{"gene":"PGR","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2016,"finding":"Progesterone (R5020) induces dose-dependent PGR mRNA and protein expression in an estrogen-independent manner requiring both PR and ERα. Rapid PR-dependent activation of MAPK/ERK and AKT leads to phosphorylation of ERα Ser118, enabling cooperative ERα/PR recruitment to an ERE/Sp1-containing region of the PGR proximal promoter. Inhibition of these kinase pathways (U0126 or LY294002) blocked ERα and PR chromatin recruitment and subsequent PGR mRNA induction.","method":"Chromatin immunoprecipitation (ChIP), pharmacologic inhibition of MAPK/ERK and AKT, receptor antagonists (RU486, ICI 182,780), qRT-PCR and Western blot in ER+/PR+ cancer cell lines","journal":"Steroids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with pharmacologic inhibition and antagonist controls, single lab, multiple orthogonal methods","pmids":["27641443"],"is_preprint":false},{"year":2022,"finding":"SOX4 stabilizes PGR protein by repressing the E3 ubiquitin ligase HERC4-mediated polyubiquitination and proteasomal degradation of PGR. Co-immunoprecipitation and mass spectrometry identified the SOX4–HERC4–PGR axis; dysregulation of this axis underlies defective decidualization and recurrent implantation failure.","method":"Co-immunoprecipitation, mass spectrometry, whole-genome SOX4 ChIP-seq, RNA sequencing, siRNA knockdown in human endometrial stromal cells","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP + MS identification of E3 ligase + genome-wide binding + functional rescue experiments, multiple orthogonal methods in one rigorous study","pmids":["35244538"],"is_preprint":false},{"year":2022,"finding":"P38α MAPK protects PGR from proteasomal degradation in the uterine stroma by phosphorylating the HECT-family E3 ubiquitin ligase Ube3c at serine 741, thereby restraining Ube3c-mediated polyubiquitination of PGR. Uterine-selective depletion of P38α led to dramatic loss of PGR protein and defective implantation.","method":"Conditional knockout mouse model, co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (Ube3c S741), Western blot, fertility phenotype analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic KO with defined molecular mechanism, in vitro ubiquitination assay, mutagenesis of phosphorylation site, replicated across multiple assays","pmids":["35914132"],"is_preprint":false},{"year":2015,"finding":"Zebrafish nuclear progesterone receptor (Pgr) knockout (via TALENs) females are infertile due to anovulation: oocytes undergo normal meiosis resumption (GVBD) and final oocyte maturation in vitro but fail to ovulate even after HCG or progestin treatment. This establishes that Pgr-mediated genomic signaling in follicular cells is required for ovulation but is not essential for non-genomic progestin signaling initiating meiosis resumption.","method":"TALEN-mediated knockout in zebrafish, in vitro oocyte maturation assays, HCG/progestin stimulation, fertility phenotyping","journal":"Frontiers in endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent mutant lines, in vivo and in vitro functional dissection, loss-of-function with specific phenotypic readout","pmids":["25852646"],"is_preprint":false},{"year":2016,"finding":"Adenoviral shRNA knockdown of PGR in macaque granulosa cells in vivo prevented follicle rupture (5/6 monkeys) and blocked the post-hCG rise in serum progesterone, demonstrating that nuclear PGR in granulosa cells is required for ovulation and for progesterone synthesis/luteinization in primates.","method":"Adenoviral shRNA knockdown injected into preovulatory follicles of rhesus monkeys, laparoscopic evaluation of ovulation, serum progesterone measurement, immunostaining for nuclear PGR","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockdown in primate follicles with direct ovulation assessment and hormonal readout, complemented by in vitro luteinized granulosa cell experiments","pmids":["26985003"],"is_preprint":false},{"year":2018,"finding":"In human periovulatory granulosa/lutein cells, PGR binds directly to the FOS gene promoter (shown by ChIP) after hCG stimulation, and PGR inhibition reduces hCG-induced FOS expression and phosphorylation. FOS in turn binds the promoters of prostaglandin synthase genes (PTGES, SLCO2A1, ABCC1), and FOS inhibition blocks hCG-induced PGE2 production, placing PGR upstream of FOS-dependent ovulatory prostaglandin synthesis.","method":"Chromatin immunoprecipitation (ChIP) in human granulosa/lutein cells, pharmacologic inhibition of PGR and EGFR, selective FOS inhibitor, PGE2 measurement, mRNA and protein analysis","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ChIP for PGR binding at FOS gene, functional inhibitor cascade experiments, PGE2 measurement, multiple orthogonal methods","pmids":["30124866"],"is_preprint":false},{"year":2021,"finding":"ARID1A physically interacts with PGR-A (but not PGR-B) isoform in mouse and human endometrium, as demonstrated by co-immunoprecipitation and proximity ligation assay. ARID1A levels positively correlate with PGR levels in eutopic endometrium from women with endometriosis.","method":"Co-immunoprecipitation, proximity ligation assay (PLA), Western blot, immunostaining in mouse and human endometrial tissue","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP confirmed by PLA, isoform specificity established, single lab","pmids":["33706098"],"is_preprint":false},{"year":2023,"finding":"PGR directly binds to the PTPN11 (SHP2) gene promoter in the region -229 to +1 bp in response to progesterone, cooperating with CREB1 to transcriptionally induce SHP2 expression during decidualization. Direct PGR and CREB1 binding was confirmed by EMSA and ChIP; knockdown of either factor inhibited SHP2 induction.","method":"Luciferase reporter assay, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), siRNA knockdown, qRT-PCR in human endometrial stromal cells","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP confirm direct PGR binding, functional siRNA validation, single lab, multiple orthogonal methods","pmids":["37786383"],"is_preprint":false},{"year":2019,"finding":"In human myometrium, genome-wide ChIP-seq reveals that PGR binding shifts between non-pregnant (predominantly intergenic sites) and term-pregnant (predominantly promoter regions including classical progesterone response elements) states. Integration of ChIP-seq, RNA-seq, and histone modification data identified ATP11A, CBX7, and TNS1 as direct PGR target genes responsive to progesterone in vitro.","method":"ChIP-seq, ATAC-seq, RNA-seq in human myometrial tissue; in vitro progesterone treatment for target gene validation","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with orthogonal RNA-seq and histone mark data, in vitro validation of specific targets, single lab","pmids":["31908010"],"is_preprint":false},{"year":2022,"finding":"In human myometrium, in-labor PGR predominantly occupies promoter regions (including PRE motifs), whereas not-in-labor PGR binds mainly to intergenic regions. Differential PGR binding analysis identified >1700 differential sites and SRF, MYOD, and STAT binding motifs co-enriched at PGR-occupied sites, suggesting PGR interacts with major muscle regulators for myometrial gene control during labor.","method":"ChIP-seq for PGR and histone marks, RNA-seq, in vitro progesterone treatment in human myometrial tissue (term in-labor vs. not-in-labor)","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genome-wide ChIP-seq with RNA-seq integration and in vitro validation, single lab","pmids":["35732928"],"is_preprint":false},{"year":2025,"finding":"H3K27 acetylation (H3K27ac) at the PGR locus positively regulates PGR expression in endometrial stromal cells; experimental depletion of H3K27ac in young human endometrial stromal cells reduced PGR protein levels. Loss of H3K27ac and PGR is associated with uterine aging and impaired endometrial receptivity, validated in a mouse aging model.","method":"CRISPR/epigenome editing to eliminate H3K27ac, transcriptomic profiling, immunostaining, mouse aging model validation","journal":"Nature aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct epigenome perturbation with PGR protein readout and in vivo mouse validation, single lab","pmids":["40394215"],"is_preprint":false},{"year":2021,"finding":"miR-181a directly represses PGR, DDX3X, and TIMP3 at the mRNA and protein level through interactions with their 3'-UTRs, as demonstrated by luciferase reporter assays in Ishikawa endometrial cancer cells. miR-181a gain-of-function reduced PGR protein expression and influenced downstream CCNE1 through DDX3X repression.","method":"miRNA transfection (gain-of-function), 3'-UTR luciferase reporter assay, qRT-PCR and Western blot in Ishikawa cells","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated direct miRNA-3'UTR interaction by luciferase assay plus protein-level confirmation, single lab","pmids":["22492871"],"is_preprint":false},{"year":2019,"finding":"In bovine cumulus cells, miR-375 directly targets PGR (and ADAMTS1) 3'-UTRs as validated by dual-luciferase reporter assay and RNA immunoprecipitation. miR-375 overexpression suppresses PGR expression and inhibits cumulus-oocyte complex maturation; restoration of PGR expression rescues maturation, placing PGR downstream of miR-375 in oocyte IVM.","method":"Dual-luciferase reporter assay, RNA immunoprecipitation, lentiviral overexpression and knockdown, Western blot in bovine cumulus cells","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR binding validated by two orthogonal methods, rescue experiment confirms pathway position, single lab","pmids":["31545267"],"is_preprint":false},{"year":2021,"finding":"LH-induced PGR expression in medaka preovulatory follicles requires the cAMP/EPAC/RAP/PI3K/AKT/CREB signaling pathway (not PKA). Phosphorylated CREB1 (phosphorylated by Akt1) acts as the transcription factor driving pgr gene expression; pharmacologic inhibitors of EPAC, RAP, PI3K, AKT, and CREB all blocked LH-induced Pgr expression and follicle ovulation.","method":"In vitro ovulation assay with specific pathway inhibitors (brefeldin A, GGTI298, wortmannin, AKT inhibitor IV, KG-501, H-89), mRNA and protein analysis in medaka follicles","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic pharmacologic pathway dissection in a defined in vitro ovulation system, multiple inhibitors targeting sequential pathway components, single lab","pmids":["33880506"],"is_preprint":false},{"year":2020,"finding":"Ancestral sequence resurrection and functional assays show that the major human PGR isoforms (PR-A and PR-B) evolved divergent transcriptional functions during the human stem-lineage, coincident with a period of relaxed evolutionary constraint rather than positive selection.","method":"Ancestral sequence resurrection, phylogenetic analysis, functional transcriptional reporter assays comparing ancestral and derived PR-A and PR-B","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transcriptional assays on reconstructed ancestral sequences, evolutionary analysis, single lab","pmids":["32302297"],"is_preprint":false},{"year":2019,"finding":"PGR gene fusions (including NR4A3-PGR) define a molecular subset of uterine epithelioid leiomyosarcomas. Targeted RNA sequencing and FISH identified these rearrangements in 35% of epithelioid leiomyosarcomas, and all fusion-positive tumors expressed desmin, ER, and PR by immunohistochemistry.","method":"Targeted next-generation RNA sequencing, FISH with custom PGR and NR4A3 probes, immunohistochemistry on FFPE tissue","journal":"The American journal of surgical pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — molecular characterization of gene fusions by RNA-seq and FISH, replicated across multiple cases, no functional reconstitution","pmids":["30829727"],"is_preprint":false},{"year":2009,"finding":"EGFRvIII constitutive signaling (activating Akt and MAPK) in breast cancer cells causes loss of PGR protein expression. EGFRvIII expression in MDA-MB-361 cells (which normally co-express ERα and PgR) resulted in pronounced reduction of PgR compared to wild-type cells, and was associated with estrogen independence and tamoxifen resistance.","method":"Stable transfection of EGFRvIII, Western blot for PgR and signaling intermediates, in vivo xenograft experiments in ovariectomized nude mice, IHC of human breast cancer specimens","journal":"International journal of cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single transfection model, mechanistic linkage between EGFRvIII→kinase activation→PgR loss inferred but not directly mechanistically dissected","pmids":["19588487"],"is_preprint":false}],"current_model":"PGR (progesterone receptor) is a ligand-activated nuclear transcription factor that binds progesterone response elements (and ERE/Sp1 sites cooperatively with ERα) to regulate downstream target genes; its protein stability is controlled by ubiquitin-proteasome degradation mediated by E3 ligases HERC4 and Ube3c, the latter restrained by P38α-mediated phosphorylation, while its transcriptional activity and genomic occupancy are context-dependent (shifting between intergenic and promoter sites in the myometrium during pregnancy/labor); PGR is required for ovulation in vertebrates through genomic signaling in follicular/granulosa cells, drives ovulatory prostaglandin synthesis via FOS induction, regulates decidualization partly through direct binding to target gene promoters (e.g., PTPN11/SHP2) in cooperation with CREB1, and is physically associated with ARID1A (isoform PGR-A) in the endometrium, while its expression is post-transcriptionally repressed by miR-181a (via 3'-UTR interaction) and epigenetically regulated by H3K27ac and promoter DNA methylation."},"narrative":{"mechanistic_narrative":"PGR (progesterone receptor) is a ligand-activated nuclear transcription factor that executes the genomic arm of progesterone signaling in reproductive tissues, where it is required for ovulation, decidualization, and the regulation of myometrial gene programs during pregnancy and labor [PMID:25852646, PMID:26985003, PMID:31908010]. In ovarian follicular and granulosa cells, nuclear PGR signaling is essential for follicle rupture and ovulation across vertebrates, while non-genomic progestin signaling driving oocyte meiotic resumption proceeds independently of it [PMID:25852646, PMID:26985003]. Mechanistically, PGR binds directly to the FOS promoter after hCG stimulation to trigger FOS-dependent ovulatory prostaglandin synthesis [PMID:30124866], and during decidualization it occupies target promoters such as PTPN11/SHP2 in cooperation with CREB1 [PMID:37786383]. PGR is recruited to its own proximal promoter together with ERα through MAPK/ERK- and AKT-dependent ERα Ser118 phosphorylation, establishing an autoregulatory induction loop [PMID:27641443]. Genome-wide, PGR occupancy is context-dependent: in myometrium it shifts from predominantly intergenic sites in the non-pregnant/not-in-labor state toward promoter regions bearing progesterone response elements in the term-pregnant/in-labor state, co-enriched with muscle-regulatory motifs [PMID:31908010, PMID:35732928]. PGR protein abundance is tightly controlled by the ubiquitin-proteasome system: the E3 ligases HERC4 and Ube3c polyubiquitinate PGR, with SOX4 stabilizing PGR by repressing HERC4 and P38α MAPK protecting PGR by phosphorylating Ube3c at Ser741 to restrain its ligase activity [PMID:35244538, PMID:35914132]. PGR expression is further constrained post-transcriptionally by miR-181a and miR-375 acting on its 3'-UTR and epigenetically by H3K27 acetylation at its locus [PMID:40394215, PMID:22492871, PMID:31545267]. Recurrent NR4A3-PGR gene fusions define a molecular subset of uterine epithelioid leiomyosarcomas [PMID:30829727].","teleology":[{"year":2015,"claim":"Established that genomic PGR signaling, rather than non-genomic progestin signaling, is the step that is indispensable for ovulation, dissociating ovulation from oocyte meiotic maturation.","evidence":"TALEN knockout of nuclear Pgr in zebrafish with in vitro maturation and ovulation phenotyping","pmids":["25852646"],"confidence":"High","gaps":["Does not identify the PGR target genes mediating follicle rupture","Zebrafish follicular context may differ from mammalian granulosa biology"]},{"year":2016,"claim":"Confirmed the requirement for granulosa-cell nuclear PGR in primate ovulation and luteinization, extending the conserved ovulatory role to mammals.","evidence":"Adenoviral shRNA knockdown of PGR in rhesus monkey preovulatory follicles with ovulation and serum progesterone readouts","pmids":["26985003"],"confidence":"High","gaps":["Downstream transcriptional effectors not defined","Knockdown efficiency and off-target effects in vivo not fully resolved"]},{"year":2016,"claim":"Defined an autoregulatory loop whereby progesterone induces PGR through PR-dependent kinase signaling and cooperative ERα/PR promoter recruitment, explaining estrogen-independent PGR upregulation.","evidence":"ChIP with MAPK/AKT inhibitors and receptor antagonists in ER+/PR+ cancer cell lines","pmids":["27641443"],"confidence":"Medium","gaps":["Demonstrated in cancer cell lines, not normal reproductive tissue","Direct PR DNA contact at the ERE/Sp1 region versus tethering not distinguished"]},{"year":2018,"claim":"Placed PGR directly upstream of ovulatory prostaglandin synthesis by showing PGR binds the FOS promoter to drive FOS-dependent induction of prostaglandin synthase genes.","evidence":"ChIP for PGR at FOS, PGR/EGFR and FOS inhibitors, PGE2 measurement in human granulosa/lutein cells","pmids":["30124866"],"confidence":"High","gaps":["Co-factors at the FOS promoter not identified","Causal contribution of this axis to actual follicle rupture in vivo not tested"]},{"year":2019,"claim":"Revealed that PGR genomic occupancy is dynamically reprogrammed in myometrium across pregnancy, shifting from intergenic to promoter/PRE sites and identifying specific progesterone-responsive target genes.","evidence":"Genome-wide ChIP-seq, ATAC-seq and RNA-seq in human myometrial tissue with in vitro target validation","pmids":["31908010"],"confidence":"Medium","gaps":["Mechanism driving the binding-site shift unknown","Single-lab dataset without independent cohort replication"]},{"year":2019,"claim":"Identified recurrent PGR gene fusions as a defining molecular feature of a uterine epithelioid leiomyosarcoma subset, linking PGR rearrangement to a tumor entity.","evidence":"Targeted RNA sequencing and FISH with PGR/NR4A3 probes and immunohistochemistry on tumor tissue","pmids":["30829727"],"confidence":"Medium","gaps":["No functional reconstitution of the fusion protein","Oncogenic mechanism of the fusion not established"]},{"year":2020,"claim":"Showed that the human PR-A and PR-B isoforms acquired divergent transcriptional functions during human evolution under relaxed constraint, framing isoform-specific PGR biology in an evolutionary context.","evidence":"Ancestral sequence resurrection, phylogenetic analysis, and transcriptional reporter assays","pmids":["32302297"],"confidence":"Medium","gaps":["Physiological consequences of functional divergence not tested in tissue","Target gene specificity of ancestral versus derived isoforms not mapped genome-wide"]},{"year":2021,"claim":"Established post-transcriptional and epigenetic control of PGR levels through miR-181a 3'-UTR repression and ARID1A isoform-specific physical association with PGR-A.","evidence":"3'-UTR luciferase reporter assays in Ishikawa cells (miR-181a); reciprocal Co-IP and PLA in mouse and human endometrium (ARID1A)","pmids":["22492871","33706098"],"confidence":"Medium","gaps":["Functional consequence of the ARID1A-PGR-A interaction on target gene transcription not defined","miR-181a regulation shown in a cancer cell line"]},{"year":2021,"claim":"Defined the LH-triggered cAMP/EPAC/RAP/PI3K/AKT/CREB signaling cascade that drives pgr transcription in preovulatory follicles, identifying CREB1 as the activating transcription factor.","evidence":"Sequential pharmacologic pathway dissection in a medaka in vitro ovulation assay","pmids":["33880506"],"confidence":"Medium","gaps":["Direct CREB1 binding at the pgr promoter not shown in this system","Conservation of the EPAC-dependent route in mammals not established"]},{"year":2022,"claim":"Identified ubiquitin-proteasome control of PGR stability via two E3 ligases and their regulators, showing SOX4 represses HERC4 and P38α phosphorylates Ube3c (Ser741) to protect PGR and support decidualization and implantation.","evidence":"Reciprocal Co-IP/MS, SOX4 ChIP-seq and rescue in human endometrial stromal cells; conditional P38α knockout mouse with ubiquitination assays and Ube3c mutagenesis","pmids":["35244538","35914132"],"confidence":"High","gaps":["Ubiquitination sites on PGR targeted by HERC4/Ube3c not mapped","Interplay between the two ligase axes in the same cell not resolved"]},{"year":2022,"claim":"Extended myometrial PGR occupancy reprogramming to the labor transition, showing promoter/PRE shift in labor and co-enrichment with muscle-regulatory motifs (SRF, MYOD, STAT).","evidence":"PGR and histone-mark ChIP-seq with RNA-seq in in-labor versus not-in-labor human myometrium","pmids":["35732928"],"confidence":"Medium","gaps":["Physical PGR interaction with SRF/MYOD/STAT factors not biochemically demonstrated","Causal link between binding shift and labor onset not tested"]},{"year":2023,"claim":"Demonstrated direct PGR-CREB1 cooperative transactivation of PTPN11/SHP2 during decidualization, mapping a specific promoter-level PGR target program.","evidence":"Luciferase reporter, EMSA, ChIP and siRNA knockdown in human endometrial stromal cells","pmids":["37786383"],"confidence":"Medium","gaps":["Broader decidualization gene network co-regulated by PGR-CREB1 not defined","Single-lab in vitro stromal cell system"]},{"year":2025,"claim":"Linked H3K27 acetylation at the PGR locus to PGR expression and endometrial receptivity, connecting epigenetic loss to uterine aging.","evidence":"CRISPR/epigenome editing depleting H3K27ac with PGR protein readout and mouse aging model validation","pmids":["40394215"],"confidence":"Medium","gaps":["Enzymes setting/removing H3K27ac at the PGR locus not identified","Upstream cause of H3K27ac loss in aging not defined"]},{"year":null,"claim":"How the multiple layers controlling PGR — kinase-driven autoinduction, dual E3-ligase degradation, miRNA repression, and histone acetylation — are integrated to set tissue- and stage-specific PGR levels remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coordinating transcriptional, post-transcriptional, and post-translational PGR regulation","Structural basis of context-dependent genomic site selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,7,8,9]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,7,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,13]}],"complexes":[],"partners":["ESR1","HERC4","UBE3C","SOX4","ARID1A","CREB1","MAPK14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06401","full_name":"Progesterone receptor","aliases":["Nuclear receptor subfamily 3 group C member 3"],"length_aa":933,"mass_kda":99.0,"function":"The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Depending on the isoform, progesterone receptor functions as a transcriptional activator or repressor Ligand-dependent transdominant repressor of steroid hormone receptor transcriptional activity including repression of its isoform B, MR and ER. Transrepressional activity may involve recruitment of corepressor NCOR2 Transcriptional activator of several progesteron-dependent promoters in a variety of cell types. Involved in activation of SRC-dependent MAPK signaling on hormone stimulation Increases mitochondrial membrane potential and cellular respiration upon stimulation by progesterone","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/P06401/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PGR","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PGR","total_profiled":1310},"omim":[{"mim_id":"621023","title":"RNA-BINDING MOTIF PROTEIN 23; RBM23","url":"https://www.omim.org/entry/621023"},{"mim_id":"619403","title":"COLON CANCER-ASSOCIATED TRANSCRIPT 2, NONCODING; CCAT2","url":"https://www.omim.org/entry/619403"},{"mim_id":"618083","title":"WW-BINDING PROTEIN 11; WBP11","url":"https://www.omim.org/entry/618083"},{"mim_id":"617639","title":"DEAFNESS, AUTOSOMAL RECESSIVE 107; DFNB107","url":"https://www.omim.org/entry/617639"},{"mim_id":"616755","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 62; TRIM62","url":"https://www.omim.org/entry/616755"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":59.9},{"tissue":"endometrium 1","ntpm":96.6},{"tissue":"fallopian tube","ntpm":32.3},{"tissue":"smooth muscle","ntpm":73.3}],"url":"https://www.proteinatlas.org/search/PGR"},"hgnc":{"alias_symbol":["PR","NR3C3"],"prev_symbol":[]},"alphafold":{"accession":"P06401","domains":[{"cath_id":"3.30.50.10","chopping":"577-631","consensus_level":"high","plddt":91.4613,"start":577,"end":631},{"cath_id":"1.10.565.10","chopping":"687-928","consensus_level":"high","plddt":93.7537,"start":687,"end":928}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06401","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06401-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06401-F1-predicted_aligned_error_v6.png","plddt_mean":56.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PGR","jax_strain_url":"https://www.jax.org/strain/search?query=PGR"},"sequence":{"accession":"P06401","fasta_url":"https://rest.uniprot.org/uniprotkb/P06401.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06401/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06401"}},"corpus_meta":[{"pmid":"10754487","id":"PMC_10754487","title":"Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study.","date":"2000","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10754487","citation_count":232,"is_preprint":false},{"pmid":"19570962","id":"PMC_19570962","title":"Discordance between core needle biopsy (CNB) and excisional biopsy (EB) for estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC).","date":"2009","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19570962","citation_count":144,"is_preprint":false},{"pmid":"15611798","id":"PMC_15611798","title":"Evaluation of ER, PgR, HER-2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer.","date":"2005","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15611798","citation_count":138,"is_preprint":false},{"pmid":"17986623","id":"PMC_17986623","title":"Expression of ER, PgR, HER1, HER2, and response: a study of preoperative chemotherapy.","date":"2007","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17986623","citation_count":89,"is_preprint":false},{"pmid":"20557310","id":"PMC_20557310","title":"Comparison of core needle biopsy (CNB) and surgical specimens for accurate preoperative evaluation of ER, PgR and HER2 status of breast cancer patients.","date":"2010","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/20557310","citation_count":79,"is_preprint":false},{"pmid":"25852646","id":"PMC_25852646","title":"Nuclear progestin receptor (pgr) knockouts in zebrafish demonstrate role for pgr in ovulation but not in rapid non-genomic steroid 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Cancer: Review.","date":"2013","source":"World journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29147345","citation_count":9,"is_preprint":false},{"pmid":"27542969","id":"PMC_27542969","title":"ESR1 and PGR polymorphisms are associated with estrogen and progesterone receptor expression in breast tumors.","date":"2016","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/27542969","citation_count":8,"is_preprint":false},{"pmid":"34351486","id":"PMC_34351486","title":"Epithelioid leiomyosarcoma of broad ligament harboring PGR-NR4A3 and UBR5-PGR gene fusions: a unique case report.","date":"2021","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34351486","citation_count":8,"is_preprint":false},{"pmid":"32302297","id":"PMC_32302297","title":"Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage.","date":"2020","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32302297","citation_count":8,"is_preprint":false},{"pmid":"32436149","id":"PMC_32436149","title":"Androgen receptor expression inversely correlates with histological grade and N stage in ER+/PgRlow male breast cancer.","date":"2020","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/32436149","citation_count":8,"is_preprint":false},{"pmid":"19897621","id":"PMC_19897621","title":"Expression of progesterone receptor related to the polymorphism in the PGR gene in the rabbit reproductive tract.","date":"2009","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/19897621","citation_count":8,"is_preprint":false},{"pmid":"24815444","id":"PMC_24815444","title":"ESR1 and PGR gene promoter methylation and correlations with estrogen and progesterone receptors in ductal and lobular breast cancer.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24815444","citation_count":8,"is_preprint":false},{"pmid":"23107922","id":"PMC_23107922","title":"Molecular markers in management of ex situ PGR-a case study.","date":"2012","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/23107922","citation_count":8,"is_preprint":false},{"pmid":"8343271","id":"PMC_8343271","title":"Evidence for bimodal distribution of breast carcinoma ER and PgR values quantitated by enzyme immunoassay.","date":"1993","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/8343271","citation_count":8,"is_preprint":false},{"pmid":"8100059","id":"PMC_8100059","title":"PCNA/cyclin expression in breast carcinomas: its relationships with Ki-67, ER, PgR immunostainings and clinico-pathologic aspects.","date":"1993","source":"Pathologica","url":"https://pubmed.ncbi.nlm.nih.gov/8100059","citation_count":8,"is_preprint":false},{"pmid":"7588146","id":"PMC_7588146","title":"Oestrogen and progesterone receptor status and PgR/ER ratios in normal and myomatous human myometrium.","date":"1995","source":"East African medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/7588146","citation_count":7,"is_preprint":false},{"pmid":"34572945","id":"PMC_34572945","title":"Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer-A Europe-Wide External Quality Assessment.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34572945","citation_count":7,"is_preprint":false},{"pmid":"32210157","id":"PMC_32210157","title":"Aromatase Inhibitors as Adjuvant Treatment for ER/PgR Positive Stage I Endometrial Carcinoma: A Retrospective Cohort Study.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32210157","citation_count":7,"is_preprint":false},{"pmid":"9143843","id":"PMC_9143843","title":"In situ hybridization of chromosome 6 on fine-needle aspirates from breast carcinomas: comparison of numerical abnormalities and ER/PgR status and staining pattern.","date":"1997","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/9143843","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55386,"output_tokens":4706,"usd":0.118374,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12854,"output_tokens":4349,"usd":0.086498,"stage2_stop_reason":"end_turn"},"total_usd":0.204872,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Progesterone (R5020) induces dose-dependent PGR mRNA and protein expression in an estrogen-independent manner requiring both PR and ERα. Rapid PR-dependent activation of MAPK/ERK and AKT leads to phosphorylation of ERα Ser118, enabling cooperative ERα/PR recruitment to an ERE/Sp1-containing region of the PGR proximal promoter. Inhibition of these kinase pathways (U0126 or LY294002) blocked ERα and PR chromatin recruitment and subsequent PGR mRNA induction.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), pharmacologic inhibition of MAPK/ERK and AKT, receptor antagonists (RU486, ICI 182,780), qRT-PCR and Western blot in ER+/PR+ cancer cell lines\",\n      \"journal\": \"Steroids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with pharmacologic inhibition and antagonist controls, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27641443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SOX4 stabilizes PGR protein by repressing the E3 ubiquitin ligase HERC4-mediated polyubiquitination and proteasomal degradation of PGR. Co-immunoprecipitation and mass spectrometry identified the SOX4–HERC4–PGR axis; dysregulation of this axis underlies defective decidualization and recurrent implantation failure.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, whole-genome SOX4 ChIP-seq, RNA sequencing, siRNA knockdown in human endometrial stromal cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP + MS identification of E3 ligase + genome-wide binding + functional rescue experiments, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"35244538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"P38α MAPK protects PGR from proteasomal degradation in the uterine stroma by phosphorylating the HECT-family E3 ubiquitin ligase Ube3c at serine 741, thereby restraining Ube3c-mediated polyubiquitination of PGR. Uterine-selective depletion of P38α led to dramatic loss of PGR protein and defective implantation.\",\n      \"method\": \"Conditional knockout mouse model, co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (Ube3c S741), Western blot, fertility phenotype analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic KO with defined molecular mechanism, in vitro ubiquitination assay, mutagenesis of phosphorylation site, replicated across multiple assays\",\n      \"pmids\": [\"35914132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Zebrafish nuclear progesterone receptor (Pgr) knockout (via TALENs) females are infertile due to anovulation: oocytes undergo normal meiosis resumption (GVBD) and final oocyte maturation in vitro but fail to ovulate even after HCG or progestin treatment. This establishes that Pgr-mediated genomic signaling in follicular cells is required for ovulation but is not essential for non-genomic progestin signaling initiating meiosis resumption.\",\n      \"method\": \"TALEN-mediated knockout in zebrafish, in vitro oocyte maturation assays, HCG/progestin stimulation, fertility phenotyping\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent mutant lines, in vivo and in vitro functional dissection, loss-of-function with specific phenotypic readout\",\n      \"pmids\": [\"25852646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adenoviral shRNA knockdown of PGR in macaque granulosa cells in vivo prevented follicle rupture (5/6 monkeys) and blocked the post-hCG rise in serum progesterone, demonstrating that nuclear PGR in granulosa cells is required for ovulation and for progesterone synthesis/luteinization in primates.\",\n      \"method\": \"Adenoviral shRNA knockdown injected into preovulatory follicles of rhesus monkeys, laparoscopic evaluation of ovulation, serum progesterone measurement, immunostaining for nuclear PGR\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockdown in primate follicles with direct ovulation assessment and hormonal readout, complemented by in vitro luteinized granulosa cell experiments\",\n      \"pmids\": [\"26985003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In human periovulatory granulosa/lutein cells, PGR binds directly to the FOS gene promoter (shown by ChIP) after hCG stimulation, and PGR inhibition reduces hCG-induced FOS expression and phosphorylation. FOS in turn binds the promoters of prostaglandin synthase genes (PTGES, SLCO2A1, ABCC1), and FOS inhibition blocks hCG-induced PGE2 production, placing PGR upstream of FOS-dependent ovulatory prostaglandin synthesis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) in human granulosa/lutein cells, pharmacologic inhibition of PGR and EGFR, selective FOS inhibitor, PGE2 measurement, mRNA and protein analysis\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ChIP for PGR binding at FOS gene, functional inhibitor cascade experiments, PGE2 measurement, multiple orthogonal methods\",\n      \"pmids\": [\"30124866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARID1A physically interacts with PGR-A (but not PGR-B) isoform in mouse and human endometrium, as demonstrated by co-immunoprecipitation and proximity ligation assay. ARID1A levels positively correlate with PGR levels in eutopic endometrium from women with endometriosis.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (PLA), Western blot, immunostaining in mouse and human endometrial tissue\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP confirmed by PLA, isoform specificity established, single lab\",\n      \"pmids\": [\"33706098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PGR directly binds to the PTPN11 (SHP2) gene promoter in the region -229 to +1 bp in response to progesterone, cooperating with CREB1 to transcriptionally induce SHP2 expression during decidualization. Direct PGR and CREB1 binding was confirmed by EMSA and ChIP; knockdown of either factor inhibited SHP2 induction.\",\n      \"method\": \"Luciferase reporter assay, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), siRNA knockdown, qRT-PCR in human endometrial stromal cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP confirm direct PGR binding, functional siRNA validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37786383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In human myometrium, genome-wide ChIP-seq reveals that PGR binding shifts between non-pregnant (predominantly intergenic sites) and term-pregnant (predominantly promoter regions including classical progesterone response elements) states. Integration of ChIP-seq, RNA-seq, and histone modification data identified ATP11A, CBX7, and TNS1 as direct PGR target genes responsive to progesterone in vitro.\",\n      \"method\": \"ChIP-seq, ATAC-seq, RNA-seq in human myometrial tissue; in vitro progesterone treatment for target gene validation\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with orthogonal RNA-seq and histone mark data, in vitro validation of specific targets, single lab\",\n      \"pmids\": [\"31908010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In human myometrium, in-labor PGR predominantly occupies promoter regions (including PRE motifs), whereas not-in-labor PGR binds mainly to intergenic regions. Differential PGR binding analysis identified >1700 differential sites and SRF, MYOD, and STAT binding motifs co-enriched at PGR-occupied sites, suggesting PGR interacts with major muscle regulators for myometrial gene control during labor.\",\n      \"method\": \"ChIP-seq for PGR and histone marks, RNA-seq, in vitro progesterone treatment in human myometrial tissue (term in-labor vs. not-in-labor)\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genome-wide ChIP-seq with RNA-seq integration and in vitro validation, single lab\",\n      \"pmids\": [\"35732928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H3K27 acetylation (H3K27ac) at the PGR locus positively regulates PGR expression in endometrial stromal cells; experimental depletion of H3K27ac in young human endometrial stromal cells reduced PGR protein levels. Loss of H3K27ac and PGR is associated with uterine aging and impaired endometrial receptivity, validated in a mouse aging model.\",\n      \"method\": \"CRISPR/epigenome editing to eliminate H3K27ac, transcriptomic profiling, immunostaining, mouse aging model validation\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct epigenome perturbation with PGR protein readout and in vivo mouse validation, single lab\",\n      \"pmids\": [\"40394215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-181a directly represses PGR, DDX3X, and TIMP3 at the mRNA and protein level through interactions with their 3'-UTRs, as demonstrated by luciferase reporter assays in Ishikawa endometrial cancer cells. miR-181a gain-of-function reduced PGR protein expression and influenced downstream CCNE1 through DDX3X repression.\",\n      \"method\": \"miRNA transfection (gain-of-function), 3'-UTR luciferase reporter assay, qRT-PCR and Western blot in Ishikawa cells\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated direct miRNA-3'UTR interaction by luciferase assay plus protein-level confirmation, single lab\",\n      \"pmids\": [\"22492871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In bovine cumulus cells, miR-375 directly targets PGR (and ADAMTS1) 3'-UTRs as validated by dual-luciferase reporter assay and RNA immunoprecipitation. miR-375 overexpression suppresses PGR expression and inhibits cumulus-oocyte complex maturation; restoration of PGR expression rescues maturation, placing PGR downstream of miR-375 in oocyte IVM.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA immunoprecipitation, lentiviral overexpression and knockdown, Western blot in bovine cumulus cells\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR binding validated by two orthogonal methods, rescue experiment confirms pathway position, single lab\",\n      \"pmids\": [\"31545267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LH-induced PGR expression in medaka preovulatory follicles requires the cAMP/EPAC/RAP/PI3K/AKT/CREB signaling pathway (not PKA). Phosphorylated CREB1 (phosphorylated by Akt1) acts as the transcription factor driving pgr gene expression; pharmacologic inhibitors of EPAC, RAP, PI3K, AKT, and CREB all blocked LH-induced Pgr expression and follicle ovulation.\",\n      \"method\": \"In vitro ovulation assay with specific pathway inhibitors (brefeldin A, GGTI298, wortmannin, AKT inhibitor IV, KG-501, H-89), mRNA and protein analysis in medaka follicles\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic pharmacologic pathway dissection in a defined in vitro ovulation system, multiple inhibitors targeting sequential pathway components, single lab\",\n      \"pmids\": [\"33880506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ancestral sequence resurrection and functional assays show that the major human PGR isoforms (PR-A and PR-B) evolved divergent transcriptional functions during the human stem-lineage, coincident with a period of relaxed evolutionary constraint rather than positive selection.\",\n      \"method\": \"Ancestral sequence resurrection, phylogenetic analysis, functional transcriptional reporter assays comparing ancestral and derived PR-A and PR-B\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transcriptional assays on reconstructed ancestral sequences, evolutionary analysis, single lab\",\n      \"pmids\": [\"32302297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PGR gene fusions (including NR4A3-PGR) define a molecular subset of uterine epithelioid leiomyosarcomas. Targeted RNA sequencing and FISH identified these rearrangements in 35% of epithelioid leiomyosarcomas, and all fusion-positive tumors expressed desmin, ER, and PR by immunohistochemistry.\",\n      \"method\": \"Targeted next-generation RNA sequencing, FISH with custom PGR and NR4A3 probes, immunohistochemistry on FFPE tissue\",\n      \"journal\": \"The American journal of surgical pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — molecular characterization of gene fusions by RNA-seq and FISH, replicated across multiple cases, no functional reconstitution\",\n      \"pmids\": [\"30829727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EGFRvIII constitutive signaling (activating Akt and MAPK) in breast cancer cells causes loss of PGR protein expression. EGFRvIII expression in MDA-MB-361 cells (which normally co-express ERα and PgR) resulted in pronounced reduction of PgR compared to wild-type cells, and was associated with estrogen independence and tamoxifen resistance.\",\n      \"method\": \"Stable transfection of EGFRvIII, Western blot for PgR and signaling intermediates, in vivo xenograft experiments in ovariectomized nude mice, IHC of human breast cancer specimens\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single transfection model, mechanistic linkage between EGFRvIII→kinase activation→PgR loss inferred but not directly mechanistically dissected\",\n      \"pmids\": [\"19588487\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PGR (progesterone receptor) is a ligand-activated nuclear transcription factor that binds progesterone response elements (and ERE/Sp1 sites cooperatively with ERα) to regulate downstream target genes; its protein stability is controlled by ubiquitin-proteasome degradation mediated by E3 ligases HERC4 and Ube3c, the latter restrained by P38α-mediated phosphorylation, while its transcriptional activity and genomic occupancy are context-dependent (shifting between intergenic and promoter sites in the myometrium during pregnancy/labor); PGR is required for ovulation in vertebrates through genomic signaling in follicular/granulosa cells, drives ovulatory prostaglandin synthesis via FOS induction, regulates decidualization partly through direct binding to target gene promoters (e.g., PTPN11/SHP2) in cooperation with CREB1, and is physically associated with ARID1A (isoform PGR-A) in the endometrium, while its expression is post-transcriptionally repressed by miR-181a (via 3'-UTR interaction) and epigenetically regulated by H3K27ac and promoter DNA methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PGR (progesterone receptor) is a ligand-activated nuclear transcription factor that executes the genomic arm of progesterone signaling in reproductive tissues, where it is required for ovulation, decidualization, and the regulation of myometrial gene programs during pregnancy and labor [#3, #4, #8]. In ovarian follicular and granulosa cells, nuclear PGR signaling is essential for follicle rupture and ovulation across vertebrates, while non-genomic progestin signaling driving oocyte meiotic resumption proceeds independently of it [#3, #4]. Mechanistically, PGR binds directly to the FOS promoter after hCG stimulation to trigger FOS-dependent ovulatory prostaglandin synthesis [#5], and during decidualization it occupies target promoters such as PTPN11/SHP2 in cooperation with CREB1 [#7]. PGR is recruited to its own proximal promoter together with ERα through MAPK/ERK- and AKT-dependent ERα Ser118 phosphorylation, establishing an autoregulatory induction loop [#0]. Genome-wide, PGR occupancy is context-dependent: in myometrium it shifts from predominantly intergenic sites in the non-pregnant/not-in-labor state toward promoter regions bearing progesterone response elements in the term-pregnant/in-labor state, co-enriched with muscle-regulatory motifs [#8, #9]. PGR protein abundance is tightly controlled by the ubiquitin-proteasome system: the E3 ligases HERC4 and Ube3c polyubiquitinate PGR, with SOX4 stabilizing PGR by repressing HERC4 and P38α MAPK protecting PGR by phosphorylating Ube3c at Ser741 to restrain its ligase activity [#1, #2]. PGR expression is further constrained post-transcriptionally by miR-181a and miR-375 acting on its 3'-UTR and epigenetically by H3K27 acetylation at its locus [#10, #11, #12]. Recurrent NR4A3-PGR gene fusions define a molecular subset of uterine epithelioid leiomyosarcomas [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that genomic PGR signaling, rather than non-genomic progestin signaling, is the step that is indispensable for ovulation, dissociating ovulation from oocyte meiotic maturation.\",\n      \"evidence\": \"TALEN knockout of nuclear Pgr in zebrafish with in vitro maturation and ovulation phenotyping\",\n      \"pmids\": [\"25852646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the PGR target genes mediating follicle rupture\", \"Zebrafish follicular context may differ from mammalian granulosa biology\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed the requirement for granulosa-cell nuclear PGR in primate ovulation and luteinization, extending the conserved ovulatory role to mammals.\",\n      \"evidence\": \"Adenoviral shRNA knockdown of PGR in rhesus monkey preovulatory follicles with ovulation and serum progesterone readouts\",\n      \"pmids\": [\"26985003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional effectors not defined\", \"Knockdown efficiency and off-target effects in vivo not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined an autoregulatory loop whereby progesterone induces PGR through PR-dependent kinase signaling and cooperative ERα/PR promoter recruitment, explaining estrogen-independent PGR upregulation.\",\n      \"evidence\": \"ChIP with MAPK/AKT inhibitors and receptor antagonists in ER+/PR+ cancer cell lines\",\n      \"pmids\": [\"27641443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in cancer cell lines, not normal reproductive tissue\", \"Direct PR DNA contact at the ERE/Sp1 region versus tethering not distinguished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed PGR directly upstream of ovulatory prostaglandin synthesis by showing PGR binds the FOS promoter to drive FOS-dependent induction of prostaglandin synthase genes.\",\n      \"evidence\": \"ChIP for PGR at FOS, PGR/EGFR and FOS inhibitors, PGE2 measurement in human granulosa/lutein cells\",\n      \"pmids\": [\"30124866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-factors at the FOS promoter not identified\", \"Causal contribution of this axis to actual follicle rupture in vivo not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed that PGR genomic occupancy is dynamically reprogrammed in myometrium across pregnancy, shifting from intergenic to promoter/PRE sites and identifying specific progesterone-responsive target genes.\",\n      \"evidence\": \"Genome-wide ChIP-seq, ATAC-seq and RNA-seq in human myometrial tissue with in vitro target validation\",\n      \"pmids\": [\"31908010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism driving the binding-site shift unknown\", \"Single-lab dataset without independent cohort replication\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified recurrent PGR gene fusions as a defining molecular feature of a uterine epithelioid leiomyosarcoma subset, linking PGR rearrangement to a tumor entity.\",\n      \"evidence\": \"Targeted RNA sequencing and FISH with PGR/NR4A3 probes and immunohistochemistry on tumor tissue\",\n      \"pmids\": [\"30829727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional reconstitution of the fusion protein\", \"Oncogenic mechanism of the fusion not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that the human PR-A and PR-B isoforms acquired divergent transcriptional functions during human evolution under relaxed constraint, framing isoform-specific PGR biology in an evolutionary context.\",\n      \"evidence\": \"Ancestral sequence resurrection, phylogenetic analysis, and transcriptional reporter assays\",\n      \"pmids\": [\"32302297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequences of functional divergence not tested in tissue\", \"Target gene specificity of ancestral versus derived isoforms not mapped genome-wide\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established post-transcriptional and epigenetic control of PGR levels through miR-181a 3'-UTR repression and ARID1A isoform-specific physical association with PGR-A.\",\n      \"evidence\": \"3'-UTR luciferase reporter assays in Ishikawa cells (miR-181a); reciprocal Co-IP and PLA in mouse and human endometrium (ARID1A)\",\n      \"pmids\": [\"22492871\", \"33706098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the ARID1A-PGR-A interaction on target gene transcription not defined\", \"miR-181a regulation shown in a cancer cell line\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the LH-triggered cAMP/EPAC/RAP/PI3K/AKT/CREB signaling cascade that drives pgr transcription in preovulatory follicles, identifying CREB1 as the activating transcription factor.\",\n      \"evidence\": \"Sequential pharmacologic pathway dissection in a medaka in vitro ovulation assay\",\n      \"pmids\": [\"33880506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CREB1 binding at the pgr promoter not shown in this system\", \"Conservation of the EPAC-dependent route in mammals not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified ubiquitin-proteasome control of PGR stability via two E3 ligases and their regulators, showing SOX4 represses HERC4 and P38α phosphorylates Ube3c (Ser741) to protect PGR and support decidualization and implantation.\",\n      \"evidence\": \"Reciprocal Co-IP/MS, SOX4 ChIP-seq and rescue in human endometrial stromal cells; conditional P38α knockout mouse with ubiquitination assays and Ube3c mutagenesis\",\n      \"pmids\": [\"35244538\", \"35914132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination sites on PGR targeted by HERC4/Ube3c not mapped\", \"Interplay between the two ligase axes in the same cell not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended myometrial PGR occupancy reprogramming to the labor transition, showing promoter/PRE shift in labor and co-enrichment with muscle-regulatory motifs (SRF, MYOD, STAT).\",\n      \"evidence\": \"PGR and histone-mark ChIP-seq with RNA-seq in in-labor versus not-in-labor human myometrium\",\n      \"pmids\": [\"35732928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical PGR interaction with SRF/MYOD/STAT factors not biochemically demonstrated\", \"Causal link between binding shift and labor onset not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated direct PGR-CREB1 cooperative transactivation of PTPN11/SHP2 during decidualization, mapping a specific promoter-level PGR target program.\",\n      \"evidence\": \"Luciferase reporter, EMSA, ChIP and siRNA knockdown in human endometrial stromal cells\",\n      \"pmids\": [\"37786383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Broader decidualization gene network co-regulated by PGR-CREB1 not defined\", \"Single-lab in vitro stromal cell system\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked H3K27 acetylation at the PGR locus to PGR expression and endometrial receptivity, connecting epigenetic loss to uterine aging.\",\n      \"evidence\": \"CRISPR/epigenome editing depleting H3K27ac with PGR protein readout and mouse aging model validation\",\n      \"pmids\": [\"40394215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymes setting/removing H3K27ac at the PGR locus not identified\", \"Upstream cause of H3K27ac loss in aging not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple layers controlling PGR — kinase-driven autoinduction, dual E3-ligase degradation, miRNA repression, and histone acetylation — are integrated to set tissue- and stage-specific PGR levels remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating transcriptional, post-transcriptional, and post-translational PGR regulation\", \"Structural basis of context-dependent genomic site selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 7, 8, 9]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ESR1\",\n      \"HERC4\",\n      \"UBE3C\",\n      \"SOX4\",\n      \"ARID1A\",\n      \"CREB1\",\n      \"MAPK14\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}