{"gene":"PTGS2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1994,"finding":"The human PTGS2 gene encodes a distinct inducible isozyme of prostaglandin-endoperoxide synthase (COX-2), separate from the constitutive PTGS1 isozyme. The gene spans >8.3 kb with 10 exons, contains a TATA box and multiple transcriptional regulatory elements (NF-κB, CRE, NF-IL6, AP-1, Sp-1 sites) in its 5'-flanking region, and maps to chromosome 1q25.2-q25.3, distinct from PTGS1 on chromosome 9q32-q33.3.","method":"Gene isolation, nucleotide sequencing, primer-extension analysis, fluorescence in situ hybridization","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct sequencing and structural characterization of the gene with multiple orthogonal methods; foundational characterization paper","pmids":["8181472"],"is_preprint":false},{"year":2007,"finding":"MyD88 (TLR signaling) acts upstream of Ptgs2/PGE2 in the colonic stem cell niche. During injury, MyD88 signaling repositions Ptgs2-expressing stromal cells to the crypt base adjacent to colonic epithelial progenitors, and this spatial reorganization (not changes in Ptgs2 expression level) is required to maintain epithelial proliferation. Exogenous dmPGE2 rescued the proliferative defect in both Myd88−/− and Ptgs2−/− mice.","method":"Genetic epistasis using Myd88−/− and Ptgs2−/− knockout mice, exogenous PGE2 rescue, histological analysis of crypt cell positioning","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — two knockout models with rescue experiment, epistasis established, replicated across genotypes","pmids":["17200722"],"is_preprint":false},{"year":2010,"finding":"PGF2α stimulates PTGS2 mRNA expression and PGF2α synthesis in the corpus luteum through ROS-mediated NF-κB activation. PGF2α injection increased nuclear NF-κB p65 and its binding to the PTGS2 gene promoter; co-administration of superoxide dismutase and catalase (ROS scavengers) abolished nuclear NF-κB accumulation, lipid peroxidation, and Ptgs2 mRNA induction. Selective PTGS2 inhibitor NS-398 abolished the PGF2α-induced rise in luteal PGF2α concentrations.","method":"In vivo rat model with pharmacological inhibitors, electrophoretic mobility shift assay (EMSA) for NF-κB binding to PTGS2 promoter, ROS scavenger co-administration, PTGS2 inhibitor NS-398","journal":"Reproduction (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — EMSA demonstrated direct NF-κB binding to PTGS2 promoter, multiple orthogonal interventions (ROS scavengers, NF-κB, PTGS2 inhibitor) in same study","pmids":["20826536"],"is_preprint":false},{"year":2011,"finding":"PTGS2-derived PGE2 is required for oocyte MAPK (ERK1/2) phosphorylation during in vitro maturation of bovine oocytes. Specific inhibition of PTGS2 with NS-398 significantly restricted MAPK activation at germinal vesicle breakdown stage, reduced cumulus expansion, and caused abnormal meiotic spindle organization. Addition of exogenous PGE2 rescued these defects. PGE2 acts via PTGER2/3/4 receptors expressed in cumulus cells and PTGER2 in oocytes.","method":"In vitro bovine oocyte maturation model with PTGS2-specific inhibitor NS-398, exogenous PGE2 rescue, immunofluorescence of spindle, mRNA/protein expression of PGE receptors","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological inhibition, receptor identification, PGE2 rescue in single rigorous study with multiple readouts","pmids":["21293029"],"is_preprint":false},{"year":2011,"finding":"PTGS2 expression in term human amnion involves rapid mRNA turnover, RNA polymerase-II 5'-pausing at the PTGS2 locus, and glucocorticoid-mediated transrepression. Dexamethasone decreased PTGS2 gene activity; glucocorticoid receptor-α (GRα) bound to the PTGS2 promoter and decreased Ser-5 and Ser-2 phosphorylation of pol-II CTD (interfering with both initiation and elongation) without affecting pol-II recruitment or pausing.","method":"Chromatin immunoprecipitation (ChIP) for pol-II binding, pol-II CTD phosphorylation states, histone acetylation/methylation; dexamethasone treatment of fresh amnion and explants; RT-qPCR","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at multiple regulatory points (pol-II, CTD phosphorylation, histones), multiple orthogonal chromatin assays in one study","pmids":["21385935"],"is_preprint":false},{"year":2013,"finding":"PTGS2 silencing by siRNA in bovine granulosa cells reduced AREG, EREG, and TNFAIP6 mRNA levels, while PTX3 was unaffected. Exogenous PGE2 rescued AREG, EREG, and TNFAIP6 expression, demonstrating that PTGS2-derived prostaglandins lie upstream of these ovulatory genes in the LH-induced ovulation cascade.","method":"siRNA knockdown of PTGS2 in bovine granulosa cells, exogenous PGE2 rescue, RT-qPCR","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with rescue, single lab, multiple gene readouts","pmids":["25323036"],"is_preprint":false},{"year":2013,"finding":"PTGS2/COX-2 activity mediates PGE2/EP4/MAPK (ERK1/2, p38) signaling to upregulate BCL2 and promote resistance to cisplatin-induced apoptosis in gastric cancer. Cisplatin induces PTGS2 expression through a ROS/NF-κB pathway. Celecoxib (PTGS2 inhibitor) reversed cisplatin resistance in xenograft models by suppressing PTGS2, BCL2, ERK1/2, and p38.","method":"siRNA knockdown, pharmacological inhibitors (celecoxib, NS-398), xenograft mouse model, western blot, pathway inhibitors","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic knockdown with in vivo validation, single lab","pmids":["31518663"],"is_preprint":false},{"year":2015,"finding":"ATF3 (activating transcription factor-3) negatively regulates Ptgs2 transcription during acute inflammation. In activated macrophages stimulated with zymosan, Atf3 accumulates in the nucleus and is recruited to the Ptgs2 promoter (shown by ChIP). Atf3−/− peritoneal macrophages show significantly higher Ptgs2 expression and prostaglandin production than wild-type, and Atf3−/− mice exhibit increased leukocyte accumulation and higher PGE2/PGD2 levels in acute peritonitis.","method":"Chromatin immunoprecipitation (ChIP) of Atf3 at Ptgs2 promoter, Atf3−/− knockout mice, peritonitis model, prostaglandin measurement","journal":"Prostaglandins & other lipid mediators","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP directly demonstrated promoter recruitment, Atf3 knockout with multiple in vivo phenotypes, single rigorous study","pmids":["25619459"],"is_preprint":false},{"year":2015,"finding":"DNA methylation of a CpG island near the PTGS2 locus disrupts CTCF/cohesin-mediated chromatin looping, abolishes enrichment of positive elongation factor b at the PTGS2 transcriptional start site, and downregulates PTGS2 expression. CTCF/cohesin complex binding to the PTGS2 CpG island is methylation-sensitive.","method":"Chromatin immunoprecipitation (ChIP) for CTCF, cohesin, transcriptional components; 3C/chromatin conformation assays; DNA methylation analysis; siRNA knockdown; luciferase reporter","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP, chromatin looping, and functional consequence established in one study with multiple orthogonal methods","pmids":["25703332"],"is_preprint":false},{"year":2016,"finding":"Activin A upregulates PTGS2 expression and increases PGE2 production in human granulosa-lutein cells via an ACVR1B-mediated SMAD2/3-SMAD4 signaling pathway. The TGF-β/activin type I receptor inhibitor SB431542 and siRNA against SMAD2/3 or SMAD4 abolished activin A-induced PTGS2 induction.","method":"Pharmacological inhibition (SB431542), siRNA knockdown of SMAD2/3/SMAD4, ELISA for PGE2, western blot and RT-qPCR in immortalized SVOG and primary granulosa-lutein cells","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor inhibitor and siRNA knockdown with multiple pathway components, single lab","pmids":["27624482"],"is_preprint":false},{"year":2017,"finding":"Nuclear anchoring of PKA by AKAP95 is required for cortisol-induced PTGS2 expression in human amnion fibroblasts. Cortisol increases AKAP95 expression, which retains PKA in the nucleus; AKAP95 knockdown reduces nuclear PKA, phospho-CREB, and PTGS2 induction. AKAP95, phospho-CREB, and COX-2 are all markedly increased in human amnion tissue after labor.","method":"siRNA knockdown of AKAP95 in primary amnion fibroblasts, subcellular fractionation, western blot for nuclear PKA/phospho-CREB/STAT3, immunohistochemistry of labor vs. non-labor amnion","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown in primary cells with multiple readouts, corroborated in human tissue; single lab with multiple orthogonal methods","pmids":["29162743"],"is_preprint":false},{"year":2019,"finding":"EPHA2 signaling in tumor cells upregulates PTGS2 (COX-2) expression through TGFβ, suppressing anti-tumor T cell infiltration in pancreatic adenocarcinoma. Epha2 deletion or Ptgs2 deletion each reversed T cell exclusion and sensitized tumors to immunotherapy, placing PTGS2 downstream of EPHA2-TGFβ signaling in the pathway controlling tumor immune phenotype.","method":"Genetic deletion (Epha2−/−, Ptgs2−/−) in murine tumor models, pharmacological PTGS2 inhibition, immunotherapy combination experiments, T cell infiltration analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent gene knockouts in vivo with pharmacological corroboration, epistasis established","pmids":["31162144"],"is_preprint":false},{"year":2019,"finding":"PTGS2 knockdown by CRISPR/Cas9 in B16F10 murine melanoma cells inhibits cell proliferation, migration, and invasiveness in vitro, impairs myeloid-derived suppressor cell differentiation, and reduces tumor development and metastasis in vivo.","method":"CRISPR/Cas9 gene knockout, in vitro proliferation/migration/invasion assays, in vivo tumor model, flow cytometry for MDSC differentiation","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockout with in vivo validation, single lab","pmids":["31920649"],"is_preprint":false},{"year":2019,"finding":"Inhibition of mitochondrial oxidative phosphorylation stabilizes Ptgs2 mRNA in IL-1α-stimulated astrocytes through AMPK activation, increasing Ptgs2 protein and downstream eicosanoid (PGE2, PGF2α, 6-keto-PGF1α) secretion. AMPK silencing prevented Ptgs2 upregulation by mitochondrial inhibitors; AMPK activators recapitulated Ptgs2 mRNA stabilization.","method":"siRNA knockdown of AMPK, pharmacological AMPK activators/inhibitors, mRNA stability assays, LC/MS measurement of eicosanoids, in neonatal rat astrocytes","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (siRNA) and pharmacological corroboration, LC/MS readout, single lab","pmids":["31581537"],"is_preprint":false},{"year":2019,"finding":"PTGS2 activates the NF-κB signaling pathway in glioma cells to prevent DNA damage and enhance radiation resistance. PTGS2 overexpression elevated radioresistance in U87 cells and reduced G2/M arrest after radiation; PTGS2 knockdown sensitized U87R cells to radiation. NF-κB inhibitor Bay 11 decreased survival rates under radiation in both cell lines.","method":"PTGS2 overexpression and siRNA knockdown in glioma cells, clonogenic survival assay, flow cytometry (cell cycle), immunofluorescence (γH2AX), western blot for NF-κB pathway proteins","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple cellular readouts, single lab","pmids":["30740906"],"is_preprint":false},{"year":2020,"finding":"PTGS2/COX-2-dependent upregulation of P-glycoprotein at the blood-brain barrier contributes to antiepileptic drug resistance. In vitro, valproate suppressed COX-2-dependent P-gp upregulation in brain endothelial cells (hCMEC/D3) under hyperexcitatory conditions. In responders to valproate, PTGS2 mRNA levels in peripheral blood were downregulated compared to non-responders, correlating with reduced plasma PGE2.","method":"In vitro brain endothelial cell model with valproate treatment, COX-2/P-gp protein expression by western blot, microarray gene expression, plasma PGE2 measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic follow-up with pharmacological inhibition corroborating clinical data, single lab","pmids":["32054883"],"is_preprint":false},{"year":2022,"finding":"The CTCF/lncRNA-PACERR complex recruits E1A binding protein p300 to the promoter regions of PACERR and PTGS2, enhancing histone acetylation and PTGS2 transcription, promoting M2 polarization of tumor-associated macrophages in pancreatic ductal adenocarcinoma. PACERR directly binds CTCF (shown by RNA immunoprecipitation and RNA pull-down); PACERR or CTCF knockdown each reduced PTGS2 expression and M2 markers.","method":"RNA immunoprecipitation (RIP), RNA pull-down, ChIP-seq, ATAC-seq, RNA-seq, lentiviral knockdown, in vitro and in vivo invasion/metastasis assays","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA-protein interaction validated by RIP and pull-down, ChIP-seq for histone acetylation, multiple orthogonal omics methods in one study","pmids":["35184402"],"is_preprint":false},{"year":2022,"finding":"The transcription factor Hif1a binds the promoter of Ptgs2 and upregulates its expression in cardiomyocytes following coronary microembolization, promoting ferroptosis and inflammation. Atorvastatin inhibits the Hif1a/Ptgs2 axis to attenuate ferroptosis-mediated myocardial injury.","method":"Chromatin immunoprecipitation (ChIP) for Hif1a binding to Ptgs2 promoter, Ptgs2 siRNA silencing, ferroptosis markers (MDA, GSH, Fe2+), cardiac function measurements, rat CME model","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrated direct Hif1a binding to Ptgs2 promoter, functional rescue with siRNA, single lab","pmids":["36569299"],"is_preprint":false},{"year":2022,"finding":"LRH-1/NR5A2 regulates the PTGS2-PGE2-PTGER1 signaling axis to promote beta cell survival. LRH-1 deletion in adult beta cells abolished BL001 agonist-mediated Ptgs2 induction and islet protection. PTGS2 inactivation reduced PGE2 levels and eliminated BL001 protection against cytokine-induced apoptosis (increased cytochrome c release, cleaved PARP). PTGER1 antagonist ONO-8130 also negated BL001-mediated islet survival.","method":"Conditional beta cell-specific LRH-1 knockout mice, PTGS2 inactivation, pharmacological PTGER1 antagonist, PGE2 ELISA, apoptosis markers (cytochrome c, cleaved PARP)","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout + PTGS2 inactivation + receptor pharmacology, multiple orthogonal interventions establishing pathway order","pmids":["35602948"],"is_preprint":false},{"year":2024,"finding":"ROBO4 interacts with IQGAP1 and TRAF7 (ubiquitin E3 ligase) to form a complex in endothelial cells; within this complex, ROBO4 enhances TRAF7-mediated ubiquitination of IQGAP1, inhibits prolonged RAC1 activation, and thereby decreases PTGS2 expression in inflammatory endothelial cells. Robo4-deficient mice show exacerbated PTGS2-associated inflammatory diseases (arthritis, edema, pain).","method":"RNA-seq, Co-immunoprecipitation for ROBO4-IQGAP1-TRAF7 complex, ubiquitination assay, Robo4-deficient mice, in vivo inflammatory disease models","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrated protein complex, ubiquitination assay, Robo4 KO in vivo phenotype, multiple orthogonal methods","pmids":["38762541"],"is_preprint":false},{"year":2024,"finding":"The transcription factor RUNX1 directly binds the PTGS2 promoter at the 1086-1096 bp binding motif and promotes transcriptional activation of PTGS2 in colorectal cancer cells. PTGS2 silencing repressed CRC cell growth, migration, and invasion.","method":"Luciferase reporter assay with PTGS2 promoter fragments, siRNA knockdown of PTGS2 and RUNX1, TCGA co-expression analysis, cell proliferation/migration/invasion assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter mapped binding motif, knockdown functional assays, single lab","pmids":["38778047"],"is_preprint":false},{"year":2025,"finding":"Tanshinone IIA induces ferroptosis in melanoma via STAT1-mediated transcriptional upregulation of PTGS2. STAT1 was identified as a transcription factor that binds the PTGS2 promoter (validated by ChIP and luciferase assay); STAT1 downregulation led to PTGS2 downregulation and inhibited ferroptosis. PTGS2 knockdown attenuated Tan IIA-induced ferroptosis.","method":"RNA sequencing, chromatin immunoprecipitation (ChIP) and luciferase assay for STAT1 binding to PTGS2 promoter, PTGS2 knockdown, STAT1 knockdown, ferroptosis markers (MDA, Fe2+, ROS, GSH), xenograft model","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase validate promoter binding, functional knockdown with in vivo model, single lab","pmids":["40222167"],"is_preprint":false},{"year":2014,"finding":"REV-ERBα (encoded by NR1D1) acts as a transcriptional repressor of PTGS2 expression in bovine uterine stromal and epithelial cells. REV-ERBα antagonist treatment increased PTGS2 transcript levels and PGF2α production in both cell types; BMAL1 knockdown by siRNA decreased NR1D1 and PTGS2 expression and PGF2α production in stromal cells.","method":"siRNA knockdown of BMAL1, pharmacological REV-ERBα agonist/antagonist, RT-qPCR, PGF2α ELISA in bovine uterine cells","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown and pharmacological intervention, two cell types, single lab","pmids":["25007867"],"is_preprint":false},{"year":2024,"finding":"Astilbin (AST) binds the transcription factor KLF4 (demonstrated by DARTS assay, molecular docking, and SPR), which in turn binds and activates the PTGS2 promoter (validated by ChIP-PCR and dual-luciferase reporter). AST-mediated KLF4-PTGS2 upregulation increases PGE2 secretion from MSCs, promoting M2 macrophage polarization. PTGS2 knockdown reversed AST-pretreated MSC-mediated M2 polarization and reduced therapeutic effects in AKI-CKD mice.","method":"DARTS assay, surface plasmon resonance (SPR), molecular docking, dual-luciferase reporter, ChIP-PCR for KLF4 binding to PTGS2 promoter, PTGS2 knockdown, in vivo AKI-CKD mouse model","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple protein-ligand binding assays (DARTS, SPR) and ChIP-PCR for promoter binding, single lab","pmids":["39543734"],"is_preprint":false},{"year":2008,"finding":"PKC activation by PMA upregulates PTGS2 mRNA in human chorion trophoblast cells through p38 and MEK1/2 (MAPK) pathways. The stimulatory effect of PMA on PTGS2 was reversed by PKC inhibition; p38 inhibitor reduced PTGS2 induction by both PMA and calcium ionophore A23187; MEK1/2 inhibitor reduced the PMA effect on PTGS2. MAPK inhibitors did not reverse effects on PGDH, indicating divergent downstream pathways.","method":"Pharmacological inhibitors of PKC, JNK, p38, MEK1/2 in human chorion trophoblast cells, RT-qPCR for PTGS2 and PGDH mRNA","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors with defined pathway dissection, single lab","pmids":["18212353"],"is_preprint":false}],"current_model":"PTGS2 (COX-2) is an inducible prostaglandin-endoperoxide synthase that catalyzes the rate-limiting step in prostaglandin synthesis; its expression is transcriptionally regulated by NF-κB (activated downstream of ROS, TLR/MyD88, and cytokine signals), ATF3 (direct promoter repressor), CTCF/cohesin-mediated chromatin looping (disrupted by DNA methylation), AKAP95-anchored nuclear PKA/CREB, SMAD2/3-SMAD4 (downstream of activin A/ACVR1B), RUNX1, STAT1, KLF4, and REV-ERBα (repressor); its mRNA is post-transcriptionally stabilized by AMPK-dependent mechanisms; the encoded enzyme produces PGE2 that acts via EP receptors (PTGER1-4) to regulate oocyte maturation (MAPK activation), colonic epithelial proliferation, beta cell survival, corpus luteum function, and ovulatory gene cascades (AREG, EREG, TNFAIP6); PTGS2 also lies downstream of EPHA2-TGFβ and upstream of NF-κB in tumor immune exclusion and chemoresistance pathways, and ROBO4 suppresses PTGS2 expression by enhancing IQGAP1 ubiquitination via TRAF7 to inhibit RAC1."},"narrative":{"mechanistic_narrative":"PTGS2 (COX-2) is the inducible prostaglandin-endoperoxide synthase that catalyzes the rate-limiting step of prostaglandin biosynthesis, producing PGE2 and related eicosanoids that act through EP receptors to control inflammation, reproduction, epithelial homeostasis, and tumor biology [PMID:8181472, PMID:31581537]. The gene is a highly regulated transcriptional hub: its TATA-containing promoter carries NF-κB, CRE, AP-1, and other regulatory elements [PMID:8181472], and multiple converging signals govern its induction. ROS-driven NF-κB activation drives PTGS2 transcription downstream of PGF2α in the corpus luteum, with NF-κB p65 binding directly to the promoter [PMID:20826536]. Additional direct promoter-binding transcription factors include the activator RUNX1 [PMID:38778047], HIF1A [PMID:36569299], STAT1 [PMID:40222167], and KLF4 [PMID:39543734], while ATF3 and the nuclear receptor REV-ERBα act as direct repressors [PMID:25619459, PMID:25007867]. The locus is further controlled epigenetically through methylation-sensitive CTCF/cohesin-mediated chromatin looping [PMID:25703332] and through a CTCF/lncRNA-PACERR complex that recruits p300 to acetylate the PTGS2 promoter [PMID:35184402]. Inducible signaling pathways feeding PTGS2 expression include TLR/MyD88 [PMID:17200722], activin A acting via ACVR1B and SMAD2/3-SMAD4 [PMID:27624482], AKAP95-anchored nuclear PKA/CREB signaling [PMID:29162743], and PKC-p38/MEK1/2 MAPK cascades [PMID:18212353], while PTGS2 mRNA is post-transcriptionally stabilized by AMPK [PMID:31581537]. Functionally, PTGS2-derived PGE2 sits upstream of the ovulatory gene cascade (AREG, EREG, TNFAIP6) and oocyte MAPK activation during maturation [PMID:21293029, PMID:25323036], supports colonic epithelial proliferation in the stem cell niche [PMID:17200722], and promotes beta cell survival through a PGE2-PTGER1 axis [PMID:35602948]. In cancer, PTGS2 mediates immune exclusion and chemo-/radioresistance, lying downstream of EPHA2-TGFβ signaling and feeding back to activate NF-κB, promoting myeloid-derived suppressor cell differentiation, M2 macrophage polarization, and drug efflux [PMID:31162144, PMID:30740906, PMID:35184402]. ROBO4 suppresses endothelial PTGS2 by forming a complex with IQGAP1 and the E3 ligase TRAF7 that promotes IQGAP1 ubiquitination and dampens RAC1 signaling [PMID:38762541].","teleology":[{"year":1994,"claim":"Establishing that PTGS2 is a genetically distinct, inducible cyclooxygenase isozyme separate from constitutive PTGS1 defined it as the regulatable arm of prostaglandin synthesis and explained how its expression could be acutely controlled.","evidence":"Gene isolation, sequencing, primer extension, and FISH mapping the human PTGS2 locus","pmids":["8181472"],"confidence":"High","gaps":["Promoter elements were identified by sequence, not yet shown to be functionally occupied","Enzymatic kinetics not characterized in this entry"]},{"year":2007,"claim":"Genetic epistasis placed Ptgs2/PGE2 downstream of TLR/MyD88 signaling in tissue repair, showing that spatial repositioning of PTGS2-expressing stromal cells, not expression level alone, sustains epithelial proliferation.","evidence":"Myd88−/− and Ptgs2−/− knockout mice with dmPGE2 rescue and crypt histology","pmids":["17200722"],"confidence":"High","gaps":["Mechanism of stromal cell repositioning not defined","EP receptor mediating epithelial response not identified here"]},{"year":2008,"claim":"Dissecting the PKC-MAPK input showed that p38 and MEK1/2 cascades drive PTGS2 induction independently of effects on prostaglandin catabolism, identifying divergent kinase routes to PTGS2 expression.","evidence":"Pharmacological PKC/JNK/p38/MEK1/2 inhibitors in human chorion trophoblasts with RT-qPCR","pmids":["18212353"],"confidence":"Medium","gaps":["Direct transcription factor linking MAPK to the promoter not identified","Pharmacological inhibitors only, no genetic confirmation"]},{"year":2010,"claim":"Demonstrating ROS-dependent NF-κB p65 binding to the PTGS2 promoter established a feed-forward loop in which PGF2α amplifies its own synthesis through oxidative NF-κB activation.","evidence":"In vivo rat model, EMSA of NF-κB at PTGS2 promoter, ROS scavengers, and PTGS2 inhibitor NS-398","pmids":["20826536"],"confidence":"High","gaps":["Source of ROS not pinpointed","Direct NF-κB binding shown by EMSA but not in situ ChIP"]},{"year":2011,"claim":"PTGS2-derived PGE2 was shown to be required for oocyte ERK1/2 activation, cumulus expansion, and spindle organization during maturation, defining a reproductive role acting through EP2/3/4 receptors.","evidence":"Bovine oocyte in vitro maturation with NS-398, PGE2 rescue, spindle immunofluorescence, receptor expression","pmids":["21293029"],"confidence":"High","gaps":["Relative contribution of each EP receptor not resolved","Downstream of ERK1/2 not mapped"]},{"year":2011,"claim":"Identifying RNA pol-II 5'-pausing and glucocorticoid receptor-mediated transrepression at the PTGS2 locus revealed that the gene is controlled at the level of transcriptional elongation, not just initiation.","evidence":"ChIP for pol-II, CTD Ser5/Ser2 phosphorylation and histone marks in dexamethasone-treated human amnion","pmids":["21385935"],"confidence":"High","gaps":["Factors releasing the paused polymerase not identified here","GRα co-repressor partners not defined"]},{"year":2013,"claim":"siRNA silencing placed PTGS2-derived prostaglandins upstream of the ovulatory effectors AREG, EREG, and TNFAIP6 (but not PTX3), ordering PTGS2 within the LH-induced ovulation cascade.","evidence":"PTGS2 siRNA knockdown in bovine granulosa cells with PGE2 rescue and RT-qPCR","pmids":["25323036"],"confidence":"Medium","gaps":["EP receptor and signaling route to these genes not defined","Single lab, single species"]},{"year":2013,"claim":"Mapping a ROS/NF-κB to PTGS2 to PGE2/EP4/MAPK to BCL2 axis explained how PTGS2 drives apoptosis resistance, establishing it as a mediator of chemoresistance.","evidence":"siRNA, celecoxib/NS-398, and gastric cancer xenografts with western blot","pmids":["31518663"],"confidence":"Medium","gaps":["Direct EP4-MAPK coupling shown pharmacologically only","Single tumor type"]},{"year":2014,"claim":"Identifying REV-ERBα as a circadian repressor of PTGS2 linked clock machinery to the temporal control of prostaglandin output in the uterus.","evidence":"BMAL1 siRNA, REV-ERBα agonist/antagonist, RT-qPCR and PGF2α ELISA in bovine uterine cells","pmids":["25007867"],"confidence":"Medium","gaps":["Direct REV-ERBα promoter occupancy not shown","Repression inferred pharmacologically"]},{"year":2015,"claim":"ChIP localization of ATF3 to the Ptgs2 promoter and the inflammatory phenotype of Atf3−/− mice identified a direct transcriptional brake limiting prostaglandin production during acute inflammation.","evidence":"ATF3 ChIP, Atf3−/− macrophages and peritonitis model with prostaglandin measurement","pmids":["25619459"],"confidence":"High","gaps":["ATF3 co-repressor complex composition not defined","Stimulus specificity beyond zymosan not tested"]},{"year":2015,"claim":"Showing that DNA methylation disrupts CTCF/cohesin-mediated chromatin looping and abolishes P-TEFb recruitment established a 3D-chromatin and epigenetic layer of PTGS2 control.","evidence":"ChIP for CTCF/cohesin/elongation factors, 3C chromatin conformation, methylation analysis, siRNA and luciferase reporter","pmids":["25703332"],"confidence":"High","gaps":["Trigger setting locus methylation status not defined","Connection to specific physiological signals unresolved"]},{"year":2016,"claim":"Demonstrating activin A induction of PTGS2 through ACVR1B-SMAD2/3-SMAD4 added a TGF-β superfamily input to PTGS2 regulation in luteinized granulosa cells.","evidence":"SB431542, SMAD2/3 and SMAD4 siRNA, PGE2 ELISA, western blot and RT-qPCR in granulosa-lutein cells","pmids":["27624482"],"confidence":"Medium","gaps":["Direct SMAD binding to the PTGS2 promoter not shown","Single lab"]},{"year":2017,"claim":"Identifying AKAP95-anchored nuclear PKA as the route for cortisol-induced PTGS2 expression revealed compartmentalized cAMP/CREB signaling controlling prostaglandin output in amnion, with relevance to labor.","evidence":"AKAP95 siRNA in primary amnion fibroblasts, fractionation, phospho-CREB western blot, and labor vs non-labor immunohistochemistry","pmids":["29162743"],"confidence":"High","gaps":["Direct CREB occupancy of PTGS2 promoter not shown here","Upstream cortisol receptor coupling to AKAP95 not fully defined"]},{"year":2019,"claim":"Two independent genetic deletions placed PTGS2 downstream of EPHA2-TGFβ in driving T cell exclusion, establishing it as a targetable node for sensitizing tumors to immunotherapy.","evidence":"Epha2−/− and Ptgs2−/− murine tumor models, PTGS2 inhibition and immunotherapy combination","pmids":["31162144"],"confidence":"High","gaps":["Immune cell type producing or responding to PGE2 not fully resolved","EP receptor mediating exclusion not identified here"]},{"year":2019,"claim":"CRISPR knockout of PTGS2 in melanoma showed it promotes proliferation, invasion, and MDSC differentiation, linking tumor-intrinsic PTGS2 to an immunosuppressive microenvironment.","evidence":"CRISPR/Cas9 knockout, in vitro invasion assays, in vivo metastasis model, MDSC flow cytometry","pmids":["31920649"],"confidence":"Medium","gaps":["Mechanism connecting PTGS2 to MDSC differentiation not detailed","Single lab"]},{"year":2019,"claim":"Demonstrating AMPK-dependent stabilization of Ptgs2 mRNA upon mitochondrial OXPHOS inhibition added a metabolic, post-transcriptional control mechanism to PTGS2 regulation.","evidence":"AMPK siRNA, AMPK activators/inhibitors, mRNA stability assays and LC/MS eicosanoid measurement in astrocytes","pmids":["31581537"],"confidence":"Medium","gaps":["RNA-binding effector mediating stabilization not identified","Single cell type"]},{"year":2019,"claim":"Gain- and loss-of-function in glioma showed PTGS2 activates NF-κB to limit DNA damage and confer radioresistance, defining a feedback loop where PTGS2 reinforces its own upstream activator.","evidence":"PTGS2 overexpression/siRNA, clonogenic survival, cell cycle, γH2AX, NF-κB inhibitor Bay 11","pmids":["30740906"],"confidence":"Medium","gaps":["Mechanism by which PTGS2 activates NF-κB not defined","Single lab"]},{"year":2020,"claim":"Linking COX-2 to P-glycoprotein upregulation at the blood-brain barrier provided a mechanism for PTGS2-driven antiepileptic drug resistance, with peripheral PTGS2 mRNA tracking treatment response.","evidence":"Brain endothelial cell model with valproate, COX-2/P-gp western blot, microarray, plasma PGE2","pmids":["32054883"],"confidence":"Medium","gaps":["Signaling between COX-2/PGE2 and P-gp induction not fully mapped","Clinical correlation is associative"]},{"year":2022,"claim":"Showing a CTCF/lncRNA-PACERR complex recruits p300 to acetylate and activate the PTGS2 promoter revealed an enhancer-RNA mechanism driving PTGS2-dependent M2 macrophage polarization in pancreatic cancer.","evidence":"RIP, RNA pull-down, ChIP-seq, ATAC-seq, RNA-seq, lentiviral knockdown and in vivo metastasis assays","pmids":["35184402"],"confidence":"High","gaps":["How PACERR is induced in the tumor context not defined","Relationship to methylation-sensitive CTCF looping not integrated"]},{"year":2022,"claim":"Identifying direct HIF1A binding to the Ptgs2 promoter connected hypoxic signaling to PTGS2-driven ferroptosis in cardiomyocytes after microembolization.","evidence":"HIF1A ChIP, Ptgs2 siLNA, ferroptosis markers and cardiac function in rat CME model with atorvastatin","pmids":["36569299"],"confidence":"Medium","gaps":["Link between PTGS2 enzymatic product and ferroptosis not mechanistically dissected","Single lab"]},{"year":2022,"claim":"Mapping the LRH-1/NR5A2 to PTGS2 to PGE2 to PTGER1 axis established a cytoprotective pathway in beta cells, ordering the receptor (PTGER1) mediating PGE2-driven survival.","evidence":"Beta cell-specific LRH-1 knockout, PTGS2 inactivation, PTGER1 antagonist ONO-8130, PGE2 ELISA and apoptosis markers","pmids":["35602948"],"confidence":"High","gaps":["Direct LRH-1 occupancy of PTGS2 promoter not shown here","Downstream of PTGER1 in survival not fully defined"]},{"year":2024,"claim":"Identifying the ROBO4-IQGAP1-TRAF7 complex defined a suppressive mechanism in which ROBO4 promotes IQGAP1 ubiquitination to dampen RAC1 and lower endothelial PTGS2, with loss exacerbating inflammation.","evidence":"RNA-seq, Co-IP, ubiquitination assay, Robo4-deficient mice in inflammatory disease models","pmids":["38762541"],"confidence":"High","gaps":["How RAC1 controls PTGS2 transcription not detailed","Co-IP without reciprocal structural mapping of the complex"]},{"year":2024,"claim":"Luciferase mapping of a defined RUNX1 binding motif in the PTGS2 promoter identified RUNX1 as a direct activator driving colorectal cancer cell growth and invasion.","evidence":"Luciferase reporter with promoter fragments, RUNX1/PTGS2 siRNA, TCGA co-expression and invasion assays","pmids":["38778047"],"confidence":"Medium","gaps":["RUNX1 occupancy validated by reporter, not endogenous ChIP","Single lab"]},{"year":2024,"claim":"Showing that the small molecule astilbin engages KLF4, which binds and activates the PTGS2 promoter, defined a KLF4-PTGS2-PGE2 axis driving M2 polarization and MSC therapeutic effects in kidney injury.","evidence":"DARTS, SPR, docking, dual-luciferase, ChIP-PCR for KLF4 binding, PTGS2 knockdown and AKI-CKD mouse model","pmids":["39543734"],"confidence":"Medium","gaps":["KLF4 as activator versus context-dependent factor not generalized","Single lab"]},{"year":2025,"claim":"Validating STAT1 binding to the PTGS2 promoter established STAT1-driven PTGS2 induction as a route to ferroptosis in melanoma, identifying another direct transcriptional activator.","evidence":"RNA-seq, ChIP and luciferase for STAT1, STAT1 and PTGS2 knockdown, ferroptosis markers and xenograft","pmids":["40222167"],"confidence":"Medium","gaps":["How PTGS2 product triggers ferroptosis not mechanistically resolved","Single lab"]},{"year":null,"claim":"How the many converging transcriptional, epigenetic, and post-transcriptional inputs to PTGS2 are integrated in a given cell, and how its enzymatic product is channeled to specific EP receptors for distinct outcomes (survival, ferroptosis, immune exclusion), remains unresolved.","evidence":"No single study in the corpus integrates the multiple regulatory layers or receptor-coupling specificity","pmids":[],"confidence":"Low","gaps":["Combinatorial logic of competing activators/repressors at the promoter not defined","Determinants of EP receptor selectivity for downstream effects unknown","Enzymatic kinetics and substrate handling not characterized in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,13]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,7,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,7,8,16,17,20,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,11,14,16]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[3,5,9]}],"complexes":["ROBO4-IQGAP1-TRAF7 complex","CTCF/lncRNA-PACERR complex"],"partners":["IQGAP1","TRAF7","ROBO4","CTCF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35354","full_name":"Prostaglandin G/H synthase 2","aliases":["Cyclooxygenase-2","COX-2","PHS II","Prostaglandin H2 synthase 2","PGH synthase 2","PGHS-2","Prostaglandin-endoperoxide synthase 2"],"length_aa":604,"mass_kda":69.0,"function":"Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the inflammatory response (PubMed:11939906, PubMed:16373578, PubMed:19540099, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:7947975, PubMed:9261177). The cyclooxygenase activity oxygenates AA to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide prostaglandin H2 (PGH2), the precursor of all 2-series prostaglandins and thromboxanes (PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:7947975, PubMed:9261177). This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:7947975, PubMed:9261177). Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins (PubMed:11939906, PubMed:19540099). In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids (PubMed:27642067). Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response (PubMed:22942274). Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols (PubMed:11034610, PubMed:11192938, PubMed:9048568, PubMed:9261177). Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation (PubMed:12391014). Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs) (PubMed:12391014). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2 (PubMed:21206090). In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection (PubMed:26236990). In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE) (PubMed:22068350, PubMed:26282205). Can also use linoleate (LA, (9Z,12Z)-octadecadienoate, C18:2(n-6)) as substrate and produce hydroxyoctadecadienoates (HODEs) in a regio- and stereospecific manner, being (9R)-HODE ((9R)-hydroxy-(10E,12Z)-octadecadienoate) and (13S)-HODE ((13S)-hydroxy-(9Z,11E)-octadecadienoate) its major products (By similarity). During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia (By similarity)","subcellular_location":"Microsome membrane; Endoplasmic reticulum membrane; Nucleus inner membrane; Nucleus outer membrane","url":"https://www.uniprot.org/uniprotkb/P35354/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTGS2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTGS2","total_profiled":1310},"omim":[{"mim_id":"621349","title":"PEROXIREDOXIN-LIKE 2B; PRXL2B","url":"https://www.omim.org/entry/621349"},{"mim_id":"618320","title":"SECRETORY PHOSPHOLIPASE A2, GROUP IIE; PLA2G2E","url":"https://www.omim.org/entry/618320"},{"mim_id":"617650","title":"PTGS2 ANTISENSE NFKB1 COMPLEX-MEDIATED EXPRESSION REGULATOR RNA, NONCODING; PACERR","url":"https://www.omim.org/entry/617650"},{"mim_id":"616793","title":"PHOSPHOLIPASE A2, GROUP IIF; PLA2G2F","url":"https://www.omim.org/entry/616793"},{"mim_id":"616473","title":"MICRO RNA 558; MIR558","url":"https://www.omim.org/entry/616473"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":110.4},{"tissue":"seminal vesicle","ntpm":120.2},{"tissue":"urinary bladder","ntpm":151.3}],"url":"https://www.proteinatlas.org/search/PTGS2"},"hgnc":{"alias_symbol":["COX2"],"prev_symbol":[]},"alphafold":{"accession":"P35354","domains":[{"cath_id":"2.10.25.10","chopping":"28-69","consensus_level":"medium","plddt":95.5243,"start":28,"end":69},{"cath_id":"1.10.640.10","chopping":"183-422_508-583","consensus_level":"medium","plddt":95.9911,"start":183,"end":583}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35354","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35354-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35354-F1-predicted_aligned_error_v6.png","plddt_mean":93.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTGS2","jax_strain_url":"https://www.jax.org/strain/search?query=PTGS2"},"sequence":{"accession":"P35354","fasta_url":"https://rest.uniprot.org/uniprotkb/P35354.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35354/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35354"}},"corpus_meta":[{"pmid":"8181472","id":"PMC_8181472","title":"Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2.","date":"1994","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8181472","citation_count":354,"is_preprint":false},{"pmid":"17200722","id":"PMC_17200722","title":"Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury.","date":"2007","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/17200722","citation_count":219,"is_preprint":false},{"pmid":"33974977","id":"PMC_33974977","title":"Verification of ferroptosis and pyroptosis and identification of PTGS2 as the hub gene in human coronary artery atherosclerosis.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33974977","citation_count":208,"is_preprint":false},{"pmid":"31533781","id":"PMC_31533781","title":"miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2.","date":"2019","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/31533781","citation_count":147,"is_preprint":false},{"pmid":"31162144","id":"PMC_31162144","title":"Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2).","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31162144","citation_count":132,"is_preprint":false},{"pmid":"37705740","id":"PMC_37705740","title":"The PTGS2/COX2-PGE2 signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37705740","citation_count":114,"is_preprint":false},{"pmid":"31345147","id":"PMC_31345147","title":"Long Non-coding RNA MALAT1 Inhibits Neuron Apoptosis and Neuroinflammation While Stimulates Neurite Outgrowth and Its Correlation With MiR-125b Mediates PTGS2, CDK5 and FOXQ1 in Alzheimer's Disease.","date":"2019","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/31345147","citation_count":114,"is_preprint":false},{"pmid":"20042743","id":"PMC_20042743","title":"Alteration of PTGS2 promoter methylation in chronic periodontitis.","date":"2009","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/20042743","citation_count":81,"is_preprint":false},{"pmid":"23852449","id":"PMC_23852449","title":"Nonsteroidal anti-inflammatory drugs suppress cancer stem cells via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1 and activating PPARG in colorectal cancer.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23852449","citation_count":77,"is_preprint":false},{"pmid":"23810915","id":"PMC_23810915","title":"PTGS2 (Cyclooxygenase-2) expression and survival among colorectal cancer patients: a systematic review.","date":"2013","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23810915","citation_count":73,"is_preprint":false},{"pmid":"30679074","id":"PMC_30679074","title":"MicroRNA-26b relieves inflammatory response and myocardial remodeling of mice with myocardial infarction by suppression of MAPK pathway through binding to PTGS2.","date":"2019","source":"International journal of 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China.","date":"2005","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/16361272","citation_count":57,"is_preprint":false},{"pmid":"25619459","id":"PMC_25619459","title":"Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation.","date":"2015","source":"Prostaglandins & other lipid mediators","url":"https://pubmed.ncbi.nlm.nih.gov/25619459","citation_count":56,"is_preprint":false},{"pmid":"24447957","id":"PMC_24447957","title":"Role of PTGS2-generated PGE2 during gonadotrophin-induced bovine oocyte maturation and cumulus cell expansion.","date":"2013","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/24447957","citation_count":54,"is_preprint":false},{"pmid":"24194923","id":"PMC_24194923","title":"Interactions between diet, lifestyle and IL10, IL1B, and PTGS2/COX-2 gene polymorphisms in relation to risk of colorectal cancer in a prospective Danish case-cohort study.","date":"2013","source":"PloS 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Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/22464751","citation_count":46,"is_preprint":false},{"pmid":"24423291","id":"PMC_24423291","title":"Hormonal therapy deregulates prostaglandin-endoperoxidase synthase 2 (PTGS2) expression in endometriotic tissues.","date":"2013","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24423291","citation_count":45,"is_preprint":false},{"pmid":"35485136","id":"PMC_35485136","title":"Suppression of lncRNA Gm47283 attenuates myocardial infarction via miR-706/ Ptgs2/ferroptosis axis.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35485136","citation_count":44,"is_preprint":false},{"pmid":"33042470","id":"PMC_33042470","title":"Long noncoding RNA MALAT1 and its target microRNA-125b are potential biomarkers for Alzheimer's disease management via interactions with FOXQ1, PTGS2 and CDK5.","date":"2020","source":"American journal of translational 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The gene spans >8.3 kb with 10 exons, contains a TATA box and multiple transcriptional regulatory elements (NF-κB, CRE, NF-IL6, AP-1, Sp-1 sites) in its 5'-flanking region, and maps to chromosome 1q25.2-q25.3, distinct from PTGS1 on chromosome 9q32-q33.3.\",\n      \"method\": \"Gene isolation, nucleotide sequencing, primer-extension analysis, fluorescence in situ hybridization\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct sequencing and structural characterization of the gene with multiple orthogonal methods; foundational characterization paper\",\n      \"pmids\": [\"8181472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MyD88 (TLR signaling) acts upstream of Ptgs2/PGE2 in the colonic stem cell niche. During injury, MyD88 signaling repositions Ptgs2-expressing stromal cells to the crypt base adjacent to colonic epithelial progenitors, and this spatial reorganization (not changes in Ptgs2 expression level) is required to maintain epithelial proliferation. Exogenous dmPGE2 rescued the proliferative defect in both Myd88−/− and Ptgs2−/− mice.\",\n      \"method\": \"Genetic epistasis using Myd88−/− and Ptgs2−/− knockout mice, exogenous PGE2 rescue, histological analysis of crypt cell positioning\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two knockout models with rescue experiment, epistasis established, replicated across genotypes\",\n      \"pmids\": [\"17200722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PGF2α stimulates PTGS2 mRNA expression and PGF2α synthesis in the corpus luteum through ROS-mediated NF-κB activation. PGF2α injection increased nuclear NF-κB p65 and its binding to the PTGS2 gene promoter; co-administration of superoxide dismutase and catalase (ROS scavengers) abolished nuclear NF-κB accumulation, lipid peroxidation, and Ptgs2 mRNA induction. Selective PTGS2 inhibitor NS-398 abolished the PGF2α-induced rise in luteal PGF2α concentrations.\",\n      \"method\": \"In vivo rat model with pharmacological inhibitors, electrophoretic mobility shift assay (EMSA) for NF-κB binding to PTGS2 promoter, ROS scavenger co-administration, PTGS2 inhibitor NS-398\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EMSA demonstrated direct NF-κB binding to PTGS2 promoter, multiple orthogonal interventions (ROS scavengers, NF-κB, PTGS2 inhibitor) in same study\",\n      \"pmids\": [\"20826536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTGS2-derived PGE2 is required for oocyte MAPK (ERK1/2) phosphorylation during in vitro maturation of bovine oocytes. Specific inhibition of PTGS2 with NS-398 significantly restricted MAPK activation at germinal vesicle breakdown stage, reduced cumulus expansion, and caused abnormal meiotic spindle organization. Addition of exogenous PGE2 rescued these defects. PGE2 acts via PTGER2/3/4 receptors expressed in cumulus cells and PTGER2 in oocytes.\",\n      \"method\": \"In vitro bovine oocyte maturation model with PTGS2-specific inhibitor NS-398, exogenous PGE2 rescue, immunofluorescence of spindle, mRNA/protein expression of PGE receptors\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological inhibition, receptor identification, PGE2 rescue in single rigorous study with multiple readouts\",\n      \"pmids\": [\"21293029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTGS2 expression in term human amnion involves rapid mRNA turnover, RNA polymerase-II 5'-pausing at the PTGS2 locus, and glucocorticoid-mediated transrepression. Dexamethasone decreased PTGS2 gene activity; glucocorticoid receptor-α (GRα) bound to the PTGS2 promoter and decreased Ser-5 and Ser-2 phosphorylation of pol-II CTD (interfering with both initiation and elongation) without affecting pol-II recruitment or pausing.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for pol-II binding, pol-II CTD phosphorylation states, histone acetylation/methylation; dexamethasone treatment of fresh amnion and explants; RT-qPCR\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at multiple regulatory points (pol-II, CTD phosphorylation, histones), multiple orthogonal chromatin assays in one study\",\n      \"pmids\": [\"21385935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTGS2 silencing by siRNA in bovine granulosa cells reduced AREG, EREG, and TNFAIP6 mRNA levels, while PTX3 was unaffected. Exogenous PGE2 rescued AREG, EREG, and TNFAIP6 expression, demonstrating that PTGS2-derived prostaglandins lie upstream of these ovulatory genes in the LH-induced ovulation cascade.\",\n      \"method\": \"siRNA knockdown of PTGS2 in bovine granulosa cells, exogenous PGE2 rescue, RT-qPCR\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with rescue, single lab, multiple gene readouts\",\n      \"pmids\": [\"25323036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTGS2/COX-2 activity mediates PGE2/EP4/MAPK (ERK1/2, p38) signaling to upregulate BCL2 and promote resistance to cisplatin-induced apoptosis in gastric cancer. Cisplatin induces PTGS2 expression through a ROS/NF-κB pathway. Celecoxib (PTGS2 inhibitor) reversed cisplatin resistance in xenograft models by suppressing PTGS2, BCL2, ERK1/2, and p38.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibitors (celecoxib, NS-398), xenograft mouse model, western blot, pathway inhibitors\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic knockdown with in vivo validation, single lab\",\n      \"pmids\": [\"31518663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATF3 (activating transcription factor-3) negatively regulates Ptgs2 transcription during acute inflammation. In activated macrophages stimulated with zymosan, Atf3 accumulates in the nucleus and is recruited to the Ptgs2 promoter (shown by ChIP). Atf3−/− peritoneal macrophages show significantly higher Ptgs2 expression and prostaglandin production than wild-type, and Atf3−/− mice exhibit increased leukocyte accumulation and higher PGE2/PGD2 levels in acute peritonitis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of Atf3 at Ptgs2 promoter, Atf3−/− knockout mice, peritonitis model, prostaglandin measurement\",\n      \"journal\": \"Prostaglandins & other lipid mediators\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP directly demonstrated promoter recruitment, Atf3 knockout with multiple in vivo phenotypes, single rigorous study\",\n      \"pmids\": [\"25619459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DNA methylation of a CpG island near the PTGS2 locus disrupts CTCF/cohesin-mediated chromatin looping, abolishes enrichment of positive elongation factor b at the PTGS2 transcriptional start site, and downregulates PTGS2 expression. CTCF/cohesin complex binding to the PTGS2 CpG island is methylation-sensitive.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for CTCF, cohesin, transcriptional components; 3C/chromatin conformation assays; DNA methylation analysis; siRNA knockdown; luciferase reporter\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP, chromatin looping, and functional consequence established in one study with multiple orthogonal methods\",\n      \"pmids\": [\"25703332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Activin A upregulates PTGS2 expression and increases PGE2 production in human granulosa-lutein cells via an ACVR1B-mediated SMAD2/3-SMAD4 signaling pathway. The TGF-β/activin type I receptor inhibitor SB431542 and siRNA against SMAD2/3 or SMAD4 abolished activin A-induced PTGS2 induction.\",\n      \"method\": \"Pharmacological inhibition (SB431542), siRNA knockdown of SMAD2/3/SMAD4, ELISA for PGE2, western blot and RT-qPCR in immortalized SVOG and primary granulosa-lutein cells\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor inhibitor and siRNA knockdown with multiple pathway components, single lab\",\n      \"pmids\": [\"27624482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nuclear anchoring of PKA by AKAP95 is required for cortisol-induced PTGS2 expression in human amnion fibroblasts. Cortisol increases AKAP95 expression, which retains PKA in the nucleus; AKAP95 knockdown reduces nuclear PKA, phospho-CREB, and PTGS2 induction. AKAP95, phospho-CREB, and COX-2 are all markedly increased in human amnion tissue after labor.\",\n      \"method\": \"siRNA knockdown of AKAP95 in primary amnion fibroblasts, subcellular fractionation, western blot for nuclear PKA/phospho-CREB/STAT3, immunohistochemistry of labor vs. non-labor amnion\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown in primary cells with multiple readouts, corroborated in human tissue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29162743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EPHA2 signaling in tumor cells upregulates PTGS2 (COX-2) expression through TGFβ, suppressing anti-tumor T cell infiltration in pancreatic adenocarcinoma. Epha2 deletion or Ptgs2 deletion each reversed T cell exclusion and sensitized tumors to immunotherapy, placing PTGS2 downstream of EPHA2-TGFβ signaling in the pathway controlling tumor immune phenotype.\",\n      \"method\": \"Genetic deletion (Epha2−/−, Ptgs2−/−) in murine tumor models, pharmacological PTGS2 inhibition, immunotherapy combination experiments, T cell infiltration analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent gene knockouts in vivo with pharmacological corroboration, epistasis established\",\n      \"pmids\": [\"31162144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTGS2 knockdown by CRISPR/Cas9 in B16F10 murine melanoma cells inhibits cell proliferation, migration, and invasiveness in vitro, impairs myeloid-derived suppressor cell differentiation, and reduces tumor development and metastasis in vivo.\",\n      \"method\": \"CRISPR/Cas9 gene knockout, in vitro proliferation/migration/invasion assays, in vivo tumor model, flow cytometry for MDSC differentiation\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockout with in vivo validation, single lab\",\n      \"pmids\": [\"31920649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inhibition of mitochondrial oxidative phosphorylation stabilizes Ptgs2 mRNA in IL-1α-stimulated astrocytes through AMPK activation, increasing Ptgs2 protein and downstream eicosanoid (PGE2, PGF2α, 6-keto-PGF1α) secretion. AMPK silencing prevented Ptgs2 upregulation by mitochondrial inhibitors; AMPK activators recapitulated Ptgs2 mRNA stabilization.\",\n      \"method\": \"siRNA knockdown of AMPK, pharmacological AMPK activators/inhibitors, mRNA stability assays, LC/MS measurement of eicosanoids, in neonatal rat astrocytes\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (siRNA) and pharmacological corroboration, LC/MS readout, single lab\",\n      \"pmids\": [\"31581537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTGS2 activates the NF-κB signaling pathway in glioma cells to prevent DNA damage and enhance radiation resistance. PTGS2 overexpression elevated radioresistance in U87 cells and reduced G2/M arrest after radiation; PTGS2 knockdown sensitized U87R cells to radiation. NF-κB inhibitor Bay 11 decreased survival rates under radiation in both cell lines.\",\n      \"method\": \"PTGS2 overexpression and siRNA knockdown in glioma cells, clonogenic survival assay, flow cytometry (cell cycle), immunofluorescence (γH2AX), western blot for NF-κB pathway proteins\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple cellular readouts, single lab\",\n      \"pmids\": [\"30740906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTGS2/COX-2-dependent upregulation of P-glycoprotein at the blood-brain barrier contributes to antiepileptic drug resistance. In vitro, valproate suppressed COX-2-dependent P-gp upregulation in brain endothelial cells (hCMEC/D3) under hyperexcitatory conditions. In responders to valproate, PTGS2 mRNA levels in peripheral blood were downregulated compared to non-responders, correlating with reduced plasma PGE2.\",\n      \"method\": \"In vitro brain endothelial cell model with valproate treatment, COX-2/P-gp protein expression by western blot, microarray gene expression, plasma PGE2 measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic follow-up with pharmacological inhibition corroborating clinical data, single lab\",\n      \"pmids\": [\"32054883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CTCF/lncRNA-PACERR complex recruits E1A binding protein p300 to the promoter regions of PACERR and PTGS2, enhancing histone acetylation and PTGS2 transcription, promoting M2 polarization of tumor-associated macrophages in pancreatic ductal adenocarcinoma. PACERR directly binds CTCF (shown by RNA immunoprecipitation and RNA pull-down); PACERR or CTCF knockdown each reduced PTGS2 expression and M2 markers.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pull-down, ChIP-seq, ATAC-seq, RNA-seq, lentiviral knockdown, in vitro and in vivo invasion/metastasis assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA-protein interaction validated by RIP and pull-down, ChIP-seq for histone acetylation, multiple orthogonal omics methods in one study\",\n      \"pmids\": [\"35184402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The transcription factor Hif1a binds the promoter of Ptgs2 and upregulates its expression in cardiomyocytes following coronary microembolization, promoting ferroptosis and inflammation. Atorvastatin inhibits the Hif1a/Ptgs2 axis to attenuate ferroptosis-mediated myocardial injury.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for Hif1a binding to Ptgs2 promoter, Ptgs2 siRNA silencing, ferroptosis markers (MDA, GSH, Fe2+), cardiac function measurements, rat CME model\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrated direct Hif1a binding to Ptgs2 promoter, functional rescue with siRNA, single lab\",\n      \"pmids\": [\"36569299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRH-1/NR5A2 regulates the PTGS2-PGE2-PTGER1 signaling axis to promote beta cell survival. LRH-1 deletion in adult beta cells abolished BL001 agonist-mediated Ptgs2 induction and islet protection. PTGS2 inactivation reduced PGE2 levels and eliminated BL001 protection against cytokine-induced apoptosis (increased cytochrome c release, cleaved PARP). PTGER1 antagonist ONO-8130 also negated BL001-mediated islet survival.\",\n      \"method\": \"Conditional beta cell-specific LRH-1 knockout mice, PTGS2 inactivation, pharmacological PTGER1 antagonist, PGE2 ELISA, apoptosis markers (cytochrome c, cleaved PARP)\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout + PTGS2 inactivation + receptor pharmacology, multiple orthogonal interventions establishing pathway order\",\n      \"pmids\": [\"35602948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ROBO4 interacts with IQGAP1 and TRAF7 (ubiquitin E3 ligase) to form a complex in endothelial cells; within this complex, ROBO4 enhances TRAF7-mediated ubiquitination of IQGAP1, inhibits prolonged RAC1 activation, and thereby decreases PTGS2 expression in inflammatory endothelial cells. Robo4-deficient mice show exacerbated PTGS2-associated inflammatory diseases (arthritis, edema, pain).\",\n      \"method\": \"RNA-seq, Co-immunoprecipitation for ROBO4-IQGAP1-TRAF7 complex, ubiquitination assay, Robo4-deficient mice, in vivo inflammatory disease models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrated protein complex, ubiquitination assay, Robo4 KO in vivo phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"38762541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The transcription factor RUNX1 directly binds the PTGS2 promoter at the 1086-1096 bp binding motif and promotes transcriptional activation of PTGS2 in colorectal cancer cells. PTGS2 silencing repressed CRC cell growth, migration, and invasion.\",\n      \"method\": \"Luciferase reporter assay with PTGS2 promoter fragments, siRNA knockdown of PTGS2 and RUNX1, TCGA co-expression analysis, cell proliferation/migration/invasion assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter mapped binding motif, knockdown functional assays, single lab\",\n      \"pmids\": [\"38778047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tanshinone IIA induces ferroptosis in melanoma via STAT1-mediated transcriptional upregulation of PTGS2. STAT1 was identified as a transcription factor that binds the PTGS2 promoter (validated by ChIP and luciferase assay); STAT1 downregulation led to PTGS2 downregulation and inhibited ferroptosis. PTGS2 knockdown attenuated Tan IIA-induced ferroptosis.\",\n      \"method\": \"RNA sequencing, chromatin immunoprecipitation (ChIP) and luciferase assay for STAT1 binding to PTGS2 promoter, PTGS2 knockdown, STAT1 knockdown, ferroptosis markers (MDA, Fe2+, ROS, GSH), xenograft model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase validate promoter binding, functional knockdown with in vivo model, single lab\",\n      \"pmids\": [\"40222167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"REV-ERBα (encoded by NR1D1) acts as a transcriptional repressor of PTGS2 expression in bovine uterine stromal and epithelial cells. REV-ERBα antagonist treatment increased PTGS2 transcript levels and PGF2α production in both cell types; BMAL1 knockdown by siRNA decreased NR1D1 and PTGS2 expression and PGF2α production in stromal cells.\",\n      \"method\": \"siRNA knockdown of BMAL1, pharmacological REV-ERBα agonist/antagonist, RT-qPCR, PGF2α ELISA in bovine uterine cells\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown and pharmacological intervention, two cell types, single lab\",\n      \"pmids\": [\"25007867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Astilbin (AST) binds the transcription factor KLF4 (demonstrated by DARTS assay, molecular docking, and SPR), which in turn binds and activates the PTGS2 promoter (validated by ChIP-PCR and dual-luciferase reporter). AST-mediated KLF4-PTGS2 upregulation increases PGE2 secretion from MSCs, promoting M2 macrophage polarization. PTGS2 knockdown reversed AST-pretreated MSC-mediated M2 polarization and reduced therapeutic effects in AKI-CKD mice.\",\n      \"method\": \"DARTS assay, surface plasmon resonance (SPR), molecular docking, dual-luciferase reporter, ChIP-PCR for KLF4 binding to PTGS2 promoter, PTGS2 knockdown, in vivo AKI-CKD mouse model\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple protein-ligand binding assays (DARTS, SPR) and ChIP-PCR for promoter binding, single lab\",\n      \"pmids\": [\"39543734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PKC activation by PMA upregulates PTGS2 mRNA in human chorion trophoblast cells through p38 and MEK1/2 (MAPK) pathways. The stimulatory effect of PMA on PTGS2 was reversed by PKC inhibition; p38 inhibitor reduced PTGS2 induction by both PMA and calcium ionophore A23187; MEK1/2 inhibitor reduced the PMA effect on PTGS2. MAPK inhibitors did not reverse effects on PGDH, indicating divergent downstream pathways.\",\n      \"method\": \"Pharmacological inhibitors of PKC, JNK, p38, MEK1/2 in human chorion trophoblast cells, RT-qPCR for PTGS2 and PGDH mRNA\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors with defined pathway dissection, single lab\",\n      \"pmids\": [\"18212353\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTGS2 (COX-2) is an inducible prostaglandin-endoperoxide synthase that catalyzes the rate-limiting step in prostaglandin synthesis; its expression is transcriptionally regulated by NF-κB (activated downstream of ROS, TLR/MyD88, and cytokine signals), ATF3 (direct promoter repressor), CTCF/cohesin-mediated chromatin looping (disrupted by DNA methylation), AKAP95-anchored nuclear PKA/CREB, SMAD2/3-SMAD4 (downstream of activin A/ACVR1B), RUNX1, STAT1, KLF4, and REV-ERBα (repressor); its mRNA is post-transcriptionally stabilized by AMPK-dependent mechanisms; the encoded enzyme produces PGE2 that acts via EP receptors (PTGER1-4) to regulate oocyte maturation (MAPK activation), colonic epithelial proliferation, beta cell survival, corpus luteum function, and ovulatory gene cascades (AREG, EREG, TNFAIP6); PTGS2 also lies downstream of EPHA2-TGFβ and upstream of NF-κB in tumor immune exclusion and chemoresistance pathways, and ROBO4 suppresses PTGS2 expression by enhancing IQGAP1 ubiquitination via TRAF7 to inhibit RAC1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTGS2 (COX-2) is the inducible prostaglandin-endoperoxide synthase that catalyzes the rate-limiting step of prostaglandin biosynthesis, producing PGE2 and related eicosanoids that act through EP receptors to control inflammation, reproduction, epithelial homeostasis, and tumor biology [#0, #13]. The gene is a highly regulated transcriptional hub: its TATA-containing promoter carries NF-\\u03baB, CRE, AP-1, and other regulatory elements [#0], and multiple converging signals govern its induction. ROS-driven NF-\\u03baB activation drives PTGS2 transcription downstream of PGF2\\u03b1 in the corpus luteum, with NF-\\u03baB p65 binding directly to the promoter [#2]. Additional direct promoter-binding transcription factors include the activator RUNX1 [#20], HIF1A [#17], STAT1 [#21], and KLF4 [#23], while ATF3 and the nuclear receptor REV-ERB\\u03b1 act as direct repressors [#7, #22]. The locus is further controlled epigenetically through methylation-sensitive CTCF/cohesin-mediated chromatin looping [#8] and through a CTCF/lncRNA-PACERR complex that recruits p300 to acetylate the PTGS2 promoter [#16]. Inducible signaling pathways feeding PTGS2 expression include TLR/MyD88 [#1], activin A acting via ACVR1B and SMAD2/3-SMAD4 [#9], AKAP95-anchored nuclear PKA/CREB signaling [#10], and PKC-p38/MEK1/2 MAPK cascades [#24], while PTGS2 mRNA is post-transcriptionally stabilized by AMPK [#13]. Functionally, PTGS2-derived PGE2 sits upstream of the ovulatory gene cascade (AREG, EREG, TNFAIP6) and oocyte MAPK activation during maturation [#3, #5], supports colonic epithelial proliferation in the stem cell niche [#1], and promotes beta cell survival through a PGE2-PTGER1 axis [#18]. In cancer, PTGS2 mediates immune exclusion and chemo-/radioresistance, lying downstream of EPHA2-TGF\\u03b2 signaling and feeding back to activate NF-\\u03baB, promoting myeloid-derived suppressor cell differentiation, M2 macrophage polarization, and drug efflux [#11, #14, #16]. ROBO4 suppresses endothelial PTGS2 by forming a complex with IQGAP1 and the E3 ligase TRAF7 that promotes IQGAP1 ubiquitination and dampens RAC1 signaling [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that PTGS2 is a genetically distinct, inducible cyclooxygenase isozyme separate from constitutive PTGS1 defined it as the regulatable arm of prostaglandin synthesis and explained how its expression could be acutely controlled.\",\n      \"evidence\": \"Gene isolation, sequencing, primer extension, and FISH mapping the human PTGS2 locus\",\n      \"pmids\": [\"8181472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promoter elements were identified by sequence, not yet shown to be functionally occupied\", \"Enzymatic kinetics not characterized in this entry\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic epistasis placed Ptgs2/PGE2 downstream of TLR/MyD88 signaling in tissue repair, showing that spatial repositioning of PTGS2-expressing stromal cells, not expression level alone, sustains epithelial proliferation.\",\n      \"evidence\": \"Myd88\\u2212/\\u2212 and Ptgs2\\u2212/\\u2212 knockout mice with dmPGE2 rescue and crypt histology\",\n      \"pmids\": [\"17200722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of stromal cell repositioning not defined\", \"EP receptor mediating epithelial response not identified here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Dissecting the PKC-MAPK input showed that p38 and MEK1/2 cascades drive PTGS2 induction independently of effects on prostaglandin catabolism, identifying divergent kinase routes to PTGS2 expression.\",\n      \"evidence\": \"Pharmacological PKC/JNK/p38/MEK1/2 inhibitors in human chorion trophoblasts with RT-qPCR\",\n      \"pmids\": [\"18212353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcription factor linking MAPK to the promoter not identified\", \"Pharmacological inhibitors only, no genetic confirmation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating ROS-dependent NF-\\u03baB p65 binding to the PTGS2 promoter established a feed-forward loop in which PGF2\\u03b1 amplifies its own synthesis through oxidative NF-\\u03baB activation.\",\n      \"evidence\": \"In vivo rat model, EMSA of NF-\\u03baB at PTGS2 promoter, ROS scavengers, and PTGS2 inhibitor NS-398\",\n      \"pmids\": [\"20826536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of ROS not pinpointed\", \"Direct NF-\\u03baB binding shown by EMSA but not in situ ChIP\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"PTGS2-derived PGE2 was shown to be required for oocyte ERK1/2 activation, cumulus expansion, and spindle organization during maturation, defining a reproductive role acting through EP2/3/4 receptors.\",\n      \"evidence\": \"Bovine oocyte in vitro maturation with NS-398, PGE2 rescue, spindle immunofluorescence, receptor expression\",\n      \"pmids\": [\"21293029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each EP receptor not resolved\", \"Downstream of ERK1/2 not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying RNA pol-II 5'-pausing and glucocorticoid receptor-mediated transrepression at the PTGS2 locus revealed that the gene is controlled at the level of transcriptional elongation, not just initiation.\",\n      \"evidence\": \"ChIP for pol-II, CTD Ser5/Ser2 phosphorylation and histone marks in dexamethasone-treated human amnion\",\n      \"pmids\": [\"21385935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Factors releasing the paused polymerase not identified here\", \"GR\\u03b1 co-repressor partners not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"siRNA silencing placed PTGS2-derived prostaglandins upstream of the ovulatory effectors AREG, EREG, and TNFAIP6 (but not PTX3), ordering PTGS2 within the LH-induced ovulation cascade.\",\n      \"evidence\": \"PTGS2 siRNA knockdown in bovine granulosa cells with PGE2 rescue and RT-qPCR\",\n      \"pmids\": [\"25323036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EP receptor and signaling route to these genes not defined\", \"Single lab, single species\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping a ROS/NF-\\u03baB to PTGS2 to PGE2/EP4/MAPK to BCL2 axis explained how PTGS2 drives apoptosis resistance, establishing it as a mediator of chemoresistance.\",\n      \"evidence\": \"siRNA, celecoxib/NS-398, and gastric cancer xenografts with western blot\",\n      \"pmids\": [\"31518663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct EP4-MAPK coupling shown pharmacologically only\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying REV-ERB\\u03b1 as a circadian repressor of PTGS2 linked clock machinery to the temporal control of prostaglandin output in the uterus.\",\n      \"evidence\": \"BMAL1 siRNA, REV-ERB\\u03b1 agonist/antagonist, RT-qPCR and PGF2\\u03b1 ELISA in bovine uterine cells\",\n      \"pmids\": [\"25007867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct REV-ERB\\u03b1 promoter occupancy not shown\", \"Repression inferred pharmacologically\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ChIP localization of ATF3 to the Ptgs2 promoter and the inflammatory phenotype of Atf3\\u2212/\\u2212 mice identified a direct transcriptional brake limiting prostaglandin production during acute inflammation.\",\n      \"evidence\": \"ATF3 ChIP, Atf3\\u2212/\\u2212 macrophages and peritonitis model with prostaglandin measurement\",\n      \"pmids\": [\"25619459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ATF3 co-repressor complex composition not defined\", \"Stimulus specificity beyond zymosan not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that DNA methylation disrupts CTCF/cohesin-mediated chromatin looping and abolishes P-TEFb recruitment established a 3D-chromatin and epigenetic layer of PTGS2 control.\",\n      \"evidence\": \"ChIP for CTCF/cohesin/elongation factors, 3C chromatin conformation, methylation analysis, siRNA and luciferase reporter\",\n      \"pmids\": [\"25703332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger setting locus methylation status not defined\", \"Connection to specific physiological signals unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating activin A induction of PTGS2 through ACVR1B-SMAD2/3-SMAD4 added a TGF-\\u03b2 superfamily input to PTGS2 regulation in luteinized granulosa cells.\",\n      \"evidence\": \"SB431542, SMAD2/3 and SMAD4 siRNA, PGE2 ELISA, western blot and RT-qPCR in granulosa-lutein cells\",\n      \"pmids\": [\"27624482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SMAD binding to the PTGS2 promoter not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying AKAP95-anchored nuclear PKA as the route for cortisol-induced PTGS2 expression revealed compartmentalized cAMP/CREB signaling controlling prostaglandin output in amnion, with relevance to labor.\",\n      \"evidence\": \"AKAP95 siRNA in primary amnion fibroblasts, fractionation, phospho-CREB western blot, and labor vs non-labor immunohistochemistry\",\n      \"pmids\": [\"29162743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CREB occupancy of PTGS2 promoter not shown here\", \"Upstream cortisol receptor coupling to AKAP95 not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two independent genetic deletions placed PTGS2 downstream of EPHA2-TGF\\u03b2 in driving T cell exclusion, establishing it as a targetable node for sensitizing tumors to immunotherapy.\",\n      \"evidence\": \"Epha2\\u2212/\\u2212 and Ptgs2\\u2212/\\u2212 murine tumor models, PTGS2 inhibition and immunotherapy combination\",\n      \"pmids\": [\"31162144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Immune cell type producing or responding to PGE2 not fully resolved\", \"EP receptor mediating exclusion not identified here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CRISPR knockout of PTGS2 in melanoma showed it promotes proliferation, invasion, and MDSC differentiation, linking tumor-intrinsic PTGS2 to an immunosuppressive microenvironment.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, in vitro invasion assays, in vivo metastasis model, MDSC flow cytometry\",\n      \"pmids\": [\"31920649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting PTGS2 to MDSC differentiation not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating AMPK-dependent stabilization of Ptgs2 mRNA upon mitochondrial OXPHOS inhibition added a metabolic, post-transcriptional control mechanism to PTGS2 regulation.\",\n      \"evidence\": \"AMPK siRNA, AMPK activators/inhibitors, mRNA stability assays and LC/MS eicosanoid measurement in astrocytes\",\n      \"pmids\": [\"31581537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding effector mediating stabilization not identified\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Gain- and loss-of-function in glioma showed PTGS2 activates NF-\\u03baB to limit DNA damage and confer radioresistance, defining a feedback loop where PTGS2 reinforces its own upstream activator.\",\n      \"evidence\": \"PTGS2 overexpression/siRNA, clonogenic survival, cell cycle, \\u03b3H2AX, NF-\\u03baB inhibitor Bay 11\",\n      \"pmids\": [\"30740906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PTGS2 activates NF-\\u03baB not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking COX-2 to P-glycoprotein upregulation at the blood-brain barrier provided a mechanism for PTGS2-driven antiepileptic drug resistance, with peripheral PTGS2 mRNA tracking treatment response.\",\n      \"evidence\": \"Brain endothelial cell model with valproate, COX-2/P-gp western blot, microarray, plasma PGE2\",\n      \"pmids\": [\"32054883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling between COX-2/PGE2 and P-gp induction not fully mapped\", \"Clinical correlation is associative\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing a CTCF/lncRNA-PACERR complex recruits p300 to acetylate and activate the PTGS2 promoter revealed an enhancer-RNA mechanism driving PTGS2-dependent M2 macrophage polarization in pancreatic cancer.\",\n      \"evidence\": \"RIP, RNA pull-down, ChIP-seq, ATAC-seq, RNA-seq, lentiviral knockdown and in vivo metastasis assays\",\n      \"pmids\": [\"35184402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PACERR is induced in the tumor context not defined\", \"Relationship to methylation-sensitive CTCF looping not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying direct HIF1A binding to the Ptgs2 promoter connected hypoxic signaling to PTGS2-driven ferroptosis in cardiomyocytes after microembolization.\",\n      \"evidence\": \"HIF1A ChIP, Ptgs2 siLNA, ferroptosis markers and cardiac function in rat CME model with atorvastatin\",\n      \"pmids\": [\"36569299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between PTGS2 enzymatic product and ferroptosis not mechanistically dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping the LRH-1/NR5A2 to PTGS2 to PGE2 to PTGER1 axis established a cytoprotective pathway in beta cells, ordering the receptor (PTGER1) mediating PGE2-driven survival.\",\n      \"evidence\": \"Beta cell-specific LRH-1 knockout, PTGS2 inactivation, PTGER1 antagonist ONO-8130, PGE2 ELISA and apoptosis markers\",\n      \"pmids\": [\"35602948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct LRH-1 occupancy of PTGS2 promoter not shown here\", \"Downstream of PTGER1 in survival not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying the ROBO4-IQGAP1-TRAF7 complex defined a suppressive mechanism in which ROBO4 promotes IQGAP1 ubiquitination to dampen RAC1 and lower endothelial PTGS2, with loss exacerbating inflammation.\",\n      \"evidence\": \"RNA-seq, Co-IP, ubiquitination assay, Robo4-deficient mice in inflammatory disease models\",\n      \"pmids\": [\"38762541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAC1 controls PTGS2 transcription not detailed\", \"Co-IP without reciprocal structural mapping of the complex\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Luciferase mapping of a defined RUNX1 binding motif in the PTGS2 promoter identified RUNX1 as a direct activator driving colorectal cancer cell growth and invasion.\",\n      \"evidence\": \"Luciferase reporter with promoter fragments, RUNX1/PTGS2 siRNA, TCGA co-expression and invasion assays\",\n      \"pmids\": [\"38778047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RUNX1 occupancy validated by reporter, not endogenous ChIP\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that the small molecule astilbin engages KLF4, which binds and activates the PTGS2 promoter, defined a KLF4-PTGS2-PGE2 axis driving M2 polarization and MSC therapeutic effects in kidney injury.\",\n      \"evidence\": \"DARTS, SPR, docking, dual-luciferase, ChIP-PCR for KLF4 binding, PTGS2 knockdown and AKI-CKD mouse model\",\n      \"pmids\": [\"39543734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KLF4 as activator versus context-dependent factor not generalized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Validating STAT1 binding to the PTGS2 promoter established STAT1-driven PTGS2 induction as a route to ferroptosis in melanoma, identifying another direct transcriptional activator.\",\n      \"evidence\": \"RNA-seq, ChIP and luciferase for STAT1, STAT1 and PTGS2 knockdown, ferroptosis markers and xenograft\",\n      \"pmids\": [\"40222167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PTGS2 product triggers ferroptosis not mechanistically resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many converging transcriptional, epigenetic, and post-transcriptional inputs to PTGS2 are integrated in a given cell, and how its enzymatic product is channeled to specific EP receptors for distinct outcomes (survival, ferroptosis, immune exclusion), remains unresolved.\",\n      \"evidence\": \"No single study in the corpus integrates the multiple regulatory layers or receptor-coupling specificity\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Combinatorial logic of competing activators/repressors at the promoter not defined\", \"Determinants of EP receptor selectivity for downstream effects unknown\", \"Enzymatic kinetics and substrate handling not characterized in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 13]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 7, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 7, 8, 16, 17, 20, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 11, 14, 16]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [3, 5, 9]}\n    ],\n    \"complexes\": [\n      \"ROBO4-IQGAP1-TRAF7 complex\",\n      \"CTCF/lncRNA-PACERR complex\"\n    ],\n    \"partners\": [\n      \"IQGAP1\",\n      \"TRAF7\",\n      \"ROBO4\",\n      \"CTCF\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}