-hydroxyandrostenedione (4-OHA) selectively inhibits aromatase activity in ovarian and peripheral tissues and reduces plasma estrogen levels in rat and non-human primate species. 4-OHA was also found to inhibit gonadotropin levels and reduce estrogen and progesterone receptor levels in treated animals. The mechanism of these effects appear to be associated with the weak androgenic activity of the compound. These effects together with aromatase inhibition may result in a synergistic response reducing estrogen production and action. In postmenopausal women, estrogens are mainly of peripheral origin. When postmenopausal breast cancer patients were administered either daily oral or parenteral weekly treatment with 4-OHA at doses that did not affect their gonadotropin levels, plasma estrogen concentrations were significantly reduced. Complete or partial response to treatment occurred in 34% of 100 patients with advanced breast cancer, while the disease was stabilized in 12%. These results indicate that 4-OHA is of benefit in postmenopausal patients with advanced disease who have relapsed from prior hormonal therapies, and that steroidal inhibitors may be of value in premenopausal patients.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:Aromatase inhibitors and hormone-dependent cancers. 225 37

The present data confirm the very complicity of the response of antiestrogen when this compound is studied in different experimental conditions. The new and potent antiestrogen ICI 164,384, which is considered as a full antagonist in most models studied, concerning the progesterone receptor in the isolated cells of the uterus and vagina of guinea-pig acts as a real agonist. However, this compound antagonizes cell proliferation, progesterone receptor, and decreases the concentration of estradiol in different hormone-dependent mammary cancer cell lines. Another interesting aspect is the response of the antiestrogen 4-hydroxytamoxifen which in isolated cells of very close tissues such as the uterus and vagina is an antagonist for the former and agonist for the latter concerning the progesterone receptor. In conclusion, the present data added new information in the complicity of the mechanism of action of antiestrogens, but using new models interesting possibilities are opened to understand their responses and their mechanism.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:Antiestrogen action in mammary cancer and in fetal cells. 225 39

The use of different techniques for assay of oestrogen receptors (ER) in breast cancer raises the question of their relative effectiveness in measuring concentrations of functional receptors. Data were obtained on soluble receptors from supernatants from 58 primary breast tumour homogenates, using the ligand ([3H]oestradiol) binding assay with dextran-coated charcoal (DCC) separation, either at a single saturating ligand dose, or by Scatchard analysis, and by using the Abbott enzyme immunoassay (EIA) kit. As previous reports have shown, the two methods gave reasonably good correlation (r = 0.8), but EIA values were systematically higher than DCC (slope = 3.0). Similar values were obtained when the ER + ve/progesterone receptor (PR) + ve subgroup were examined separately (n = 34, r = 0.86, slope = 3.0). However the two sets of data were in much better agreement in the ER + ve/PR - ve subgroup (n = 10, r = 0.98, slope = 1.24). When analysed by isoelectric focusing on polyacrylamide gels (IEF), two major specific binding components were identified, at pI 6.1 and at pI 6.6. Both isoforms were present in 50/66 ER + ve PR + ve breast tumour samples, but only the pI 6.6 (4S) was present in most ER + ve/PR - ve samples (13/20). It appears that, compared with DCC, the EIA method gives much higher values for the 8S isoform, whereas the two methods detect the 4S isoform with similar sensitivity. In assays on the tumour cell lines, T47D and MCF-7, still greater discrepancies, at least 10-fold, were found between EIA and DCC data.
J Steroid Biochem Mol Biol 1990 Dec 10
PMID:Discrepancies between antibody (EIA) and saturation analysis of oestrogen receptor content in breast tumour samples. 227 49

Displacement curves with estradiol (E2) and Tamoxifen (Tam) of the [3H]E2-ER binding in 49 ER+ mammary neoplasia showed a great heterogeneity suggesting the existence of more than one population of ER+ tumors when the relative binding affinity of both ligands for the ER was considered. The (D50E2/D50Tam) x 100 ratio was called Displacement Index (DI) with values asymmetrically distributed from 0.05 to 2.90. The range from 0.18 to 0.54 was adopted as central interval given by the median +/- SE (median: 0.36; SE: 0.09). DI values below 0.18 (24% of the tumors in our series) were considered as "lower", indicating that higher Tam doses would be necessary to displace the E2-ER binding. The potency of Tam as displacer is dependent not only of its own affinity for the ER, but also of that of E2 for the same receptor. The DI expresses their relative binding "strength". DI values were not correlated with ER and progesterone receptor content nor with the D50 Tam and D50E2 taken separately. Antiestrogen binding sites (AEBS) were determined in the cytosol (AEBSc) and in the microsomal fraction of 10 ER+ tumors from our series. The AEBSc/ER ratio was inversely correlated with the DI, that is, displacement of 3HE2 from the E2-ER complex by Tam would be lower in tumors with higher AEBSc/ER ratio. The DI is another parameter to be considered in the study of the sensitivity of breast neoplasias to antiestrogen treatments.
J Steroid Biochem Mol Biol 1990 Dec 10
PMID:Displacement by tamoxifen of the estradiol-estrogen receptor binding: a functional assay for breast cancer studies. 227 51

Nonactivated chick progesterone receptor from hypotonic tissue extracts exists in a large complex containing the heat shock proteins hsp90 and hsp70 plus additional smaller proteins; activation of receptor to a DNA-binding form involves the dissociation of proteins from the complex. Whereas numerous attempts to reversibly bind components to the activated receptor have been unsuccessful, we now report conditions that promote the reassociation of hsp90 and hsp70 to progesterone receptor. Cytosolic receptor was dissociated from hsp90 and hsp70 by treatment with 0.5 M KCl and 10 mM ATP in the absence of progesterone. It was then purified by binding to immunoaffinity resins. After wash steps, the receptor-resin complex was incubated in rabbit reticulocyte lysate at 30 C, rewashed, and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Saturable binding of rabbit hsp90 and hsp70 to chick receptor was found after incubation with reticulocyte lysate; hsp binding was temperature dependent, but not dependent on exogenous ATP. Incubation of dissolved receptor with oviduct cytosol, from which receptor was obtained, or with purified hsp did not result in hsp binding. Furthermore, mixing oviduct cytosol with lysate inhibited hsp reconstitution, suggesting negative factors for hsp binding in oviduct cytosol. The steroid-binding domain of the receptor was required, since no hsp binding was observed in the reconstitution system using a receptor mutant lacking this domain. When the receptor was isolated in the presence of progesterone, reconstitution with hsp90 and hsp70 did not occur. This is consistent with the in vivo effects of progesterone in promoting hsp dissociation.
Mol Endocrinol 1990 Nov
PMID:Reconstitution of progesterone receptor with heat shock proteins. 228 Jul 72

Onapristone and other antiprogestins proved to possess a potent antitumor activity in several hormone-dependent experimental breast cancer models. This activity is as strong or even better than that of tamoxifen or ovariectomy in the MXT-mammary tumor of the mouse and the DMBA-and MNU-induced mammary tumor of the rat. The antitumor activity is evident in these models in spite of elevated serum levels of ovarian and pituitary hormones. The detailed analysis of all our data including the morphological (ultrastructure) studies of the mammary tumors of treated animals and the effects on growth and cell cycle kinetics using DNA flow cytometry indicates that the antitumor action of antiprogestins is mediated via the progesterone receptor and related to the induction of terminal cell differentiation leading to increased cell death. The strong antitumor activity of antiprogestins in our experimental breast cancer models does not primarily depend on a classical antihormonal mechanism. The antiprogestin-related reduction of the number of mammary tumor cells in the S-phase in our experimental tumor models (G0G1 arrest) emphasizes the unique innovative mechanism of action of these new agents in the treatment of human breast cancer.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Antitumor activity and mechanism of action of different antiprogestins in experimental breast cancer models. 228 91

Steroid receptors exist in cytosol as 9S, non-DNA-binding species and as 4S (transformed) species that bind to DNA or nuclei. Labeling the progesterone receptor from rabbit uterine cytosol with [3H]progesterone in the presence of 10 mM sodium molybdate revealed a 9S species on sucrose gradient centrifugation. Without molybdate, the receptor sedimented as an intermediate species of 6S, which converted to 4S in 0.3 M NaCl. The 6S species could also be generated from the 4S species by dialysis. Dilution of the same 4S species gave only partial re-aggregation with 50% of the receptor remaining as 4S. Dialysis appeared to retain the association of a macromolecular aggregation factor present in cytosol. Serum did not seem to be the source of the aggregation factor, as perfusion of the uterine vasculature before excision did not affect the S value of the receptor. We tested whether RNA was involved by treating receptor with RNase A (100 micrograms/400 microliters cytosol). While the molybdate-stabilized cytosol receptor (9S) was unaffected, RNase A partially (50%) converted the 6S form of receptor to 4S. RNase A also partially converted the re-aggregated form back to 4S. Protease inhibitors had no effect on this action of RNase. Formation of receptor-ribonucleotide protein particles may play a role in steroid action in the cell.
Mol Cell Biochem 1987 Jan
PMID:Occurrence of a 6S intermediate form of the progesterone receptor that is sensitive to ribonuclease. 243 71


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