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PubMed2005

Expression of progesterone receptor(s) during capacitation and incidence of acrosome reaction induced by progesterone and zona proteins in boar spermatozoa.

Sperm acrosome reaction (AR) is a prerequisite step for in vivo fertilization. In the vicinity of the oocyte, zona protein(s) (ZP) and progesterone (P4), a component of follicular fluid, are proven to be responsible for physiological AR induction. In the present study, a thorough analysis of the role of the progesterone receptor (PR) in this processing including in vitro physiological studies and biochemical isolation and characterization of the receptor protein was conducted. Following capacitation for 0, 2, 4 and 6h, pooled fertile boar semen samples (n=6) with >70% sperm motility were labeled with P4-BSA-FITC (100 microg/ml) to detect the activation of PR. Parallel sperm samples were treated with P4 (10 microg/ml) for 20 min to test AR inducing efficiency at different time points. To compare the ability of ZP and P4 to induce AR, spermatozoa capacitated in a modified medium supplemented with 1mg/ml heparin for 4h, were then treated with heat solubilized ZP (150 microg/ml), P4 (10 microg/ml) or ZP+P4 for 20 min. FITC-peanut agglutinin staining was applied to observe the disrupt acrosomal morphology. A purification protocol for crude boar sperm membrane proteins was developed based on ligand-receptor affinity chromatography procedures. The PR proteins were then identified by using mAb C262 raised against intracellular PR, combined with second antibody (SDS-PAGE, Western blotting). Their N-terminal amino acid sequence was determined. The amount of PR-activated spermatozoa was enhanced with time (onset: 27+/-5%, 2h: 41+/-4%, 4h: 49+/-3% and 6h: 52+/-4%, mean+/-S.E., n=6) as evidenced by increasing percentage of spermatozoa with completed cap fluorescent staining. In parallel sperm samples, percentages of AR induced by P4 were 9+/-2, 14+/-2, 18+/-2, and 24+/-2%, respectively. In solvent control at all time points, less than 10% spermatozoa had undergone AR. Capacitation for 4h or greater time periods resulted in optimal percentage of PR-activated and acrosome-reacted spermatozoa. After sperm incubation in heparin-medium, ZP+P4 treatment induced greater amounts of AR than either P4 or ZP alone (13+/-1% compared with 8+/-1 and 10+/-1%, P<0.01). Inducing capacity of P4 was comparable to that of ZP. The molecule weights of two apparent PR molecular masses were detected to be at Mr 74 kDa and Mr 63 kDa. N-terminal amino acid sequence of 74 kDa protein was XPXNIVLIFADXLXY, which had 78% homology to arylsulfatase A and 88% homology to 72 kDa protein from boar spermatozoa. The activation of PR is associated with the capacitating process and that appears to be required for P4-induced AR. P4 and ZP appear to be equally capable of independently inducing the AR but lack synergetic or additive effects in this induction process. Both might represent alternative pathways thus resulting in alternative systems for induction of the prerequisite acrosomal exocytosis (supported by NSC 90-2313-B-005-114; 91-2313-B-005-131).

Acrosome Reaction↗
PubMed2003

Progesterone antagonists and progesterone receptor modulators: an overview.

Since the original description of the structure of the antiprogestin, mifepristone, was published, numerous related compounds have been synthesized which may function as progesterone antagonists (PAs) or progesterone receptor modulators (PRMs). The latter are mixed agonists-antagonists. Both PAs and PRMs have therapeutic applications in female health care. Mifepristone is predominantly a PA and displays only minimum agonist activity in certain systems. Together with a prostaglandin, mifepristone can terminate pregnancies of less than 9 weeks duration, and it may also be used at later gestational ages. Mifepristone causes expulsion of the uterine contents following intrauterine fetal death. A mifepristone-prostaglandin combination has been shown to be very effective treatment in women with menses delay of 11 days or less. Many PAs and PRMs display antiproliferative effects in the endometrium. Serum estradiol levels however remain in the early to mid-follicular phase range. For this reason, they have application in the treatment of endometriosis and myoma without being associated with bone loss and hypoestrogenism. PRMs may also find application in the treatment of dysfunctional bleeding as well as an adjunct to estrogens in hormone replacement therapy in postmenopausal women. Many PAs have contraceptive potential by suppressing follicular development and blocking the LH surge. Low doses may also be potential contraceptives by retarding endometrial maturation without affecting ovulation or inducing bleeding. Mifepristone is an excellent agent for use as an emergency "postcoital" contraceptive. PAs may also be useful in IVF programs to prevent a premature LH surge and to delay the emergence of the implantation window. In addition to their use in women's health care, mifepristone and several other PAs are potent antiglucocorticoid agents and may be used to treat ACTH-independent Cushing's syndrome. They may also be used in the treatment of tumors containing steroid receptors and in other situations which require suppression of the ACTH-cortisol axis.

Abortifacient Agents, Steroidal↗
PubMed2002

Progesterone and progesterone receptors in reptiles.

The role of progesterone (P) has been most extensively studied in the female reproductive tissues (ovary, reproductive tract, mammary gland) and in the brain, in which it is an important regulator and modulator in conjunction with estradiol (E). In nonmammalian vertebrate species, less work has been done on P metabolites involved in ovulation. In addition, P induces the expression of egg-white proteins, decreases myometrial contractility, and facilitates processing of eggs, formation of eggshell, and deposition of egg-white proteins. Actions of P may be synergistic with, or antagonist to, the actions of E, depending on hormone ratios, timing of exposure, and physiological state. These effects of P are mediated through progesterone receptor isoform A (PRA), a general transcription inhibitor of P target genes, and isoform B (PRB), a specific transcriptional stimulator of some reproductive tract genes. In this review, we focus on P action and PR expression in the liver and reproductive tissues of several reptilian species, especially Chelonia, since most of the data obtained are from this group. We also present novel data showing the expression of PR in nonreproductive tissues (such as kidney, spleen, gastrointestinal tract) in the painted turtle, Chrysemys picta.

Animals↗
PubMedDate not supplied

Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium.

Progesterone antagonists (PAs, antiprogestins) can modulate estrogenic effects in various estrogen-dependent tissues. These modulatory effects are complex and depend on species, tissue, type of compound, dose, and duration of treatment. In non-human primates, PAs, including mifepristone, ZK 137 316 and ZK 230 211, inhibit endometrial proliferation and induce amenorrhea. When administered chronically at relatively low doses, these compounds block the mitotic activity of endometrial epithelium and induce stromal compaction in a dose-dependent manner in both spayed and intact monkeys at high estradiol concentrations. These effects were accompanied by an atrophy of spiral arteries. The antiproliferative effects were endometrium-specific, since the estrogenic effects in the oviduct and vagina were not inhibited by PAs. Similar endometrial antiproliferative effects were also found after treatment with the progesterone receptor modulator (PRM), mesoprogestin J1042. The endometrial antiproliferative effects of PAs, particularly within the endometrial glands, were also observed in spayed rabbits. In spayed rats, however, the PAs did not inhibit, but rather enhanced, various estrogen responses, including endometrial proliferation, pointing to species-specific differences. In conclusion, our studies indicate that both pure PAs and PRMs selectively inhibit estrogen-dependent endometrial proliferation in the primate endometrium without affecting estrogenic response in other estrogen-dependent tissues or inducing unscheduled bleeding. Our studies indicate that the spiral arteries, which are unique to the primate endometrium, are the primary targets that are damaged or inhibited by PAs and PRMs. The damage to these unique vessels may underlay the paradoxical, endometrium-specific, antiproliferative effects of these compounds. Hence, the properties of PAs and PRMs (mesoprogestins) open up new applications in gynecological therapy and hormone replacement therapy.

Animals↗
PubMedDate not supplied

Progesterone receptor modulators and progesterone antagonists in women's health.

Both progesterone receptor modulators (PRMs) as well as pure progesterone antagonists (PAs) have numerous proven and potential therapeutic applications in female health care. Mifepristone, a PRM with only marginal agonistic activity, together with a prostaglandin can terminate pregnancies of less than 9 weeks duration; mifepristone is also used in the preparation of women at later gestational stages whose pregnancies are terminated with prostaglandins or surgery. Mifepristone causes expulsion of the uterine contents following intrauterine fetal death and promotes dilation of the non-pregnant primigravid uterus. It is also effective in the treatment of missed abortion. Together with methotrexate, mifepristone can be used in the medical treatment of ectopic pregnancy. Both PAs and PRMs display antiproliferative effects on the endometrium. Because of this, they have application in the treatment of endometriosis, an estrogen-dependent condition. They may also be utilized to reduce myoma size, acting as both a PA and antiproliferative agent. Unlike GnRH agonists, long-term use in endometriosis and myoma is not associated with loss of bone and hypoestrogenism. PRMs may also be useful in IVF programs to prevent a premature LH surge and to delay the emergence of the implantation window. Some PRMs have potential use as hormone replacement therapy in women during menopause or in those with dysfunctional uterine bleeding.

Abortifacient Agents, Nonsteroidal↗
PubMedDate not supplied

Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer.

Progesterone antagonists (PAs) (antiprogestins) or progesterone receptor modulators (PRMs) form an interesting category of new hormonal agents in the treatment of breast cancer. In vitro, antiproliferative effects of different PAs are mainly observed in estrogen-stimulated growth of PR-positive tumor cell lines. Both progestin agonist/antagonist actions on mammary tumor cells are dependent on the type of cell line, culture medium and concentrations of the PAs used, and type of biologic response measured. In various experimental animal tumor models, different PAs showed a greater antitumor activity than tamoxifen or high-dose progestins. Most interestingly, combination treatment of different PAs (mifepristone, ORG 31710, onapristone) or PRMs with different antiestrogens (tamoxifen, droloxifen, ICI 164384) or with an aromatase inhibitor (atemestane) showed greater antitumor efficacy than treatment with each single type of drug alone. These additive antiproliferative effects were demonstrated in various experimental in vitro and in vivo models. In some studies, these effects were accompanied by additive effects on several cell biologic parameters. In pretreated postmenopausal patients with metastatic breast cancer, objective responses have been observed in 10-12%, and stable disease in 42-46% of the patients; in previously untreated patients objective response rates of 11 and 56% have been reported. The clinical development of onapristone was stopped because of liver toxicity. At the present time, apart from development of new pure potent PAs, clinical investigation of combined therapy of PAs with antiestrogens are urgently needed.

Breast Neoplasms↗
PubMed2002

Estrogen and progesterone receptor content in the pituitary gland and uterus of progesterone-primed and gonadotropin releasing hormone-treated anestrous ewes.

The objective of this work was to investigate the effect of progesterone (P) and gonadotropin-releasing hormone (GnRH) treatment on estrogen receptor (ER) and P receptor (PR) concentrations in the pituitary gland and uterus of anestrous ewes. Ewes were either not treated (group C, n = 4); were treated with 0.33 g P-controlled internal drug release (P-CIDR) for 10 days (group P, n = 4), with GnRH, 6.7 ng i.v. injections every 2 h for 18 h followed by a 4 microg bolus administration of Receptal at 20 h (group GnRH, n = 4), or with a combination of the P and GnRH treatment (group P + GnRH, n = 3). Ewes were humanely killed either at the beginning of the experiment (group C), when the CIDR was removed (group P), or 24 h after the GnRH bolus treatment (groups GnRH and P + GnRH). Progesterone treatment increased serum P concentrations, indicating that the treatment was effective. All GnRH treated ewes had similar luteinizing hormone (LH) surges, which lasted 8 h. At slaughter, estradiol (E2) concentrations in the GnRH group were higher than in groups C, P, and P + GnRH. Treatment with GnRH increased more than 10-fold the content of ER and PR in the pituitary gland without altering steroid receptor concentrations in the uterus. When GnRH was combined with P the uterine receptor contents were higher than with P treatment alone. The treatment with P decreased ER and PR content in the uterus, but had no effect on the pituitary gland. The results show that regulation by P and GnRH of ER and PR content in anestrous ewes is tissue-specific.

Anestrus↗
PubMed1997

Distribution of progesterone receptor in chicken: novel target organs for progesterone and estrogen action.

Expression of progesterone receptor (PR) in various organs of sexually immature chickens and after estrogen treatment was studied by immunohistochemical and Western blotting analyses. Constitutive PR expression was observed in the mesothelium and stroma of the esophagus, proventriculus, liver, spleen, pancreas, heart and lung. In the urogenital tract, PR was expressed in the mesothelial and stromal cells and smooth muscle of blood vessels. Estrogen treatment induced PR expression in the stroma and smooth muscle of the gall bladder and in the epithelium and stroma of the trachea. In the ovary of immature chickens PR was localized in the epithelium, stroma and smooth muscle and was induced in the granulosal cells by estrogen. In most tissues there was more PR-B than PR-A expression and this PR-B dominance remained after estrogen treatment. These results suggest that progesterone and estrogen may have physiological effects on many organs outside the genital tract not previously known as steroid-target tissues.

Animals↗
PubMed1996

Characterization of the functional progesterone receptor in an endometrial adenocarcinoma cell line (Ishikawa): progesterone-induced expression of the alpha1 integrin.

Endometrial progesterone receptors (PR) are regulated by both estrogen (E2) and progesterone (P) and mediate the expression of specific endometrial proteins. Ishikawa cells are a well-differentiated human endometrial adenocarcinoma cell line, with both estrogen receptors (ER) and PR, regulated in a manner similar to that of normal endometrium. Immunohistochemical and biochemical analyses demonstrate that the concentration of PR is increased by E2 priming and decreased by subsequent treatment with P. Scatchard plot analysis showed a K(d) of 1 nM. On the basis of biochemical analysis, PR concentrations reached approximately 1400 fmol/mg cytosol protein in cells after treatment with E2 (10(-8) M) for 4 days. Immunoprecipitation and Western blot studies revealed the presence of both the 116 kDa and 81 kDa proteins with multiple isoforms of the high molecular weight (MW) protein. Northern blot analysis demonstrated transcriptional control of PR by steroid treatment. These studies demonstrate the coordinate regulation of all PR mRNA species. The functionality of Ishikawa PR was demonstrated by the expression of alpha1beta1 integrin in response to E2 plus P, at the level of transcription and translation. This effect was blocked by the addition of the anti-progestin, RU-486. These studies reconfirm that the Ishikawa cell line is an excellent model for the study of hormonally regulated events in the human endometrial epithelium.

Adenocarcinoma↗
PubMed1992

Modulation of progesterone receptor binding to progesterone response elements by positioned nucleosomes.

In cells, steroid hormone receptors interact with target enhancer elements on nucleosomes to regulate transcription of genes. To elucidate how nucleosomes can potentially regulate the interactions of steroid receptors with steroid response elements, we have examined the effects of nucleosome positioning and histone source on the binding of the progesterone receptor to DNA elements on nucleosomes reconstituted in vitro. We find that the affinity of the receptor for its response element is dependent on the position of the element within the nucleosome, but not on the histone source, active or inactive chromatin. Our results suggest that the strength of DNA-histone interactions within the nucleosome modulates the binding of progesterone receptor to response elements. Thus, nucleosome positioning is likely to influence the function of steroid receptors in vivo.

Animals↗
PubMed1965

THE METABOLISM OF PROGESTERONE BY ANIMAL TISSUES IN VITRO. SEX AND SPECIES DIFFERENCES IN CONJUGATE FORMATION DURING THE METABOLISM OF (4-14C)PROGESTERONE BY LIVER HOMOGENATES.

1. Sex and species differences during the metabolism of [4-(14)C]progesterone by liver homogenates from rat, rabbit, guinea pig and hamster have been investigated. 2. Liver homogenate from male rat formed ;water-soluble' metabolites faster and in significantly larger amounts than did liver homogenate from female rat. About 65-70% of the added progesterone was conjugated as glucuronide by liver homogenate from male rat and about 45-50% by that from female rat. Liver homogenate from male rat also formed glucuronides faster than did liver homogenate from female rat. Sulphate formation was low (8-16%) in liver homogenates from both male and female rats. 3. Hamster-liver homogenate did not show any sex difference in the rate of formation of ;water-soluble' metabolites, but a sex difference was observed in the amount of free steroids recovered at low tissue:steroid ratios. Liver homogenate from female hamster formed glucuronides faster and in significantly larger amounts than did liver homogenate from male hamster, the reverse of what was found in rat liver. 4. Liver homogenates from male and female rabbits and guinea pigs formed ;water-soluble' metabolites that were almost entirely glucuronides. 5. Neither rabbit liver nor guinea-pig liver showed any significant sex difference in the rate or amount of formation of total ;water-soluble' metabolites or glucuronides, but guinea-pig liver was considerably less active than rabbit liver. 6. Glucuronides were quantitatively the major type of conjugate formed by the liver homogenates from both sexes of all species except the male hamster.

Animals↗
PubMed2005

Use of the progesterone receptor antagonist RU 486 to identify novel progesterone receptor-regulated pathways in implantation.

The steroid hormone progesterone (P) is a critical regulator of embryo implantation and maintenance of pregnancy. P acting through the nuclear progesterone receptors (PRs) regulates the expression of specific gene networks that in turn control the extensive cell proliferation, differentiation, and remodeling that occur in various uterine cell types during the progressive phases of implantation. To identify the P-regulated pathways that underlie the implantation process in the mouse, we employed RU 486, a well-characterized PR antagonist that binds to the receptor and blocks its gene regulatory function. We performed messenger RNA (mRNA) profiling in the peri-implantation uterus using oligonucleotide microarrays to analyze changes in mRNA levels in response to RU 486. This analysis provided, for the first time, a comprehensive profile of PR-regulated gene networks with potential roles during implantation. Our study identified a variety of novel PR-regulated molecules, such as growth factors, protease inhibitors, metabolic enzymes, peptide hormones, transcription factors, immune response molecules, cytoskeletal proteins, and cell adhesion molecules, that are potential mediators of P action in the peri-implantation mouse uterus. This article provides a brief description of the expression and function of these newly identified molecular pathways.

Animals↗
PubMed1998

Interference between progesterone and dioxin signal transduction pathways. Different mechanisms are involved in repression by the progesterone receptor A and B isoforms.

Interactions between transcription factors are an important means of regulating gene transcription, leading to modifications in the pattern of gene expression and cell fate. In this study, we report that the progesterone receptor (PR) can strongly interfere with transactivation mediated by the arylhydrocarbon receptor (AhR) in T47D breast cancer cells. This interference was not only demonstrated by induction of a transfected dioxin-responsive reporter plasmid but also on the AhR-mediated up-regulation of the endogenous cytochrome P450-1A1 activity. The interference was not mutual, as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent activator of the AhR, did not inhibit progestin-induced promoter activity. When the isoforms of the human PR, hPR-A and hPR-B, were expressed separately in HepG-2 hepatocarcinoma cells, both negatively interfered with the AhR signaling, indicating that the effect is not restricted to T47D cells. In addition, results obtained from studies with both antiprogestins and mutant receptors indicate differences in the underlying molecular mechanisms of repression for both PR isoforms. The suppression by hPR-A does not require additional gene expression or a full transcriptional competent conformation of the receptor. For the repressive effects of hPR-B, however, additional gene expression seems to be involved, as only the agonist-bound, wild-type hPR-B could clearly repress the TCDD-induced response. In conclusion, these studies highlight different mechanisms of repression for the progesterone receptor isoforms on the AhR-mediated trans-activation and underscore the importance of interactions between transcription factors of different families in the regulation of gene transcription.

Breast Neoplasms↗
PubMed1990

Progesterone maintenance of the placental progesterone receptor and placental growth in ovariectomized rats.

These studies examine the trophic effects of progesterone (P) on the progesterone receptor (Rp) and growth of the decidua basalis (DB) and junctional zone (JZ) in the rat placenta. Pregnant rats were ovariectomized (Ovx) in mid-pregnancy and received steroid replacement therapy consisting of implantation of P pellets (25 mg) and injections of estradiol (E), 2 micrograms s.c., daily. Placental protein synthesis, measured by 3H-leucine incorporation in vitro, decreased more than 99% within 24 h of Ovx. However, treatment with P immediately after castration maintained control levels of synthesis. Delay of P treatment for 4 h caused a 60% decline in protein production measured 20 h later (p less than 0.01). Intraperitoneal implantation of a 50-mg pellet of the antiprogestin, RU-38486, in intact pregnant rats decreased protein synthesis by 50% within 6 h and by more than 90% 12 h and 24 h post-implantation (p less than 0.01). Growth of DB and JZ in Ovx rats treated for 48 h with P and/or E was studied both histologically and by changes in protein and DNA content. Rp binding activity was also measured by exchange assay under equilibrium conditions. Only P was able to reverse the effects of Ovx on growth of the DB and JZ. P also maintained Rp levels in the DB above those observed in Ovx and Ovx + E-treated groups (p less than 0.01). The Rp may be a constitutive product in the JZ since binding activity was not altered by Ovx or by steroid treatments. This study shows that P is clearly a trophic hormone of the maternal and chorioallantoic placenta and is essential for placental growth, cellular differentiation, and histological integrity.

Animals↗
PubMed1998

Progesterone mediates its anti-mitogenic and anti-apoptotic actions in rat granulosa cells through a progesterone-binding protein with gamma aminobutyric acidA receptor-like features.

Progesterone (P4) inhibits small granulosa cell (GC) mitosis and large GC apoptosis. These actions are steroid specific and dose dependent and are inhibited by the progesterone receptor (PR) antagonist, RU-486. However, these cells do not express the nuclear PR but rather an ill-defined P4-binding protein (P4BP). This binding protein could function as a receptor and mediate P4's actions in GCs. Therefore, a series of studies was designed to characterize this P4BP. First, an antibody directed against the ligand-binding site of the nuclear PR was used in a Western blot analysis. This analysis revealed the presence of a 60-kDa P4BP within ovarian and GC lysates as well as within an ovarian membrane preparation. This protein was not observed in lysates of cells derived from the ovarian surface epithelium. In addition, this P4BP was immunoprecipitated by an antibody to the alpha1 chain of the gamma aminobutyric acidA (GABA(A)) receptor, suggesting that the P4BP could be the ovarian GABA(A) receptor. Since activation of the rat ovarian GABA(A) receptor increases intracellular cAMP levels, GCs were cultured with control medium supplemented with either 8-bromo-cAMP (8-br-cAMP), P4, or muscimol (a GABA agonist). Increases in cAMP were detected by monitoring the cAMP-dependent phosphorylation of cAMP response element-binding protein (CREB). Phosphorylated CREB was not observed in control or P4-treated cultures, but it was detected in the majority of both small and large GCs exposed to either 8-br-cAMP or muscimol. Since activation of the GABA(A) receptor with muscimol increases phosphorylated CREB but P4 does not, this study indicates that P4 does not activate the ovarian GABA(A) receptor. However, both bicuculline, a GABA(A) receptor antagonist, and the antibody to PR inhibited P4's ability to prevent both insulin-dependent mitosis and apoptosis. Collectively, these studies suggest that P4 mediates its anti-mitotic and anti-apoptotic effects through this 60-kDa P4BP, which has GABA(A) receptor-like properties and is localized within the surface membrane of GCs.

Animals↗
PubMed2000

Decreased progesterone levels and progesterone receptor antagonists promote apoptotic cell death in bovine luteal cells.

We tested the hypothesis that progesterone (P(4)) acts at a local level to inhibit luteal apoptosis. Initial experiments employed aminoglutethimide, a P450 cholesterol side-chain cleavage inhibitor, to inhibit steroid synthesis. Cultured bovine luteal cells were treated with aminoglutethimide (0.15 mM) +/- P(4) (500 ng/ml) for 48 h. Luteal cells were recovered and snap frozen for isolation and analysis of oligonucleosomal DNA fragmentation or fixed for morphological analysis. Medium was collected for analysis of P(4) levels by RIA. Aminoglutethimide inhibited P(4) synthesis by > 95% and increased the level of apoptosis as evidenced by (32)P-labeled oligonucleosomal DNA fragmentation (> 40%). P(4) supplementation inhibited the onset of apoptosis that was induced by aminoglutethimide. These data were further supported by morphological assessment of apoptotic cells utilizing a Hoechst staining technique and together strongly suggest that P(4) has anti-apoptotic capacity. Using reverse transcription-polymerase chain reaction, we were able to isolate a 380-base pair cDNA from the bovine corpus luteum (CL) that was 100% homologous to the progesterone receptor (PR) previously found in bovine oviductal tissue. Furthermore, PR transcripts were present in large and small luteal cells. Immunohistochemistry also revealed that PR protein was present in both large and small luteal cells. To determine whether the anti-apoptotic effect of P(4) was regulated at the receptor level, luteal cells were cultured in the presence of PR antagonists, RU-486 and onapristone, for 48 h. Both antagonists caused approximately a 40% increase in (32)P-labeled oligonucleosomal DNA fragmentation. Interestingly, there was no difference (P >/= 0.05) in P(4) levels after treatment with PR antagonists. These observations support the concept that P(4) represses the onset of apoptosis in the CL by a PR-dependent mechanism.

Aminoglutethimide↗
PubMed2000

Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus.

The objective of this study was to determine whether uterine stromal and/or epithelial progesterone receptor (PR) is required for the antagonism by progesterone (P(4)) of estradiol-17beta (E(2)) action on expression of PR and lactoferrin in uterine epithelium. Uterine tissue recombinants were prepared with epithelium (E) and stroma (S) from wild-type (wt) and PR knockout (PRKO) mice: wt-S+wt-E and PRKO-S+wt-E. P(4) action on epithelial PR expression was studied in wt-S+wt-E and PRKO-S+wt-E tissue recombinants. E(2) down-regulated epithelial PR in both types of tissue recombinants, but P(4) blocked E(2)-induced down-regulation of epithelial PR only in wt-S+wt-E tissue recombinants. Thus, P(4) requires stromal PR to inhibit E(2)-induced down-regulation of epithelial PR. Epithelial PR is not sufficient in itself. The inhibitory effect of P(4) on lactoferrin expression was studied in 4 types of tissue recombinants (wt-S+wt-E, PRKO-S+wt-E, wt-S+PRKO-E, and PRKO-S+PRKO-E). E(2) induced lactoferrin in all 4 types of tissue recombinants. P(4) blocked E(2)-induced lactoferrin expression only in wt-S+wt-E tissue recombinants. In wt-S+PRKO-E tissue recombinants, P(4) inhibited lactoferrin expression only partially. P(4) failed to block E(2)-induced lactoferrin expression in PRKO-S+wt-E and PRKO-S+PRKO-E tissue recombinants. Thus, both epithelial and stromal PR are essential for full P(4) inhibition of E(2)-induced lactoferrin expression.

Animals↗
PubMed2003

Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells.

In breast cancer cells, estrogens activate the Src/Erk pathway through an interaction of the estrogen receptor alpha (ERalpha) with the SH2 domain of c-Src. Progestins have been reported to activate also this pathway either via an interaction of the progesterone receptor isoform B (PRB) with ERalpha, which itself activates c-Src, or by direct interaction of PRB with the SH3 domain of c-Src. Here we identify two domains of PRB, ERID-I and -II, mediating a direct interaction with the ligand-binding domain of ERalpha. ERID-I and ERID-II flank a proline cluster responsible for binding of PRB to c-Src. In mammalian cells, the interaction of PRB with ERalpha and the progestin activation of the Src/Erk cascade are abolished by deletion of either ERID-I or ERID-II. These regions are not required for transactivation of a progesterone-responsive reporter gene. Mutations in the proline cluster of PRB that prevent a direct interaction with c-Src do not affect the strong activation of c-Src by progestins in the presence of ERalpha. Thus, in cells with ERalpha, ERID-I and ERID-II are necessary and sufficient for progestin activation of the endogenous Src/Erk pathway.

Animals↗