The Mechanism by Which Agonist and Antagonist Occupied Progesterone Receptors Regulate Target Genes

1998 ◽  
Author(s):  
Maria C. Keightley
Keyword(s):  
Target Genes ◽  
Progesterone Receptors ◽  
Agonist And Antagonist

scholarly journals Differential Response of Progesterone Receptor Isoforms in Hormone-Dependent and -Independent Facilitation of Female Sexual Receptivity

2006 ◽  
Vol 20 (6) ◽  
pp. 1322-1332 ◽  
Author(s):  
Shaila K. Mani ◽  
Andrea M. Reyna ◽  
Jian Zhong Chen ◽  
Biserka Mulac-Jericevic ◽  
Orla M. Conneely
Keyword(s):  
Signaling Pathways ◽  
Reproductive Behavior ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Critical Role ◽  
Progesterone Receptors ◽  
Protein Isoforms ◽  
Sexual Receptivity ◽  
Progesterone Receptor Isoforms ◽  
Null Mutant Mice

Abstract Neurobehavioral effects of progesterone are mediated primarily by its interaction with neural progesterone receptors (PRs), expressed as PR-A and PR-B protein isoforms. Whereas the expression of two isoforms in the neural tissues is suggestive of their selective cellular responses and modulation of distinct subsets of PR-induced target genes, the role of individual isoforms in brain and behavior is unknown. We have previously demonstrated a critical role for PRs as transcriptional mediators of progesterone (ligand-dependent), and dopamine (ligand-independent)-facilitated female reproductive behavior in female mice lacking both the isoforms of PR. To further elucidate the selective contribution of the individual PR isoforms in female sexual receptive behavior, we used the recently generated PR-A and PR-B isoform-specific null mutant mice. We present evidence for differential responses of each isoform to progesterone and dopamine agonist, SKF 81297 (SKF), and demonstrate a key role for PR-A isoform in both hormone-dependent and -independent facilitation of sexual receptive behavior. Interestingly, whereas both the isoforms were essential for SKF-facilitated sexual behavior, PR-A appeared to play a more important role in the 8-bromo-cAMP-facilitated lordosis response, raising the possibility of distinct intracellular signaling pathways mediating the responses. Finally, we also demonstrate that antiprogestin, RU38486, was an effective inhibitor of PR-A-mediated, progesterone-dependent, but not SKF or 8-bromo-cAMP-dependent sexual receptivity. The data reveal the selective contributions of individual isoforms to the signaling pathways mediating female reproductive behavior.

scholarly journals Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

2016 ◽  
Vol 2 (6) ◽  
pp. e1501924 ◽  
Author(s):  
Hari Singhal ◽  
Marianne E. Greene ◽  
Gerard Tarulli ◽  
Allison L. Zarnke ◽  
Ryan J. Bourgo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Tumor Regression ◽  
Progesterone Receptors ◽  
Estrogen Signaling ◽  
Breast Cancers ◽  
Estrogen Action ◽  
Cellular Processes ◽  
Estrogen Receptor Positive ◽  
Estrogen Antagonist

The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor–positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored.

scholarly journals Phosphorylated Progesterone Receptor Isoforms Mediate Opposing Stem Cell and Proliferative Breast Cancer Cell Fates

Endocrinology ◽  
2018 ◽  
Vol 160 (2) ◽  
pp. 430-446 ◽  
Author(s):  
Thu H Truong ◽  
Amy R Dwyer ◽  
Caroline H Diep ◽  
Hsiangyu Hu ◽  
Kyla M Hagen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Progression ◽  
Target Genes ◽  
Progesterone Receptors ◽  
Late Recurrence ◽  
Luminal Breast Cancer ◽  
Clear Understanding ◽  
Progesterone Receptor Isoforms ◽  
Advanced Tumor

Abstract Progesterone receptors (PRs) are key modifiers of estrogen receptor (ER) target genes and drivers of luminal breast cancer progression. Total PR expression, rather than isoform-specific PR expression, is measured in breast tumors as an indicator of functional ER. We identified phenotypic differences between PR-A and PR-B in luminal breast cancer models with a focus on tumorsphere biology. Our findings indicated that PR-A is a dominant driver of cancer stem cell (CSC) expansion in T47D models, and PR-B is a potent driver of anchorage-independent proliferation. PR-A+ tumorspheres were enriched for aldehyde dehydrogenase (ALDH) activity, CD44+/CD24−, and CD49f+/CD24− cell populations relative to PR-B+ tumorspheres. Progestin promoted heightened expression of known CSC-associated target genes in PR-A+ but not PR-B+ cells cultured as tumorspheres. We report robust phosphorylation of PR-A relative to PR-B Ser294 and found that this residue is required for PR-A–induced expression of CSC-associated genes and CSC behavior. Cells expressing PR-A S294A exhibited impaired CSC phenotypes but heightened anchorage-independent cell proliferation. The PR target gene and coactivator, FOXO1, promoted PR phosphorylation and tumorsphere formation. The FOXO1 inhibitor (AS1842856) alone or combined with onapristone (PR antagonist), blunted phosphorylated PR, and tumorsphere formation in PR-A+ and PR-B+ T47D, MCF7, and BT474 models. Our data revealed unique isoform-specific functions of phosphorylated PRs as modulators of distinct and opposing pathways relevant to mechanisms of late recurrence. A clear understanding of PR isoforms, phosphorylation events, and the role of cofactors could lead to novel biomarkers of advanced tumor behavior and reveal new approaches to pharmacologically target CSCs in luminal breast cancer.

scholarly journals Different agonist- and antagonist-induced conformational changes in retinoic acid receptors analyzed by protease mapping.

1994 ◽  
Vol 14 (1) ◽  
pp. 287-298 ◽  
Author(s):  
S Keidel ◽  
P LeMotte ◽  
C Apfel
Keyword(s):  
Retinoic Acid ◽  
Conformational Changes ◽  
Vitamin D3 ◽  
Target Genes ◽  
Retinoic Acid Receptors ◽  
Proteolytic Fragment ◽  
Retinoid Receptors ◽  
Agonist And Antagonist ◽  
X Receptors ◽  
Differentiation And Proliferation

The pleiotropic effects of retinoic acid on cell differentiation and proliferation are mediated by two subfamilies of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Recently the synthetic retinoid Ro 41-5253 was identified as a selective RAR alpha antagonist. As demonstrated by gel retardation assays, Ro 41-5253 and two related new RAR alpha antagonists do not influence RAR alpha/RXR alpha heterodimerization and DNA binding. In a limited trypsin digestion assay, complexation of RAR alpha with retinoic acid or several other agonistic retinoids altered the degradation of the receptor such that a 30-kDa proteolytic fragment became resistant to proteolysis. This suggests a ligand-induced conformational change, which may be necessary for the interaction of the DNA-bound RAR alpha/RXR alpha heterodimer with other transcription factors. Our results demonstrate that antagonists compete with agonists for binding to RAR alpha and may induce a different structural alteration, suggested by the tryptic resistance of a shorter 25-kDa protein fragment in the digestion assay. This RAR alpha conformation seems to allow RAR alpha/RXR alpha binding to DNA but not the subsequent transactivation of target genes. Protease mapping with C-terminally truncated receptors revealed that the proposed conformational changes mainly occur in the DE regions of RAR alpha. Complexation of RAR beta, RAR gamma, and RXR alpha, as well as the vitamin D3 receptor, with their natural ligands resulted in a similar resistance of fragments to proteolytic digestion. This could mean that ligand-induced conformational changes are a general feature in the hormonal activation of vitamin D3 and retinoid receptors.

scholarly journals Secretory phospholipase A2-X (Pla2g10) is a novel progesterone receptor target gene exclusively induced in uterine luminal epithelium for uterine receptivity in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hee Kyoung Park ◽  
So Hee Park ◽  
Miji Lee ◽  
Gyeong Ryeong Kim ◽  
Mira Park ◽  
...  
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Embryo Implantation ◽  
Progesterone Receptors ◽  
Apical Region ◽  
Uterine Receptivity ◽  
Critical Function ◽  
Secretory Phospholipase ◽  
Ovariectomized Mice ◽  
Arachidonic Acids

Abstract Background Aberration of estrogen (E2) and/or progesterone (P4) signaling pathways affects expression of their target genes, which may lead to failure of embryo implantation and following pregnancy. Although many target genes of progesterone receptors (PRs) have been identified in uterine stroma, only a few PR targets have been reported in the epithelium. Secretory phospholipase A2-(PLA2)-X, a member of the PLA2 family that releases arachidonic acids for the synthesis of prostaglandins that are important for embryo implantation, is dysregulated in the endometrium of patients suffering from repeated implantation failure. However, it is not clear whether sPLA2-X is directly regulated by ovarian steroid hormones for embryo implantation in the uterus. Result P4 induced the Pla2g10 encoding of secretory PLA2-X in the apical region of uterine LE of ovariectomized mice via PR in both time- and dose-dependent manners, whereas E2 significantly inhibited it. This finding is consistent with the higher expression of Pla2g10 at the diestrus stage, when P4 is elevated during the estrous cycle, and at P4-treated delayed implantation. The level of Pla2g10 on day 4 of pregnancy (day 4) was dramatically decreased on day 5, when PRs are absent in the LE. Luciferase assays of mutagenesis in uterine epithelial cells demonstrated that four putative PR response elements in a Pla2g10 promoter region are transcriptionally active for Pla2g10. Intrauterine delivery of small interfering RNA for Pla2g10 on day 3 significantly reduced the number of implantation sites, reinforcing the critical function(s) of Pla2g10 for uterine receptivity in mice. Conclusions Pla2g10 is a novel PR target gene whose expression is exclusively localized in the apical region of the uterine LE for uterine receptivity for embryo implantation in mice.

scholarly journals Secretory phospholipase A2-X (Pla2g10) is a novel progesterone receptor target gene exclusively induced in uterine luminal epithelium for uterine receptivity in mice

2020 ◽  
Author(s):  
Hee Kyoung Park ◽  
So Hee Park ◽  
Miji Lee ◽  
Gyeong Ryeong Kim ◽  
Mira Park ◽  
...  
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Embryo Implantation ◽  
Progesterone Receptors ◽  
Apical Region ◽  
Uterine Receptivity ◽  
Critical Function ◽  
Secretory Phospholipase ◽  
Ovariectomized Mice ◽  
Arachidonic Acids

Abstract Background: Aberration of estrogen (E2) and/or progesterone (P4) signaling pathways affects expression of their target genes, which may lead to failure of embryo implantation and following pregnancy. Although many target genes of progesterone receptors (PRs) have been identified in uterine stroma, only a few PR targets have been reported in the epithelium. Secretory phospholipase A2-(PLA2)-X, a member of the PLA2 family that releases arachidonic acids for the synthesis of prostaglandins that are important for embryo implantation, is dysregulated in the endometrium of patients suffering from repeated implantation failure. However, it is not clear whether sPLA2-X is directly regulated by ovarian steroid hormones for embryo implantation in the uterus.Result: P4 induced the Pla2g10 encoding of secretory PLA2-X in the apical region of uterine LE of ovariectomized mice via PR in both time- and dose-dependent manners, whereas E2 significantly inhibited it. This finding is consistent with the higher expression of Pla2g10 at the diestrus stage, when P4 is elevated during the estrous cycle, and at P4-treated delayed implantation. The level of Pla2g10 on day 4 of pregnancy (Day 4) was dramatically decreased on Day 5, when PRs are absent in the LE. Luciferase assays of mutagenesis in uterine epithelial cells demonstrated that four putative PR response elements in a Pla2g10 promoter region are transcriptionally active for Pla2g10. Intrauterine delivery of small interfering RNA for Pla2g10 on Day 3 significantly reduced the number of implantation sites, reinforcing the critical function(s) of Pla2g10 for uterine receptivity in mice.Conclusions: Pla2g10 is a novel PR target gene whose expression is exclusively localized in the apical region of the uterine LE for uterine receptivity for embryo implantation in mice.

70 EXPRESSION OF NUCLEAR AND MEMBRANE PROGESTERONE RECEPTORS IN THE CANINE OVIDUCT DURING THE PERIOVULATORY PERIOD

2012 ◽  
Vol 24 (1) ◽  
pp. 147 ◽  
Author(s):  
M. Z. Tahir ◽  
K. Reynaud ◽  
S. Thoumire ◽  
S. Chastant-Maillard ◽  
M. Saint-Dizier
Keyword(s):  
Target Genes ◽  
Geometric Mean ◽  
Progesterone Receptors ◽  
Blastocyst Stage ◽  
Mrna Levels ◽  
Standard Curve ◽  
Relative Standard ◽  
Relative Standard Curve Method ◽  
Curve Method ◽  
Roche Diagnostics

In the bitch, the oviduct is the site of oocyte maturation (Day 1 to 3 after ovulation), sperm transport/capacitation, fertilization (Day 3 to 4) and embryo development to the morula/blastocyst stage (Day 4 to 8). Unlike other mammals, these events occur in the presence of high (>6 ng mL–1) and increasing plasma levels of progesterone (P4), but little is known about the regulation of oviductal functions by P4 in the bitch. The objective of this work was to study the mRNA expression of nuclear (PR) and membrane (PGRMC1, PGRMC2, mPRβ and mPRγ) P4 receptors in the canine oviduct during the periovulatory period. Thirty-six Beagle bitches were ovariectomized at 6 stages: anestrus, before the LH peak (pre-LH), after the LH peak (pre-ov) and after ovulation (Day 1, 4 and 7). Three oviductal regions were collected [i.e. ampulla, isthmus and utero-tubal junction (UTJ)]. Total RNA was extracted and then reverse transcribed. The expression of target genes was assessed in duplicate by quantitative PCR (LightCycler® 480; Roche Diagnostics, Meylan, France) using the relative standard curve method and normalized by the geometric mean of 2 reference genes (RPS19 and GAPDH). Relative amounts of mRNA were compared between groups by ANOVA followed, when necessary, by Duncan's test. The expression of nuclear and membrane P4 receptor mRNA varied according to the stage. Expression of PR mRNA was significantly higher at pre-LH, pre-ov and Day 1 stages [means of 1.8, 1.6 and 1.5 arbitrary units (AU), respectively] than at anoestrus, Day 4 and Day 7 (1, 0.4 and 0.5 AU, respectively) in the ampulla. Same patterns of expression were observed for PR in the isthmus and UTJ. Expression of PGRMC1 and PGRMC2 mRNA were at the lowest level during anoestrus (1 AU) and increased significantly from pre-LH to Day 7 in the ampulla (from 2.2 to 8.3 AU and from 1.3 to 5.4 AU for PGRMC1 and PGRMC2, respectively) and in the isthmus (from 0.4 to 2.6 AU and from 0.5 to 1.8 AU for PGRMC1 and PGRMC2, respectively). In the UTJ, mRNA levels for PGRMC1 and PGRMC2 were the highest at Day 4 (3.9 AU) and pre-LH (2.1 AU), respectively, compared to other stages. Expression of mPRβ mRNA did not vary according to the stage in the ampulla and the isthmus, whereas it was significantly lower at Days 4 and 7 (0.6–0.7 AU) compared to other stages (1–1.2 AU) in the UTJ. Expression of mPRγ was significantly higher at Day 7 (5.0 AU) compared to other stages (0.2–1 AU) in the ampulla and was significantly higher at both anoestrus (1 AU) and Day 7 (0.9 AU) compared to other stages (0.02–0.09 AU) in the isthmus, whereas it did not vary significantly in the UTJ. In conclusion, our data suggests that P4 may be an important regulating factor of oviductal functions and could mediate its actions through genomic as well as non-genomic pathways.

Progesterone Receptors Promote Quiescence & Ovarian Cancer Cell Phenotypes via DREAM in p53-Mutant Fallopian Tube Models

2021 ◽  
Author(s):  
Laura J Mauro ◽  
Megan I Seibel ◽  
Caroline H Diep ◽  
Angela Spartz ◽  
Carlos Perez Kerkvliet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Ovarian Cancer ◽  
Fallopian Tube ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Progesterone Receptors ◽  
Invasive Disease ◽  
Clinical Samples ◽  
Oncogenic Signaling

Abstract Content The ability of ovarian steroids to modify ovarian cancer (OC) risk remains controversial. Progesterone is considered to be protective; recent studies indicate no effect or enhanced OC risk. Knowledge of progesterone receptor (PR) signaling during altered physiology that typifies OC development is limited. This study defines PR-driven oncogenic signaling mechanisms in p53-mutant human fallopian tube epithelia (hFTE), a precursor of the most aggressive OC subtype. Methods PR expression in clinical samples of serous tubal intraepithelial carcinoma (STIC) lesions and high grade serous OC (HGSC) tumors was analyzed. Novel PR-A and PR-B isoform-expressing hFTE models were characterized for gene expression and cell cycle progression, emboli formation, and invasion. PR regulation of the DREAM quiescence complex and DYRK1 kinases was established. Results STICs and HGSC express abundant activated phospho-PR. Progestin promoted reversible hFTE cell cycle arrest, spheroid formation and invasion. RNAseq/biochemical studies revealed potent ligand-independent/-dependent PR actions, progestin induced regulation of the DREAM quiescence complex and cell-cycle target genes through enhanced complex formation and chromatin recruitment. Disruption of DREAM/DYRK1s by pharmacological inhibition, HPV E6/E7 expression or DYRK1A/B depletion blocked progestin-induced cell arrest and attenuated PR-driven gene expression and associated OC phenotypes. Conclusion Activated PRs support quiescence and pro-survival/pro-dissemination cell behaviors that may contribute to early HGSC progression. Our data support an alternative perspective on the tenant that progesterone always confers protection against OC. STICs can reside undetected for decades prior to invasive disease; our studies reveal clinical opportunities to prevent the ultimate development of HGSC by targeting PRs, DREAM, and/or DYRKs.

Different agonist- and antagonist-induced conformational changes in retinoic acid receptors analyzed by protease mapping

1994 ◽  
Vol 14 (1) ◽  
pp. 287-298
Author(s):  
S Keidel ◽  
P LeMotte ◽  
C Apfel
Keyword(s):  
Retinoic Acid ◽  
Conformational Changes ◽  
Vitamin D3 ◽  
Target Genes ◽  
Retinoic Acid Receptors ◽  
Proteolytic Fragment ◽  
Retinoid Receptors ◽  
Agonist And Antagonist ◽  
X Receptors ◽  
Differentiation And Proliferation

The pleiotropic effects of retinoic acid on cell differentiation and proliferation are mediated by two subfamilies of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Recently the synthetic retinoid Ro 41-5253 was identified as a selective RAR alpha antagonist. As demonstrated by gel retardation assays, Ro 41-5253 and two related new RAR alpha antagonists do not influence RAR alpha/RXR alpha heterodimerization and DNA binding. In a limited trypsin digestion assay, complexation of RAR alpha with retinoic acid or several other agonistic retinoids altered the degradation of the receptor such that a 30-kDa proteolytic fragment became resistant to proteolysis. This suggests a ligand-induced conformational change, which may be necessary for the interaction of the DNA-bound RAR alpha/RXR alpha heterodimer with other transcription factors. Our results demonstrate that antagonists compete with agonists for binding to RAR alpha and may induce a different structural alteration, suggested by the tryptic resistance of a shorter 25-kDa protein fragment in the digestion assay. This RAR alpha conformation seems to allow RAR alpha/RXR alpha binding to DNA but not the subsequent transactivation of target genes. Protease mapping with C-terminally truncated receptors revealed that the proposed conformational changes mainly occur in the DE regions of RAR alpha. Complexation of RAR beta, RAR gamma, and RXR alpha, as well as the vitamin D3 receptor, with their natural ligands resulted in a similar resistance of fragments to proteolytic digestion. This could mean that ligand-induced conformational changes are a general feature in the hormonal activation of vitamin D3 and retinoid receptors.

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