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HPMR

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progesterone receptor membrane component 1 OKDB#: 2912
 Symbols: PGRMC1 Species: human
 Synonyms: IZA, MPR, Dap1, HPR6.6  Locus: Xq24 in Homo sapiens
HPMR


For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment Enhancement of cell surface expression and receptor functions of membrane progestin receptor alpha (mPRa) by progesterone receptor membrane component 1 (PGRMC1): evidence for a role of PGRMC1 as an adaptor protein for steroid receptors. Thomas P 2014 et al. A variety of functions have been proposed for progesterone receptor membrane component 1 (PGRMC1), including acting as a component of a membrane progestin receptor and as an adaptor protein. Here we show that stable over expression of human PGRMC1 in progesterone receptor-negative breast cancer cell lines causes increased expression of PGRMC1 and membrane progesterone receptor alpha (mPRa) on cell membranes which is associated with increased specific [(3)H]progesterone binding. The membrane progestin binding affinity and specificity were characteristic of mPRa, with a Kd of 4.7 nM and high affinity for the mPR-specific agonist, Org OD 02-0 and low affinity for corticosteroids. Progestin treatment caused activation of G proteins, further evidence for increased expression of functional mPRs on PGRMC1-transfected cell membranes. Immunocytochemical and co-immunoprecipitation studies showed a close association of PGRMC1 with mPRa in cell membranes. Transfection of PGRMC1 into spontaneously immortalized rat granulosa cells was associated with membrane expression of PGRMC1 and mPRa as well as antiapoptotic effects of progestins which were abolished after co-transfection with siRNA for mPRa. These data demonstrate that PGRMC1 can act as an adaptor protein, transporting mPRa to the cell surface, and that the progestin binding and apoptotic functions previously ascribed to PGRMC1 are dependent on cell surface expression of mPRa. Collectively, the results suggest PGRMC1 and mPRa are components of a membrane progesterone receptor protein complex. Increased expression of estrogen receptor beta (ER? was also observed in the membranes of PGRMC1-transfected cells, suggesting PGRMC1 can act as an adaptor protein for multiple classes of steroid receptors. /////////////////////////

NCBI Summary: This gene encodes a putative membrane-associated progesterone steroid receptor. The protein is expressed predominantly in the liver and kidney. [provided by RefSeq, Mar 2010]
General function Receptor
Comment Proteomic Profiling for Identification of Novel Biomarkers Differentially Expressed in Human Ovaries from Polycystic Ovary Syndrome Patients. Li L et al. (2016) To identify differential protein expression pattern associated with polycystic ovary syndrome (PCOS). Twenty women were recruited for the study, ten with PCOS as a test group and ten without PCOS as a control group. Differential in-gel electrophoresis (DIGE) analysis and mass spectroscopy were employed to identify proteins that were differentially expressed between the PCOS and normal ovaries. The differentially expressed proteins were further validated by western blot (WB) and immunohistochemistry (IHC). DIGE analysis revealed eighteen differentially expressed proteins in the PCOS ovaries of which thirteen were upregulated, and five downregulated. WB and IHC confirmed the differential expression of membrane-associated progesterone receptor component 1 (PGRMC1), retinol-binding protein 1 (RBP1), heat shock protein 90B1, calmodulin 1, annexin A6, and tropomyosin 2. Also, WB analysis revealed significantly (P<0.05) higher expression of PGRMC1 and RBP1 in PCOS ovaries as compared to the normal ovaries. The differential expression of the proteins was also validated by IHC. The present study identified novel differentially expressed proteins in the ovarian tissues of women with PCOS that can serve as potential biomarkers for the diagnosis and development of novel therapeutics for the treatment of PCOS using molecular interventions.//////////////////
Cellular localization Plasma membrane
Comment candidate123
Ovarian function Follicle endowment, Follicle development, Cumulus expansion, Follicle atresia, Luteinization, Oocyte maturation, Early embryo development
Comment Progesterone Receptor Membrane Component 1 and 2 regulate granulosa cell mitosis and survival through a NFΚB-dependent mechanism. Peluso JJ et al. (2019) Progesterone Receptor Membrane Component 1 (PGRMC1) interacts with PGRMC2 and disrupting this interaction in spontaneously immortalized granulosa cells (SIGCS) leads to an inappropriate entry into the cell cycle, mitotic arrest and ultimately cell death. The present study revealed that PGRMC1 and PGRMC2 localize to the cytoplasm of murine granulosa cells of non-atretric follicles with their staining intensity being somewhat diminished in granulosa cells of atretic follicles. Compared to controls (Pgrmc1fl/fl), the rate at which granulosa cells entered the cell cycle increased in non-atretic and atretic follicles of mice in which Pgrmc1 was conditionally deleted (Pgrmc1d/d) from granulosa cells. This increased rate of entry into the cell cycle was associated with a ≥ 2 fold increase in follicular atresia and the nuclear localization of Nuclear Factor-Kappa-B Transcription Factor P65; (NFΚB/p65, or RELA). GTPase Activating Protein Binding Protein 2 (G3BP2) binds NFΚB/p65 through an interaction with NFΚB Inhibitor Alpha (IκBα), thereby maintaining NFΚB/p65's cytoplasmic localization and restricting its transcriptional activity. Since PGRMC1 and PGRMC2 bind G3BP2, studies were designed to assess the functional relationship between PGRMC1, PGRMC2 and NFΚB/p65 in SIGCs. In these studies, disrupting the interaction between PGRMC1 and PGRMC2 increased the nuclear localization of NFΚB/p65, and depleting PGRMC1, PGRMC2 or G3BP2 increased NFΚB transcriptional activity and the progression into the cell cycle. Taken together, these studies suggest that PGRMC1 and 2 regulate granulosa cell cycle entry in follicles by precisely controlling the localization and thereby the transcriptional activity of NFΚB/p65.////////////////// Progesterone Receptor Membrane Component 1 Mediates Progesterone-Induced Suppression of Oocyte Meiotic Prophase I and Primordial Folliculogenesis. Guo M et al. (2016) Well-timed progression of primordial folliculogenesis is essential for mammalian female fertility. Progesterone (P4) inhibits primordial follicle formation under physiological conditions; however, P4 receptor that mediates this effect and its underlying mechanisms are unclear. In this study, we used an in vitro organ culture system to show that progesterone receptor membrane component 1 (PGRMC1) mediated P4-induced inhibition of oocyte meiotic prophase I and primordial follicle formation. We found that membrane-impermeable BSA-conjugated P4 inhibited primordial follicle formation similar to that by P4. Interestingly, PGRMC1 and its partner serpine1 mRNA-binding protein 1 were highly expressed in oocytes in perinatal ovaries. Inhibition or RNA interference of PGRMC1 abolished the suppressive effect of P4 on follicle formation. Furthermore, P4-PGRMC1 interaction blocked oocyte meiotic progression and decreased intra-oocyte cyclic AMP (cAMP) levels in perinatal ovaries. cAMP analog dibutyryl cAMP reversed P4-PGRMC1 interaction-induced inhibition of meiotic progression and follicle formation. Thus, our results indicated that PGRMC1 mediated P4-induced suppression of oocyte meiotic progression and primordial folliculogenesis by decreasing intra-oocyte cAMP levels.////////////////// PGRMC1 participates in late events of bovine granulosa cells mitosis and oocyte meiosis. Terzaghi L et al. (2016) Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in both oocyte and ovarian somatic cells, where it is found in multiple cellular sub-compartments including the mitotic spindle apparatus. Strikingly, PGRMC1 localization in the maturing bovine oocytes mirrors its localization in mitotic cells, suggesting a possible common action in mitosis and meiosis. To test the hypothesis that altering PGRMC1 activity leads to similar defects in mitosis and meiosis, PGRMC1 function was perturbed in cultured bovine granulosa cells (bGC) and maturing oocytes and the effect on mitotic and meiotic progression assessed. RNA interference-mediated PGRMC1 silencing in bGC significantly reduced cell proliferation, with a concomitant increase in the percentage of cells arrested at G2/M phase, which is consistent with an arrested or prolonged M-phase. This observation was confirmed by time-lapse imaging that revealed defects in late karyokinesis. In agreement with a role during late mitotic events, a direct interaction between PGRMC1 and Aurora Kinase B (AURKB) was observed in the central spindle at of dividing cells. Similarly, treatment with the PGRMC1 inhibitor AG205 or PGRMC1 silencing in the oocyte impaired completion of meiosis I. Specifically the ability of the oocyte to extrude the first polar body was significantly impaired while meiotic figures aberration and chromatin scattering within the ooplasm increased. Finally, analysis of PGRMC1 and AURKB localization in AG205-treated oocytes confirmed an altered localization of both proteins when meiotic errors occur. The present findings demonstrate that PGRMC1 participates in late events of both mammalian mitosis and oocyte meiosis, consistent with PGRMC's localization at the mid-zone and mid-body of the mitotic and meiotic spindle.////////////////// Progestin and adipoQ Receptor 7, Progesterone Membrane Receptor Component 1 (PGRMC1) and PGRMC2 and Their Role in Regulating Progesterone's Ability to Suppress Human Granulosa/Luteal Cells from Entering into the Cell Cycle. Sueldo C et al. (2015) The present studies were designed to determine the role of Progesterone Receptor Membrane Component 1 (PGRMC1), PGRMC2, Progestin and AdipoQ Receptor 7 (PAQR7) and Progesterone Receptor (PGR) in mediating the anti-mitotic action of progesterone (P4) in human granulosa/luteal cells. For these studies granulosa/luteal cells of ten women undergoing controlled ovarian hyperstimulation were isolated, maintained in culture, and depleted of PGRMC1, PGRMC2, PAQR7 or PGR by siRNA treatment. The rate of entry into the cell cycle was assessed using the FUCCI cell cycle sensor to determine the percentage of cells in the G1/S stage of the cell cycle. PGRMC1, PGRMC2, PAQR7 or PGR mRNA levels were assessed by real-time PCR and their interactions monitored by in situ proximity ligation assays (PLAs). These studies revealed that PGRMC1, PGRMC2, PAQR7 and PGR were expressed by granulosa/luteal cells from all patients with PGRMC1 mRNA being most abundant followed by PAQR7, PGRMC2 and PGR. However, their mRNA levels showed considerable patient variation. P4's ability to suppress entry into the cell cycle was dependent on PGRMC1, PGRMC2 and PAQR7 but not PGR. Moreover, PLAs indicated that PGRMC1, PGRMC2 and PAQR7 formed a complex within the cytoplasm. Based on these studies, it is proposed that these three P4 mediators form a complex within the cytoplasm that is required for P4's action. Moreover, P4's ability to regulate human follicle development may be dependent in part on the expression levels of each of these P4 mediators.////////////////// Hyaluronic acid prevents immunosuppressive drug-induced ovarian damage via up-regulating PGRMC1 expression. Zhao G et al. (2015) Chemotherapy treatment in women can frequently cause damage to the ovaries, which may lead to primary ovarian insufficiency (POI). In this study, we assessed the preventative effects of hyaluronic acid (HA) in immunosuppressive drug-induced POI-like rat models and investigated the possible mechanisms. We found that HA, which was reduced in primary and immunosuppressant-induced POI patients, could protect the immunosuppressant-induced damage to granulosa cells (GCs) in vitro. Then we found that HA blocked the tripterygium glycosides (TG) induced POI-like presentations in rats, including delayed or irregular estrous cycles, reduced 17 beta-estradiol(E2) concentration, decreased number of follicles, destruction of follicle structure, and damage of reproductive ability. Furthermore, we investigated the mechanisms of HA prevention effects on POI, which was associated with promotion of GC proliferation and PGRMC1 expression. In conclusion, HA prevents chemotherapy-induced ovarian damage by promoting PGRMC1 in GCs. This study may provide a new strategy for prevention and treatment of POI.////////////////// The Effects of Progesterone on Oocyte Maturation and Embryo Development. Salehnia M 2014 et al. Oocyte maturation and embryo development are controlled by intra-ovarian factors such as steroid hormones. Progesterone (P4) exists in the follicular fluid that contributes to normal mammalian ovarian function and has several critical functions during embryo development and implantation, including endometrial receptivity, embryonic survival during gestation and transformation of the endometrial stromal cells to decidual cells. It is well known that the physiological effects of P4 during the pre-implantation stages of some mammal's embryos are mediated by P4 receptors and their gene expression is determined. The effects of P4 on oocytes and embryo development have been assessed by some investigations, with contradictory results. P4, a dominant steroid in follicular fluid at approximately 18 hours after the luteinizing hormone (LH ) surge may have a critical role in maturation of oocytes at the germinal stage. However, it has been shown that different concentrations of P4 could not improve in vitro maturation rates of germinal vesicles (GV) in cumulus oocyte complexes (COCs) and cumulus denuded oocytes (CDOs). Culture media supplemented with P4 significantly improved mouse embryo development. In addition, an in vivo experimental design has shown high blastocyst survival and implantation rates in P4-treated mice. In this review we explain some of the findings that pertain to the effects of P4 on oocyte maturation and embryo development both in vitro and in vivo. ///////////////////////// Progesterone receptor membrane component-1 expression and putative function in bovine oocyte maturation, fertilization and early embryonic development. Luciano AM et al. Although mRNA encoding progesterone receptor membrane component-1 (PGRMC1) is present in mammalian oocytes, nothing is known about either PGRMC1's expression pattern or function in oocytes during maturation, fertilization and subsequent embryonic development. Since in somatic cells PGRMC1 associates with the mitotic spindle, we hypothesized that PGRMC1 is involved in oocyte meiosis. Western blot analysis confirmed the presence of PGRMC1 in bovine oocytes. Furthermore, PGRMC1 was present at the germinal vesicle (GV) and MII-stage oocyte, was associated with male and female pronuclei and was expressed in blastocysts. PGRMC1 localization using confocal imaging demonstrated that in GV-stage oocytes, PGRMC1 was concentrated throughout the GV but did not localize to the chromatin. With the resumption of meiosis in vitro, PGRMC1 concentrated in the centromeric region of metaphase I chromosomes, while in anaphase I/telophase I stages the majority of PGRMC1 concentrated between the separating chromosomes. At the metaphase II stage, PGRMC1 re-associated with the centromeric region. A colocalization study demonstrated that PGRMC1 associated with the phosphorylated form of Aurora kinase-B, which localizes to the centromeres at metaphase. Finally, PGRMC1 antibody injection significantly lower the percentage of oocytes that matured and reached the metaphase II stage after 24 h of culture with the majority arrested in the prometaphase I stage of meiosis and most with disorganized and scattered chromosomes. Taken together these data demonstrate that PGRMC1 is expressed in bovine oocytes and its localization changes at specific stages of oocyte maturation. These observations suggest an important role for PGRMC1 in oocyte maturation, which may be specifically related to the mechanism by which chromosomes segregate. Progesterone Membrane Receptor Component 1 Expression in the Immature Rat Ovary and Its role in Mediating Progesterone's Anti-Apoptotic Action. Peluso JJ et al. Progesterone Receptor Membrane Component-1 (PGRMC1) interacts with Plasminogen Activator Inhibitor RNA binding protein-1 (PAIRBP1), a membrane-associated protein involved in the anti-apoptotic action of progesterone (P4). In this paper, the first studies were designed to assess the ovarian expression pattern of PGRMC1 and PAIRBP1. Western blot analysis revealed that spontaneously immortalized granulosa cells (SIGCs) as well as granulosa and luteal cells express both proteins. Luteal cells were shown to express more PGRMC1 than granulosa cells. Immunohistochemical studies confirmed this and demonstrated that PGRMC1 was present in thecal/stromal cells, ovarian surface epithelial cells and oocytes. PAIRBP1 was also expressed in thecal/stromal cells and ovarian surface epithelial cells but not oocytes. Further, PAIRBP1 and PGRMC1 were detected among the biotinylated surface proteins that were isolated by avidin affinity purification, indicating that they localized to the extracellular surface of the plasma membrane. Confocal microscopy revealed that both of these proteins co-localize to the plasma membrane as well as the cytoplasm. The second studies were design to assess PGRMC1's role in P4's anti-apoptotic actions. These studies showed that over expression of PGRMC1 increased (3)H-P4 binding and P4 responsiveness. Conversely, treatment with a PGRMC1antibody blocked P4's anti-apoptotic action. Taken together, the present findings indicate that both PAIRBP1 and PGRMC1 1) show a similar expression pattern within the ovary and 2) co-localize to the extracellular surface of the plasma membrane. At the plasma membrane, these two proteins interact to form a complex that is required for P4 to transduce its anti-apoptotic action. Progesterone Receptor Membrane Component-1 (PGRMC1) is the Mediator of Progesterone's Anti-apoptotic Action in Spontaneously Immortalized Granulosa Cells as Revealed by PGRMC1 siRNA Treatment and Functional Analysis of PGRMC1 Mutations. Peluso JJ et al. Progesterone receptor membrane component-1 (PGRMC1) and its binding partner, plasminogen activator inhibitor 1 RNA binding protein (PAIRBP1) are thought to form a complex that functions as membrane receptor for progesterone (P4). The present investigations confirm PGRMC1's role in this membrane receptor complex by demonstrating that depleting PGMRC1 with PGRMC1 siRNA results in a 60% decline in (3)H-P4 binding and the loss of P4's anti-apoptotic action. Studies conducted on partially purified GFP-PGRMC1 fusion protein indicate that (3)H-P4 specifically binds to PGRMC1 at a single site with an apparent Kd of approximately 35 nM. In addition experiments utilizing various deletion mutations reveal that the entire PGRMC1 molecule is required for maximum (3)H-P4 binding and P4 responsiveness. Analysis of the binding data also suggests that the P4 binding site is within a segment of PGRMC1 that is composed of the transmembrane domain and the initial segment of the C-terminus. Interestingly, PAIRBP1 appears to bind to the C-terminus between amino acids 70-130, which is distal to the putative P4 binding site. Taken together, these data provide compelling evidence that PGRMC1 is the P4 binding protein that mediates P4's anti-apoptotic action. Moreover, the deletion mutation studies indicate that each domain of PGRMC1 plays an essential role in modulating PGRMC1's capacity to both bind and respond to P4. Additional studies are required to more precisely delineate the role of each PGRMC1 domain in transducting P4's anti-apoptotic action. Progesterone Regulation of Primordial Follicle Assembly In Bovine Fetal Ovaries. Nilsson EE et al. Fertility in mammals is dependant on females having an adequate primordial follicle pool to supply oocytes for fertilization. The formation of primordial follicles is called ovarian follicular assembly. In rats and mice progesterone and estradiol have been shown to inhibit follicle assembly with assembly occurring after birth when the pups are removed from the high-steroid maternal environment. In contrast, primordial follicle assembly in other species, such as cattle and humans, occurs during fetal development before birth. The objective of the current study is to determine if progesterone levels regulate primordial follicle assembly in fetal bovine ovaries. Ovaries and blood were collected from bovine fetuses. Interestingly, ovarian progesterone and estradiol concentrations were found to decrease with increasing fetal age and correlated to increased primordial follicle assembly. Microarray analysis of fetal ovary RNA suggests that progesterone membrane receptor and estrogen nuclear receptor are expressed. Treatment of fetal bovine ovary cultures with a higher progesterone concentration significantly decreased primordial follicle assembly. Observations indicate that progesterone affects ovarian primordial follicle assembly in cattle, as it does in rats and mice. Expression, Regulation, and Function of Progesterone Receptors in Bovine Cumulus Oocyte Complexes During In Vitro Maturation. Aparicio IM et al. Progesterone (P4) exerts its effects by binding to specific genomic (nPR-A/B) and non-genomic (mPRalpha/beta, PGRMC1/2) receptors. P4 has a role in the regulation of the ovulatory cycle, but its participation in oocyte maturation in mammals has not yet been clarified. Therefore, the aim of the present study was to characterize the protein expression of P4 receptors in bovine oocytes and cumulus cells during in vitro maturation (IVM) and to study the effect of P4 and its receptors on oocyte developmental competence. Cumulus-oocyte complexes (COCs) were subjected to IVM, fertilization (IVF) and culture (IVC). IVM was performed for 24 h in the presence or absence of P4, LH, FSH, Trilostane, promegestone (R5020), mifepristone (RU 486) or antibodies against mPRalpha or mPRbeta. Protein expression of PRs was studied by western blotting and immunofluorescence. The results demonstrate the presence of both genomic and non genomic P4 receptors in bovine COCs. The dynamic changes observed in the protein expression of PRs following IVM or in response to supplementation with LH, FSH or P4 suggest an important role during bovine oocyte maturation. Inhibition of P4 synthesis by cumulus cells or blocking of nPR and mPRalpha activity produced a decrease in bovine embryo development, indicating that P4 intracellular signaling is mediated by its interaction with nuclear and membrane progesterone receptors and is important for oocyte developmental competence.The relationship between follicle development and progesterone receptor membrane component-1 expression in women undergoing in vitro fertilization. Elassar A et al. To determine the relationship between progesterone receptor membrane component-1 (PGRMC1) expression and the outcome of IVF treatment.
Expression regulated by LH, Steroids, hyaluronic acid
Comment Hyaluronic Acid Promotes the Expression of Progesterone Receptor Membrane Component 1 via Epigenetic Silencing of miR-139-5p in Granulosa Cells. Zhao G 2014 et al. Primary ovarian insufficiency (POI) is a serious reproductive dysfunction with the follicle pool reduced and depleted. Abnormal apoptosis of ovarian granulosa cells (GCs) is believed to result in follicle loss. Progesterone receptor membrane component (PGRMC) 1, critical for the GC survival, was reported to reduce in POI patients, but the mechanism is unknown. Here we found that PGRMC1 expression was correlated with hyaluronic acid (HA) level in POI patients. HA up-regulated PGRMC1 expression in GCs via suppression of miR-139-5p, which was proved to target PGRMC1 by Western blotting and luciferase reporter assays. Consistent with these findings, miR-139-5p level was significantly increased and presented an inverse correlation with PGRMC1 in POI patients. Noticeably, HA inhibited CD44-mediated miR-139-5p expression, but had no effect on luciferase activity after insertion of miR-139 promoter into luciferase plasmid. Interestingly, miR-139-5p was significantly up-regulated in the KGN cells (GC tumor cell line) by histone deacetylase inhibitor, trichostatin A, indicating that HA down-regulated miR-139-5p expression via histone deacetylation. Taken together, we report an unrecognized mechanism of HA in the promotion of PGRMC1 expression, suggesting that HA may be a potential molecule for the prevention and treatment of POI. ///////////////////////// Progesterone Regulation of Progesterone Receptor Membrane Component 1 (PGRMC1) Sumoylation and Transcriptional Activity in Spontaneously Immortalized Granulosa Cells. Peluso JJ et al. Progesterone (P4) receptor membrane component (PGRMC)1 is detected as a 22-kDa band as well as higher molecular mass bands (>50 kDa) in spontaneously immortalized granulosa cells. That these higher molecular mass bands represent PGRMC1 is supported by the findings that they are not detected when either the primary antibody is omitted or the PGRMC1 antibody is preabsorbed with recombinant PGRMC1. Some but not most of the higher molecular mass bands are due to oligomerization. At least one of the higher molecular mass bands is sumoylated, because PGRMC1 coimmunoprecipitates with small ubiquitin-like modifier protein-1. Moreover, in situ proximity assays reveal a direct interaction between PGRMC1 and small ubiquitin-like modifier protein-1. This interaction is increased by P4. Finally, the higher molecular mass forms of PGRMC1 localize to the nucleus. An analysis of transcription factor activity demonstrates that P4 suppresses T-cell factor/lymphoid enhancer factor (Tcf/Lef) activity through a PGRMC1-dependent mechanism, because treatment with PGRMC1 small interfering RNA depletes PGRMC1 levels and attenuates P4's effects on Tcf/Lef activity. In addition, transfection of a PGRMC1-Flag fusion protein enhances basal Tcf/Lef activity, which is suppressed by P4 treatment. Conversely, transfection of a PGRMC1-Flag protein in which all the sumoylation sites are mutated increases basal Tcf/Lef activity but attenuates P4's ability to suppress Tcf/Lef activity. Therefore, the ability to suppress Tcf/Lef activity is likely an essential part of the mechanism through which P4 activation of PGRMC1 regulates the gene cascades that control granulosa cell function with this action being dependent in part on the sumoylation status of PGRMC1.
Ovarian localization Oocyte, Granulosa, Theca, Luteal cells, Surface epithelium
Comment Expression and Regulation of Progestin Membrane Receptors in the Rat Corpus Luteum Cai Z, et al . Despite evidence strongly supporting progesterone's autocrine actions in the rat corpus luteum (CL), classical progesterone receptors (PR) have not been detected in this gland. Alternatively, in several other systems, progestins have been reported to activate non-genomic pathways via putative progestin membrane receptors (PMRs). The aim of this investigation was to determine whether rat CL membranes bind progestins and contain PMR homologs, and whether these proteins are expressed during CL development in a manner that parallels luteal function. We found that luteal cell membranes specifically bind progesterone. Low levels of progesterone and 20alpha-dihydroprogesterone decreased binding of (3)H-progesterone, whereas androstendione, 17alpha-hydroxyprogesterone, and pregnenolone were less potent. Other steroids, including corticosterone, mifepristone, and estradiol, were ineffective. We found that the rat CL expresses five genes previously postulated to encode for putative PMRs: PMRalpha, PMRbeta, PMRgamma, PR membrane component 1 (PRMC1), and Rda288. Pmralpha, Pmrgamma, and Prmc1 transcripts rose steadily during pregnancy whereas Pmrbeta and Rda288 remained constant. Just before parturition, concomitant with falling progesterone levels, Pmralpha, Pmrbeta, and Prmc1 decreased. Luteal PMRalpha and PRMC1 protein levels were lower in samples taken at the end of pregnancy compared with mid-pregnancy samples. Ergocriptine, which inhibits the secretion of prolactin, the primary luteotrophic hormone in the rat CL, reduced Pmralpha, Pmrbeta, and Prmc1 expression significantly. Ergocriptine effects were prevented by co-administration of prolactin. These findings provide evidence for the expression and regulation of putative membrane-bound progestin binding proteins in the rat CL, a tissue that does not express detectable levels of nuclear progesterone receptors. Changes in mouse granulosa cell gene expression during early luteinization.
Follicle stages Corpus luteum
Comment
Phenotypes PCO (polycystic ovarian syndrome)
POF (premature ovarian failure)
Mutations 4 mutations

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure. Mansouri MR et al. Premature ovarian failure (POF) is characterized by hypergonadotropic hypogonadism and amenorrhea before the age of 40. The condition has a heterogeneous background but genetic factors are demonstrated by the occurrence of familial cases. We identified a mother and daughter with POF both of whom carry an X;autosome translocation [t(X;11)(q24;q13)]. RNA expression studies of genes flanking the X-chromosome breakpoint revealed that both patients have reduced expression levels of the gene Progesterone Receptor Membrane Component-1 (PGRMC1). Mutation screening of 67 females with idiopathic POF identified a third patient with a missense mutation (H165R) located in the cytochrome b5 domain of PGRMC1. PGRMC1 mediates the anti-apoptotic action of progesterone in ovarian cells and it acts as a positive regulator of several cytochrome P450 (CYP)-catalyzed reactions. The CYPs are critical for intracellular sterol metabolism, including biosynthesis of steroid hormones. We show that the H165R mutation associated with POF abolishes the binding of cytochrome P450 7A1 (CYP7A1) to PGRMC1. In addition, the missense mutation attenuates PGRMC1's ability to mediate the anti-apoptotic action of progesterone in ovarian cells. These findings suggest that mutant or reduced levels of PGMRC1 may cause POF through impaired activation of the microsomal cytochrome P450 and increased apoptosis of ovarian cells.

Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Analysis of progesterone receptor membrane component 1 mutation in Han Chinese women with premature ovarian failure. Wang JL et al. (2014) The gene PGRMC1 is highly expressed in the granulose and luteal cells of rodent and primate ovaries. Its role in anti-apoptosis and regulating cell-cycle progression suggests a role in regulating follicle growth. The hypothesis is supported by the study in mice and studies in Sweden. In this study, the coding exons of PGRMC1 were sequenced among 196 Chinese women with premature ovarian failure (POF) and 200 controls, and one novel missense mutation was identified (C.556C>T, p. Pro186Ser) in the POF group and one novel SNP (C.533C>T, p. Trh177Ile) was identified in both groups. The mutation is not considered causative because protein prediction did not indicate a deleterious effect. It is concluded that coding mutations of PGRMC1 do not seem to be a common cause of the disease in Han Chinese women. Future studies in larger cohorts from other ethnic groups are necessary to establish the role of PGRMC1 in POF.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: PGRMC1/2 promotes luteal vascularization and maintains the primordial follicles of mice Peluso JJ et al. (2018) To determine whether conditional depletion of progesterone receptor membrane component (PGRMC) 1 and PGRMC2 affected ovarian follicle development, follicle distribution was assessed in ovaries of young (≈3-month-old) and middle-aged (≈6-month-old) control (Pgrmc1/2fl/fl) and double conditional PGRMC1/2-knockout (Pgrmc1/2d/d) mice. This study revealed that the distribution of primary, preantral and antral follicles was not altered in Pgrmc1/2d/d mice, regardless of the age. Although the number of primordial follicles was similar at ≈3 months of age, their numbers were reduced by ≈80% in 6-month-old Pgrmc1/2d/d mice compared to age-matched Pgrmc1/2fl/fl mice. The Pgrmc1/2d/d mice were generated using Pgr-cre mice, so ablation of Pgrmc1 and Pgrmc2 in the ovary was restricted to peri-ovulatory follicles and subsequent corpora lutea (CL). In addition, the vascularization of CL was attenuated in Pgrmc1/2d/d mice, although mRNA levels of vascular endothelial growth factor A (Vegfa) were elevated. Moreover, depletion of Pgrmc1 and Pgrmc2 altered the gene expression profile in the non-luteal component of the ovary such that Vegfa expression, a stimulator of primordial follicle growth, was elevated; Kit Ligand expression, another stimulator of primordial follicle growth, was suppressed and anti-Mullerian hormone, an inhibitor of primordial follicle growth, was enhanced compared to Pgrmc1/2fl/fl mice. These data reveal that luteal cell depletion of Pgrmc1 and 2 alters the expression of growth factors within the non-luteal component of the ovary, which could account for the premature demise of the adult population of primordial follicles. In summary, the survival of adult primordial follicles is dependent in part on progesterone receptor membrane component 1 and 2.//////////////////

Species: other
Mutation name:
type: null mutation
fertility: subfertile
Comment: Pgrmc1 Knockout Impairs Oocyte Maturation in Zebrafish. Wu XJ et al. (2018) Recent investigations suggest progestin receptor membrane component 1 (PGRMC1) associates with and transports a wide range of molecules such as heme, cytochromes P450, steroids with 21 carbons, membrane progestin receptor alpha (mPRα/Paqr7), epidermal growth factor receptor (EGFR), and insulin receptor. It is difficult to discriminate the true functions of PGRMC1 from the functions of its associated molecules using biochemical and pharmacological approaches. To determine the physiological function(s) of PGRMC1, we generated global knockouts for pgrmc1 (pgrmc1-/-) in zebrafish. We found a reduction in both spawning frequency and the number of embryos produced by female mutants. We also observed reduced sensitivity of fully-grown immature oocytes to a progestin hormone and a reduced number of oocytes undergone meiotic maturation both in vivo and in vitro in pgrmc1-/-. This reduced sensitivity to progestin corresponds well with significant reduced expression of mPRα, the receptor mainly responsible for mediating oocyte maturation and meiosis resumption in fish. The results provide in vivo and in vitro evidence for the physiological functions of Pgrmc1 in oocyte maturation and fertility, as well as a plausible molecular mechanism via regulation of mPRα, which in turn directly regulates oocyte maturation and affects fertility in zebrafish.//////////////////

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created: Aug. 31, 2005, 11:42 a.m. by: hsueh   email:
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last update: March 21, 2020, 11:22 p.m. by: hsueh    email:



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