{"gene":"OIP5","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2010,"finding":"Knockdown of OIP5 (protein-coding gene) by siRNA resulted in growth inhibition of colorectal and gastric cancer cell lines with increased sub-G1 DNA content, suggesting OIP5 promotes cell survival and its loss induces apoptosis.","method":"siRNA knockdown, flow cytometry, growth inhibition assays","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype (growth inhibition, sub-G1 accumulation), single lab, single study","pmids":["20510019"],"is_preprint":false},{"year":2017,"finding":"OIP5 protein activates AKT signaling via both mTORC2 and p38/PTEN; AKT activation links to mTORC1 (cell growth) and GSK-3β/β-catenin (metastasis) signaling in hepatocellular carcinoma. miR-15b-5p targets OIP5 and inhibits these downstream oncogenic signals.","method":"Proteome kinase profiling, shRNA knockdown, orthotopic mouse model, miRNA PCR array","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase profiling plus in vivo orthotopic model and miRNA array, single lab, multiple orthogonal methods","pmids":["28184024"],"is_preprint":false},{"year":2018,"finding":"OIP5 protein is downstream of E2F1 transcription factor (E2F1 activates OIP5 expression by binding its promoter), and OIP5 in turn stabilizes and maintains E2F1 signaling in a positive feedback loop, promoting cell cycle progression in glioblastoma.","method":"Immunoprecipitation, chromatin immunoprecipitation (ChIP), luciferase assays, shRNA knockdown, orthotopic tumor model","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm E2F1 binding to OIP5 promoter; reciprocal feedback supported by IP and in vivo model; single lab","pmids":["29547938"],"is_preprint":false},{"year":2018,"finding":"OIP5 protein promotes growth, migration, and cisplatin resistance in bladder cancer cells; knockdown reduces colony formation, migration, and sensitizes cells to cisplatin. RNA-seq identified 38 DEGs including TOP2A, SPAG5, SKA1, EXO1, TK1 as downstream effectors.","method":"shRNA knockdown, scratch/transwell assays, cisplatin sensitivity assay, RNA-seq, in vivo xenograft","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO/KD with defined phenotype and RNA-seq, single lab","pmids":["30588253"],"is_preprint":false},{"year":2023,"finding":"OIP5 protein interacts directly with NCK2 (as shown by Co-IP, IP-MS, and GST pulldown), and this interaction mediates human spermatogonial stem cell self-renewal and apoptosis through regulation of cell cycle proteins including cyclins A2, B1, D1, E1 and H.","method":"Co-immunoprecipitation (Co-IP), IP-MS (mass spectrometry), GST pulldown, siRNA knockdown, flow cytometry, whole-exome sequencing","journal":"Research (Washington, D.C.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct physical interaction confirmed by three independent methods (Co-IP, IP-MS, GST pulldown); functional rescue experiments; multiple orthogonal approaches in one study","pmids":["37292517"],"is_preprint":false},{"year":2017,"finding":"lncRNA OIP5-AS1 (cyrano) suppresses cell proliferation by reducing GAK mRNA stability and GAK protein abundance; silencing OIP5-AS1 causes aberrant mitotic spindles (monopolar, multipolar, misaligned) that are partly rescued by simultaneous GAK silencing, placing OIP5-AS1 upstream of GAK in mitotic regulation.","method":"RNA pulldown of OIP5-AS1-bound mRNAs, proteomics of differentially expressed proteins upon OIP5-AS1 silencing, mRNA stability assay, siRNA double knockdown rescue, immunofluorescence of mitotic spindles","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (pulldown, proteomics, stability assay) plus epistasis rescue experiment; mechanism clearly established in single rigorous study","pmids":["28472763"],"is_preprint":false},{"year":2016,"finding":"lncRNA OIP5-AS1 binds the RNA-binding protein HuR, which stabilizes OIP5-AS1; high OIP5-AS1 levels sequester HuR away from its target mRNAs (encoding proliferative proteins), acting as a competing endogenous RNA sponge for HuR. miR-424 competes with HuR for OIP5-AS1 binding.","method":"MS2-hairpin tagging of OIP5-AS1 to identify associated miRNAs, RIP, RNA pulldown, HuR-target mRNA interaction assays upon OIP5-AS1 modulation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — MS2-tagging, RIP, and mRNA interaction assays with modulation experiments; multiple orthogonal methods in single rigorous study establishing the HuR sponge mechanism","pmids":["26819413"],"is_preprint":false},{"year":2022,"finding":"During human myogenesis, lncRNA OIP5-AS1 binds miR-7 and induces its decay via target RNA-directed miRNA decay (TDMD); this OIP5-AS1-mediated miR-7 degradation de-represses the miR-7 target MYMX mRNA (encoding fusogenic protein myomixer), promoting myoblast fusion into myotubes. An oligonucleotide site blocker that prevents OIP5-AS1-directed miR-7 decay allowed miR-7 to accumulate and suppressed myotube formation.","method":"qRT-PCR of OIP5-AS1 and miR-7 levels during myogenesis, siRNA/antagonist functional assays, oligonucleotide site blocker, MYMX luciferase reporter, myotube formation assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — TDMD mechanism established with multiple orthogonal approaches (site blocker, antagonists, reporter assays, functional myotube readout) in single rigorous study","pmids":["35736212"],"is_preprint":false},{"year":2021,"finding":"Loss of OIP5-AS1 (global CRISPR knockout) in female but not male mice leads to exacerbated heart failure following cardiac pressure overload (transverse aortic constriction); RNA-sequencing suggests OIP5-AS1 regulates pathways impacting mitochondrial function in a sex-specific manner.","method":"CRISPR knockout mice, transverse aortic constriction model, cardiac function assessment, RNA-sequencing","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean CRISPR KO with defined in vivo cardiac phenotype and transcriptomic pathway analysis; sex-specific finding replicated in multiple animals","pmids":["34142046"],"is_preprint":false},{"year":2024,"finding":"lncRNA Oip5-as1 selectively interacts with AKAP1 and calcineurin (CaN) proteins; by binding CaN, Oip5-as1 inhibits CaN activation and thereby prevents DRP1 dephosphorylation at Ser637, blocking DRP1 translocation to mitochondria and reducing excessive mitochondrial fission during myocardial ischemia/reperfusion injury.","method":"RNA pulldown, RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), CRISPR/Cas9 conditional knockout mice, AAV9 overexpression, immunofluorescence, Western blot, echocardiography","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct protein-RNA interaction confirmed by pulldown, RIP and Co-IP; causal mechanism validated in both KO and overexpression in vivo models with functional cardiac readouts","pmids":["38745296"],"is_preprint":false},{"year":2024,"finding":"Oip5-as1 delivery via lipid nanoparticles inhibits the p53 signaling pathway in cardiomyocytes, preserving mitochondrial function and reducing myocardial infarct size after ischemia/reperfusion injury; cardioprotective effects are abrogated by the p53 activator Nutlin-3a.","method":"Lipid nanoparticle delivery, H/R cell model and murine MI/R model, pharmacological rescue with Nutlin-3a, echocardiography","journal":"ACS applied materials & interfaces","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro models with pharmacological epistasis (Nutlin-3a rescue); single lab, mechanism (p53 inhibition) inferred from pathway rather than direct binding","pmids":["39485791"],"is_preprint":false},{"year":2020,"finding":"lncRNA OIP5-AS1 (Oip5-as1) acts as a competing endogenous RNA for miR-29a; by sponging miR-29a, OIP5-AS1 de-represses SIRT1 expression and activates the AMPK/PGC1α pathway, reducing mitochondria-mediated apoptosis during myocardial ischemia/reperfusion injury.","method":"Dual-luciferase reporter assay, RIP assay, miR-29a overexpression rescue, SIRT1 inhibitor (EX527) rescue, rat MI/R model and H9c2 OGD/R model","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase and RIP confirm sponging; pharmacological and miRNA rescue experiments establish pathway placement; single lab","pmids":["32468629"],"is_preprint":false},{"year":2019,"finding":"lncRNA OIP5-AS1 binds EZH2 (a PRC2 component) and recruits it to the GSK-3β promoter region, leading to epigenetic silencing of GSK-3β expression; ChIP confirmed EZH2 direct binding to the GSK-3β promoter upon OIP5-AS1 overexpression, accelerating ox-LDL-mediated endothelial cell apoptosis.","method":"Chromatin immunoprecipitation (ChIP), OIP5-AS1 silencing/rescue experiments, Western blot","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly confirms EZH2 binding to GSK-3β promoter; functional rescue validates pathway; single lab, single study","pmids":["30972206"],"is_preprint":false},{"year":2019,"finding":"lncRNA OIP5-AS1 binds EZH2 and epigenetically silences NLRP6 expression in gastric cancer cells; OIP5-AS1 was found to localize predominantly in the nucleus, consistent with its role in chromatin-based gene silencing.","method":"Nuclear/cytoplasmic fractionation (OIP5-AS1 nuclear localization), RIP assay (OIP5-AS1–EZH2 interaction), qRT-PCR and functional assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — nuclear localization confirmed by fractionation; EZH2 binding by RIP; downstream NLRP6 silencing assayed; single lab","pmids":["31219209"],"is_preprint":false},{"year":2020,"finding":"lncRNA OIP5-AS1 located in the nucleus of hepatoblastoma cells targets miR-186a-5p (confirmed by RIP and dual luciferase assay) and thereby up-regulates ZEB1, an miR-186a-5p target gene, promoting EMT, proliferation and metastasis.","method":"Nuclear separation experiment (subcellular localization), RIP assay, dual luciferase assay, rescue assays","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — nuclear localization confirmed by fractionation; sponging confirmed by RIP and luciferase; single lab","pmids":["29475118"],"is_preprint":false},{"year":2021,"finding":"N6-methyladenosine (m6A) modification on lncRNA OIP5-AS1 enables binding by IGF2BP3, which stabilizes OIP5-AS1 (RNA pulldown and RIP confirmed). OIP5-AS1 in turn prevents Trim21-mediated ubiquitination and degradation of hnRNPA1, stabilizing hnRNPA1 protein to promote PKM2 signaling and glycolysis in gastric cancer.","method":"RNA pulldown assay, RNA immunoprecipitation (RIP), ubiquitination assay, patient-derived xenograft models, Western blot","journal":"Gastric cancer","confidence":"High","confidence_rationale":"Tier 1 / Strong — m6A-IGF2BP3 interaction confirmed by pulldown and RIP; Trim21-hnRNPA1 ubiquitination mechanism established biochemically; multiple orthogonal methods in single rigorous study","pmids":["37897508"],"is_preprint":false},{"year":2021,"finding":"lncRNA OIP5-AS1 positively regulates cell proliferation by promoting G2/M phase progression in HeLa cells; silencing OIP5-AS1 with siRNA or antisense oligonucleotides causes G2/M arrest without inducing apoptosis.","method":"siRNA and antisense oligonucleotide knockdown, cell cycle analysis by flow cytometry, apoptosis analysis","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cell-cycle phenotype using two independent silencing approaches; single lab, single study","pmids":["29277759"],"is_preprint":false},{"year":2023,"finding":"Exosome-derived lncRNA OIP5-AS1 (from M2 microglia) binds TXNIP protein and recruits the E3 ubiquitin ligase ITCH to promote TXNIP ubiquitination and proteasomal degradation, reducing TXNIP protein (but not mRNA) levels and inhibiting neuronal pyroptosis after cerebral ischemia/reperfusion injury.","method":"RNA pulldown, RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), ubiquitination assay, MCAO/R mouse model and OGD/R cell model","journal":"International immunopharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct OIP5-AS1–TXNIP interaction and ITCH recruitment confirmed by pulldown, RIP and Co-IP; ubiquitination and degradation mechanism validated biochemically; in vivo model corroborates","pmids":["38103409"],"is_preprint":false},{"year":2020,"finding":"lncRNA OIP5-AS1 promotes cataract formation under oxidative stress by acting through HuR: HuR functions as a scaffold that carries both OIP5-AS1 and POLG mRNA, mediating decay of POLG mRNA; reduced POLG lowers mtDNA copy number and mitochondrial membrane potential, increasing ROS and apoptosis of lens epithelial cells. TFAP2A binds the OIP5-AS1 promoter and drives its expression.","method":"Ribonucleoprotein immunoprecipitation (RIP)-qPCR (OIP5-AS1–HuR–POLG mRNA complex), chromatin immunoprecipitation (ChIP)-qPCR (TFAP2A at OIP5-AS1 promoter), POLG overexpression rescue, JC-1 staining, flow cytometry, ex vivo cataract model","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1 / Strong — RIP confirms ternary complex; ChIP confirms upstream transcription factor; POLG rescue validates pathway; multiple orthogonal methods in single rigorous study","pmids":["33006594"],"is_preprint":false},{"year":2021,"finding":"SUMOylation of IGF2BP2 at K497/K505/K509 (reducible by SENP1) increases IGF2BP2 protein stability by blocking ubiquitin-proteasome degradation; SUMOylated IGF2BP2 enhances stability of lncRNA OIP5-AS1, thereby increasing OIP5-AS1 sponging of miR-495-3p, de-repressing HIF1A and MMP14 and promoting vasculogenic mimicry in glioma.","method":"Ni2+-NTA agarose bead pulldown, Co-IP, in vitro SUMOylation assay, immunoprecipitation, immunofluorescence, RIP and luciferase reporter assays, nude mouse xenograft","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro SUMOylation assay plus multiple pulldown/IP methods define SUMO modification sites and stability mechanism; functional consequence confirmed in vivo; rigorous single study","pmids":["34345216"],"is_preprint":false},{"year":2021,"finding":"METTL14 suppresses PTC cell proliferation and migration by binding to and inhibiting lncRNA OIP5-AS1 expression (confirmed by RIP and RNA pulldown); OIP5-AS1 in turn acts as a sponge for miR-98 to up-regulate ADAMTS8, activating EGFR and MEK/ERK pathways.","method":"RIP assay, RNA pulldown assay, luciferase reporter assay, siRNA/overexpression functional assays, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and pulldown confirm METTL14–OIP5-AS1 interaction; ceRNA axis validated by luciferase; single lab, multiple methods","pmids":["34131102"],"is_preprint":false}],"current_model":"OIP5 protein promotes cell proliferation by interacting with NCK2 (confirmed by Co-IP/pulldown), activating AKT/mTORC1 and GSK-3β/β-catenin signaling, and participating in an E2F1 positive-feedback loop; its antisense lncRNA OIP5-AS1 (cyrano) operates as a multifunctional noncoding regulator that (1) sequesters HuR protein away from pro-proliferative target mRNAs, (2) suppresses GAK mRNA stability to prevent aberrant mitosis, (3) drives miR-7 decay via TDMD to promote MYMX-dependent myoblast fusion, (4) binds AKAP1/calcineurin to block DRP1 dephosphorylation and excessive mitochondrial fission, (5) recruits EZH2 to epigenetically silence target genes, (6) stabilizes hnRNPA1 by blocking Trim21-mediated ubiquitination, and (7) recruits the E3 ligase ITCH to ubiquitinate and degrade TXNIP, with context-specific ceRNA activity sponging dozens of miRNAs across cancer, cardiac, and neurological settings."},"narrative":{"mechanistic_narrative":"The OIP5 locus encodes two functionally distinct products: a protein-coding OIP5 transcript that acts as a pro-proliferative oncoprotein, and the antisense long noncoding RNA OIP5-AS1, a multifunctional regulator of RNA stability, miRNA decay, epigenetic silencing, and protein turnover [PMID:20510019, PMID:26819413]. The OIP5 protein promotes cell survival and cell-cycle progression across colorectal, gastric, hepatocellular, bladder, and glioblastoma cells, where its loss induces growth inhibition and sub-G1 accumulation [PMID:20510019, PMID:30588253]. Mechanistically, OIP5 protein activates AKT signaling through mTORC2 and p38/PTEN, feeding into mTORC1-driven growth and GSK-3β/β-catenin-driven metastasis [PMID:28184024], operates in a positive-feedback loop with the E2F1 transcription factor that binds the OIP5 promoter [PMID:29547938], and engages NCK2 in a direct physical interaction (Co-IP, IP-MS, GST pulldown) that governs spermatogonial stem cell self-renewal via cyclin regulation [PMID:37292517]. The antisense lncRNA OIP5-AS1 controls gene expression through several biochemically distinct routes: it binds and sequesters the RNA-binding protein HuR to modulate the stability of HuR target mRNAs, including reducing GAK mRNA stability to safeguard mitotic spindle integrity and mediating POLG mRNA decay under oxidative stress [PMID:28472763, PMID:26819413, PMID:33006594]; it directs target RNA-directed decay of miR-7 to de-repress the fusogen MYMX during myogenesis [PMID:35736212]; it recruits the PRC2 component EZH2 to promoters for epigenetic silencing [PMID:30972206]; and it controls protein turnover by blocking Trim21-mediated ubiquitination of hnRNPA1 and by recruiting the E3 ligase ITCH to degrade TXNIP [PMID:37897508, PMID:38103409]. In the heart, OIP5-AS1 binds AKAP1/calcineurin to prevent DRP1 dephosphorylation and excessive mitochondrial fission, and its loss exacerbates pressure-overload heart failure in a sex-specific manner [PMID:34142046, PMID:38745296]. OIP5-AS1 stability is itself controlled by m6A-dependent IGF2BP3 binding and by SUMOylated IGF2BP2 [PMID:37897508, PMID:34345216].","teleology":[{"year":2010,"claim":"Established that the OIP5 protein-coding gene is required for cancer cell survival, framing it as a candidate oncogene rather than a passenger.","evidence":"siRNA knockdown with flow cytometry and growth assays in colorectal and gastric cancer lines","pmids":["20510019"],"confidence":"Medium","gaps":["No molecular partner or signaling pathway identified","Mechanism of apoptosis induction unresolved"]},{"year":2017,"claim":"Connected OIP5 protein to defined oncogenic signaling, showing it activates AKT via mTORC2 and p38/PTEN to drive growth and metastasis programs.","evidence":"Kinase profiling, shRNA, orthotopic mouse model and miRNA array in hepatocellular carcinoma","pmids":["28184024"],"confidence":"Medium","gaps":["Direct biochemical link between OIP5 and the kinases not shown","How OIP5 activates these kinases mechanistically is unclear"]},{"year":2018,"claim":"Placed OIP5 protein in a transcriptional circuit by showing E2F1 drives its expression and OIP5 reciprocally stabilizes E2F1, creating a proliferative feedback loop.","evidence":"ChIP, luciferase, IP, shRNA and orthotopic tumor model in glioblastoma","pmids":["29547938"],"confidence":"Medium","gaps":["Mechanism by which OIP5 stabilizes E2F1 not defined","Single tumor context"]},{"year":2023,"claim":"Identified the first validated direct protein partner of OIP5, NCK2, linking the interaction to stem cell self-renewal and cyclin control.","evidence":"Co-IP, IP-MS and GST pulldown with functional assays in human spermatogonial stem cells","pmids":["37292517"],"confidence":"High","gaps":["Structural basis of the OIP5–NCK2 interaction unknown","How the interaction connects to the AKT/E2F1 axes not tested"]},{"year":2016,"claim":"Defined the antisense lncRNA OIP5-AS1 as an HuR-binding RNA that sequesters HuR from its target mRNAs, establishing a protein-sponge mode of action.","evidence":"MS2-tagging, RIP, RNA pulldown and HuR-target interaction assays","pmids":["26819413"],"confidence":"High","gaps":["Full repertoire of affected HuR targets not enumerated","Stoichiometry of HuR sequestration unclear"]},{"year":2017,"claim":"Showed OIP5-AS1 controls mitotic fidelity by destabilizing GAK mRNA, with epistasis rescue placing it upstream of GAK in spindle regulation.","evidence":"RNA pulldown, proteomics, mRNA stability assay, double-knockdown rescue and spindle immunofluorescence","pmids":["28472763"],"confidence":"High","gaps":["Whether GAK destabilization is HuR-dependent not directly tested","Other mitotic targets not excluded"]},{"year":2018,"claim":"Demonstrated nuclear OIP5-AS1 acts as a ceRNA for miR-186a-5p to upregulate ZEB1, supporting a cytoplasmic/nuclear miRNA-sponge function in cancer.","evidence":"Nuclear fractionation, RIP, dual luciferase and rescue assays in hepatoblastoma","pmids":["29475118"],"confidence":"Medium","gaps":["ceRNA stoichiometry not quantified","Single cancer context"]},{"year":2019,"claim":"Established an epigenetic silencing mode in which OIP5-AS1 binds EZH2 and guides it to specific promoters (GSK-3β, NLRP6); nuclear localization corroborated the chromatin role.","evidence":"ChIP, RIP, nuclear/cytoplasmic fractionation and functional rescue in endothelial and gastric cancer cells","pmids":["30972206","31219209"],"confidence":"Medium","gaps":["How OIP5-AS1 confers promoter specificity unknown","PRC2 recruitment generality across genes untested"]},{"year":2020,"claim":"Extended the HuR mechanism to mitochondrial maintenance, showing OIP5-AS1 and POLG mRNA share HuR as a scaffold so OIP5-AS1 promotes POLG decay and oxidative damage in lens cells, with TFAP2A as an upstream driver.","evidence":"RIP-qPCR of the ternary complex, ChIP, POLG rescue and ex vivo cataract model","pmids":["33006594"],"confidence":"High","gaps":["Generality of POLG regulation in other tissues untested","Quantitative balance between HuR sequestration and scaffolding unclear"]},{"year":2020,"claim":"Showed OIP5-AS1 protects cardiomyocytes by sponging miR-29a to de-repress SIRT1 and activate AMPK/PGC1α, framing a cardioprotective ceRNA axis.","evidence":"Dual-luciferase, RIP, miR-29a and SIRT1-inhibitor rescue in rat MI/R and H9c2 models","pmids":["32468629"],"confidence":"Medium","gaps":["Endogenous miR-29a sponging stoichiometry unquantified","Single signaling output measured"]},{"year":2021,"claim":"Defined how OIP5-AS1 levels are set post-transcriptionally, showing m6A-dependent IGF2BP3 binding and SUMOylated IGF2BP2 each stabilize the lncRNA.","evidence":"RNA pulldown, RIP, in vitro SUMOylation assay and xenografts in gastric cancer and glioma","pmids":["37897508","34345216"],"confidence":"High","gaps":["Relative contribution of each stabilizer in vivo unclear","Whether the two pathways act in the same cells untested"]},{"year":2021,"claim":"Revealed OIP5-AS1 controls protein turnover, blocking Trim21-mediated ubiquitination of hnRNPA1 to sustain PKM2-driven glycolysis.","evidence":"RNA pulldown, RIP, ubiquitination assay and patient-derived xenografts in gastric cancer","pmids":["37897508"],"confidence":"High","gaps":["Direct binding interface with hnRNPA1/Trim21 not mapped","Whether this is gastric-cancer specific unknown"]},{"year":2021,"claim":"Confirmed OIP5-AS1 supports proliferation through G2/M progression independent of apoptosis, and identified METTL14 as a negative upstream regulator feeding a miR-98/ADAMTS8/EGFR ceRNA axis.","evidence":"siRNA/ASO knockdown with cell-cycle analysis; RIP, pulldown, luciferase and xenografts in papillary thyroid cancer","pmids":["29277759","34131102"],"confidence":"Medium","gaps":["Mechanistic link between G2/M control and named axes not unified","Single-context ceRNA validation"]},{"year":2022,"claim":"Demonstrated OIP5-AS1 actively degrades a specific miRNA via TDMD, driving miR-7 decay to de-repress the fusogen MYMX during myoblast fusion.","evidence":"qRT-PCR, oligonucleotide site blocker, MYMX luciferase reporter and myotube formation assays in human myogenesis","pmids":["35736212"],"confidence":"High","gaps":["TDMD machinery components recruited by OIP5-AS1 not identified","Whether TDMD operates in non-muscle contexts untested"]},{"year":2021,"claim":"Established a physiological in vivo role for OIP5-AS1 in the heart, with global knockout worsening pressure-overload heart failure selectively in females via mitochondrial pathways.","evidence":"CRISPR knockout mice, transverse aortic constriction and RNA-seq","pmids":["34142046"],"confidence":"High","gaps":["Molecular basis of sex specificity unresolved","Direct effector linking knockout to mitochondrial defects not defined"]},{"year":2023,"claim":"Showed OIP5-AS1 can act as a protein scaffold for an E3 ligase, recruiting ITCH to ubiquitinate and degrade TXNIP and thereby suppress neuronal pyroptosis after cerebral ischemia.","evidence":"RNA pulldown, RIP, Co-IP, ubiquitination assay and MCAO/R mouse and OGD/R cell models","pmids":["38103409"],"confidence":"High","gaps":["Binding interfaces among OIP5-AS1, ITCH and TXNIP not mapped","Generality beyond the neuronal/exosome context untested"]},{"year":2024,"claim":"Defined a mitochondrial-fission control mechanism in which Oip5-as1 binds calcineurin to prevent DRP1 Ser637 dephosphorylation, limiting fission during ischemia/reperfusion injury.","evidence":"RNA pulldown, RIP, Co-IP, conditional CRISPR knockout and AAV9 overexpression with echocardiography","pmids":["38745296"],"confidence":"High","gaps":["Role of AKAP1 binding versus calcineurin binding not fully separated","Direct effect on calcineurin catalytic activity not biochemically isolated"]},{"year":null,"claim":"It remains unresolved whether the OIP5 protein and its antisense lncRNA OIP5-AS1 are functionally coupled within the same cells, and how the many context-specific OIP5-AS1 mechanisms (HuR sponging, TDMD, EZH2 silencing, E3-ligase scaffolding, calcineurin binding) are selected in a given tissue.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study integrates OIP5 protein and OIP5-AS1 functions in one system","Determinants of which OIP5-AS1 mechanism dominates per cell type unknown","No structural models for any OIP5/OIP5-AS1 interaction"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,7,9,12,17]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[5,7]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[17,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,14]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8,9]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,16]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,17]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["NCK2","HUR","EZH2","AKAP1","CALCINEURIN","ITCH","HNRNPA1","IGF2BP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43482","full_name":"Protein Mis18-beta","aliases":["Cancer/testis antigen 86","CT86","Opa-interacting protein 5","OIP-5"],"length_aa":229,"mass_kda":24.7,"function":"Required for recruitment of CENPA to centromeres and normal chromosome segregation during mitosis","subcellular_location":"Nucleus; Chromosome; Chromosome, centromere","url":"https://www.uniprot.org/uniprotkb/O43482/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/OIP5","classification":"Common 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APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/26107214","citation_count":19,"is_preprint":false},{"pmid":"32585630","id":"PMC_32585630","title":"Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/32585630","citation_count":19,"is_preprint":false},{"pmid":"34592882","id":"PMC_34592882","title":"Overexpressing long non-coding RNA OIP5-AS1 ameliorates sepsis-induced lung injury in a rat model via regulating the miR-128-3p/Sirtuin-1 pathway.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34592882","citation_count":19,"is_preprint":false},{"pmid":"33092644","id":"PMC_33092644","title":"LncRNA OIP5-AS1 upregulates snail expression by sponging miR-34a to promote ovarian carcinoma cell invasion and migration.","date":"2020","source":"Biological research","url":"https://pubmed.ncbi.nlm.nih.gov/33092644","citation_count":18,"is_preprint":false},{"pmid":"36577153","id":"PMC_36577153","title":"Tetramethylpyrazine and Astragaloside IV have synergistic effects against spinal cord injury-induced neuropathic pain via the OIP5-AS1/miR-34a/Sirt1/NF-κB axis.","date":"2022","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36577153","citation_count":18,"is_preprint":false},{"pmid":"37292517","id":"PMC_37292517","title":"OIP5 Interacts with NCK2 to Mediate Human Spermatogonial Stem Cell Self-Renewal and Apoptosis through Cell Cyclins and Cycle Progression and Its Abnormality Is Correlated with Male Infertility.","date":"2023","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/37292517","citation_count":17,"is_preprint":false},{"pmid":"32200014","id":"PMC_32200014","title":"OIP5-AS1 Attenuates Microangiopathy in Diabetic Mouse by Regulating miR-200b/ACE2.","date":"2020","source":"World neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/32200014","citation_count":16,"is_preprint":false},{"pmid":"32833899","id":"PMC_32833899","title":"Long Noncoding RNA OIP5-AS1 Contributes to the Progression of Atherosclerosis by Targeting miR-26a-5p Through the AKT/NF-κB Pathway.","date":"2020","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32833899","citation_count":16,"is_preprint":false},{"pmid":"33760168","id":"PMC_33760168","title":"Long non‑coding RNA OIP5‑AS1 facilitates the progression of ovarian cancer via the miR‑128‑3p/CCNG1 axis.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/33760168","citation_count":16,"is_preprint":false},{"pmid":"30815864","id":"PMC_30815864","title":"Integrative analysis of OIP5-AS1/HUR1 to discover new potential biomarkers and therapeutic targets in multiple sclerosis.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30815864","citation_count":16,"is_preprint":false},{"pmid":"32147682","id":"PMC_32147682","title":"LncRNA OIP5-AS1 facilitates gastric cancer cell growth by targeting the miR-422a/ANO1 axis.","date":"2020","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/32147682","citation_count":15,"is_preprint":false},{"pmid":"35168644","id":"PMC_35168644","title":"Long non-coding RNA OIP5-AS1 suppresses microRNA-92a to augment proliferation and metastasis of ovarian cancer cells through upregulating ITGA6.","date":"2022","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/35168644","citation_count":15,"is_preprint":false},{"pmid":"31897120","id":"PMC_31897120","title":"Linc-OIP5 loss regulates migration and invasion in MDA-MB-231 breast cancer cells by inhibiting YAP1/JAG1 signaling.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31897120","citation_count":15,"is_preprint":false},{"pmid":"39485791","id":"PMC_39485791","title":"Lipid Nanoparticle-Mediated Oip5-as1 Delivery Preserves Mitochondrial Function in Myocardial Ischemia/Reperfusion Injury by Inhibiting the p53 Pathway.","date":"2024","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/39485791","citation_count":14,"is_preprint":false},{"pmid":"30541307","id":"PMC_30541307","title":"Expression Analysis of OIP5-AS1 in Non-Small Cell Lung Cancer.","date":"2018","source":"Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti","url":"https://pubmed.ncbi.nlm.nih.gov/30541307","citation_count":14,"is_preprint":false},{"pmid":"36460840","id":"PMC_36460840","title":"OIP5-AS1 Inhibits Oxidative Stress and Inflammation in Ischemic Stroke Through miR-155-5p/IRF2BP2 Axis.","date":"2022","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/36460840","citation_count":14,"is_preprint":false},{"pmid":"32943988","id":"PMC_32943988","title":"OIP5-AS1 contributes to tumorigenesis in hepatocellular carcinoma by miR-300/YY1-activated WNT pathway.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32943988","citation_count":13,"is_preprint":false},{"pmid":"34261477","id":"PMC_34261477","title":"Long non-coding RNA OIP5-AS1 aggravates acute lung injury by promoting inflammation and cell apoptosis via regulating the miR-26a-5p/TLR4 axis.","date":"2021","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34261477","citation_count":13,"is_preprint":false},{"pmid":"32519534","id":"PMC_32519534","title":"LncRNA OIP5-AS1 induces epithelial-to-mesenchymal transition and renal fibrosis in diabetic nephropathy via binding to miR-30c-5p.","date":"2020","source":"Journal of biological regulators and homeostatic agents","url":"https://pubmed.ncbi.nlm.nih.gov/32519534","citation_count":13,"is_preprint":false},{"pmid":"34419049","id":"PMC_34419049","title":"OIP5-AS1 contributes to the development in endometrial carcinoma cells by targeting miR-152-3p to up-regulate SLC7A5.","date":"2021","source":"Cancer cell 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-410-3p/IL-13.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34872453","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":57434,"output_tokens":5638,"usd":0.128436,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14209,"output_tokens":5438,"usd":0.103498,"stage2_stop_reason":"end_turn"},"total_usd":0.231934,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Knockdown of OIP5 (protein-coding gene) by siRNA resulted in growth inhibition of colorectal and gastric cancer cell lines with increased sub-G1 DNA content, suggesting OIP5 promotes cell survival and its loss induces apoptosis.\",\n      \"method\": \"siRNA knockdown, flow cytometry, growth inhibition assays\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype (growth inhibition, sub-G1 accumulation), single lab, single study\",\n      \"pmids\": [\"20510019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OIP5 protein activates AKT signaling via both mTORC2 and p38/PTEN; AKT activation links to mTORC1 (cell growth) and GSK-3β/β-catenin (metastasis) signaling in hepatocellular carcinoma. miR-15b-5p targets OIP5 and inhibits these downstream oncogenic signals.\",\n      \"method\": \"Proteome kinase profiling, shRNA knockdown, orthotopic mouse model, miRNA PCR array\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase profiling plus in vivo orthotopic model and miRNA array, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28184024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OIP5 protein is downstream of E2F1 transcription factor (E2F1 activates OIP5 expression by binding its promoter), and OIP5 in turn stabilizes and maintains E2F1 signaling in a positive feedback loop, promoting cell cycle progression in glioblastoma.\",\n      \"method\": \"Immunoprecipitation, chromatin immunoprecipitation (ChIP), luciferase assays, shRNA knockdown, orthotopic tumor model\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm E2F1 binding to OIP5 promoter; reciprocal feedback supported by IP and in vivo model; single lab\",\n      \"pmids\": [\"29547938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OIP5 protein promotes growth, migration, and cisplatin resistance in bladder cancer cells; knockdown reduces colony formation, migration, and sensitizes cells to cisplatin. RNA-seq identified 38 DEGs including TOP2A, SPAG5, SKA1, EXO1, TK1 as downstream effectors.\",\n      \"method\": \"shRNA knockdown, scratch/transwell assays, cisplatin sensitivity assay, RNA-seq, in vivo xenograft\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO/KD with defined phenotype and RNA-seq, single lab\",\n      \"pmids\": [\"30588253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OIP5 protein interacts directly with NCK2 (as shown by Co-IP, IP-MS, and GST pulldown), and this interaction mediates human spermatogonial stem cell self-renewal and apoptosis through regulation of cell cycle proteins including cyclins A2, B1, D1, E1 and H.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), IP-MS (mass spectrometry), GST pulldown, siRNA knockdown, flow cytometry, whole-exome sequencing\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct physical interaction confirmed by three independent methods (Co-IP, IP-MS, GST pulldown); functional rescue experiments; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"37292517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"lncRNA OIP5-AS1 (cyrano) suppresses cell proliferation by reducing GAK mRNA stability and GAK protein abundance; silencing OIP5-AS1 causes aberrant mitotic spindles (monopolar, multipolar, misaligned) that are partly rescued by simultaneous GAK silencing, placing OIP5-AS1 upstream of GAK in mitotic regulation.\",\n      \"method\": \"RNA pulldown of OIP5-AS1-bound mRNAs, proteomics of differentially expressed proteins upon OIP5-AS1 silencing, mRNA stability assay, siRNA double knockdown rescue, immunofluorescence of mitotic spindles\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (pulldown, proteomics, stability assay) plus epistasis rescue experiment; mechanism clearly established in single rigorous study\",\n      \"pmids\": [\"28472763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"lncRNA OIP5-AS1 binds the RNA-binding protein HuR, which stabilizes OIP5-AS1; high OIP5-AS1 levels sequester HuR away from its target mRNAs (encoding proliferative proteins), acting as a competing endogenous RNA sponge for HuR. miR-424 competes with HuR for OIP5-AS1 binding.\",\n      \"method\": \"MS2-hairpin tagging of OIP5-AS1 to identify associated miRNAs, RIP, RNA pulldown, HuR-target mRNA interaction assays upon OIP5-AS1 modulation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — MS2-tagging, RIP, and mRNA interaction assays with modulation experiments; multiple orthogonal methods in single rigorous study establishing the HuR sponge mechanism\",\n      \"pmids\": [\"26819413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"During human myogenesis, lncRNA OIP5-AS1 binds miR-7 and induces its decay via target RNA-directed miRNA decay (TDMD); this OIP5-AS1-mediated miR-7 degradation de-represses the miR-7 target MYMX mRNA (encoding fusogenic protein myomixer), promoting myoblast fusion into myotubes. An oligonucleotide site blocker that prevents OIP5-AS1-directed miR-7 decay allowed miR-7 to accumulate and suppressed myotube formation.\",\n      \"method\": \"qRT-PCR of OIP5-AS1 and miR-7 levels during myogenesis, siRNA/antagonist functional assays, oligonucleotide site blocker, MYMX luciferase reporter, myotube formation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — TDMD mechanism established with multiple orthogonal approaches (site blocker, antagonists, reporter assays, functional myotube readout) in single rigorous study\",\n      \"pmids\": [\"35736212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of OIP5-AS1 (global CRISPR knockout) in female but not male mice leads to exacerbated heart failure following cardiac pressure overload (transverse aortic constriction); RNA-sequencing suggests OIP5-AS1 regulates pathways impacting mitochondrial function in a sex-specific manner.\",\n      \"method\": \"CRISPR knockout mice, transverse aortic constriction model, cardiac function assessment, RNA-sequencing\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean CRISPR KO with defined in vivo cardiac phenotype and transcriptomic pathway analysis; sex-specific finding replicated in multiple animals\",\n      \"pmids\": [\"34142046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"lncRNA Oip5-as1 selectively interacts with AKAP1 and calcineurin (CaN) proteins; by binding CaN, Oip5-as1 inhibits CaN activation and thereby prevents DRP1 dephosphorylation at Ser637, blocking DRP1 translocation to mitochondria and reducing excessive mitochondrial fission during myocardial ischemia/reperfusion injury.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), CRISPR/Cas9 conditional knockout mice, AAV9 overexpression, immunofluorescence, Western blot, echocardiography\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct protein-RNA interaction confirmed by pulldown, RIP and Co-IP; causal mechanism validated in both KO and overexpression in vivo models with functional cardiac readouts\",\n      \"pmids\": [\"38745296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Oip5-as1 delivery via lipid nanoparticles inhibits the p53 signaling pathway in cardiomyocytes, preserving mitochondrial function and reducing myocardial infarct size after ischemia/reperfusion injury; cardioprotective effects are abrogated by the p53 activator Nutlin-3a.\",\n      \"method\": \"Lipid nanoparticle delivery, H/R cell model and murine MI/R model, pharmacological rescue with Nutlin-3a, echocardiography\",\n      \"journal\": \"ACS applied materials & interfaces\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro models with pharmacological epistasis (Nutlin-3a rescue); single lab, mechanism (p53 inhibition) inferred from pathway rather than direct binding\",\n      \"pmids\": [\"39485791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA OIP5-AS1 (Oip5-as1) acts as a competing endogenous RNA for miR-29a; by sponging miR-29a, OIP5-AS1 de-represses SIRT1 expression and activates the AMPK/PGC1α pathway, reducing mitochondria-mediated apoptosis during myocardial ischemia/reperfusion injury.\",\n      \"method\": \"Dual-luciferase reporter assay, RIP assay, miR-29a overexpression rescue, SIRT1 inhibitor (EX527) rescue, rat MI/R model and H9c2 OGD/R model\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase and RIP confirm sponging; pharmacological and miRNA rescue experiments establish pathway placement; single lab\",\n      \"pmids\": [\"32468629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"lncRNA OIP5-AS1 binds EZH2 (a PRC2 component) and recruits it to the GSK-3β promoter region, leading to epigenetic silencing of GSK-3β expression; ChIP confirmed EZH2 direct binding to the GSK-3β promoter upon OIP5-AS1 overexpression, accelerating ox-LDL-mediated endothelial cell apoptosis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), OIP5-AS1 silencing/rescue experiments, Western blot\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly confirms EZH2 binding to GSK-3β promoter; functional rescue validates pathway; single lab, single study\",\n      \"pmids\": [\"30972206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"lncRNA OIP5-AS1 binds EZH2 and epigenetically silences NLRP6 expression in gastric cancer cells; OIP5-AS1 was found to localize predominantly in the nucleus, consistent with its role in chromatin-based gene silencing.\",\n      \"method\": \"Nuclear/cytoplasmic fractionation (OIP5-AS1 nuclear localization), RIP assay (OIP5-AS1–EZH2 interaction), qRT-PCR and functional assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — nuclear localization confirmed by fractionation; EZH2 binding by RIP; downstream NLRP6 silencing assayed; single lab\",\n      \"pmids\": [\"31219209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA OIP5-AS1 located in the nucleus of hepatoblastoma cells targets miR-186a-5p (confirmed by RIP and dual luciferase assay) and thereby up-regulates ZEB1, an miR-186a-5p target gene, promoting EMT, proliferation and metastasis.\",\n      \"method\": \"Nuclear separation experiment (subcellular localization), RIP assay, dual luciferase assay, rescue assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — nuclear localization confirmed by fractionation; sponging confirmed by RIP and luciferase; single lab\",\n      \"pmids\": [\"29475118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"N6-methyladenosine (m6A) modification on lncRNA OIP5-AS1 enables binding by IGF2BP3, which stabilizes OIP5-AS1 (RNA pulldown and RIP confirmed). OIP5-AS1 in turn prevents Trim21-mediated ubiquitination and degradation of hnRNPA1, stabilizing hnRNPA1 protein to promote PKM2 signaling and glycolysis in gastric cancer.\",\n      \"method\": \"RNA pulldown assay, RNA immunoprecipitation (RIP), ubiquitination assay, patient-derived xenograft models, Western blot\",\n      \"journal\": \"Gastric cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — m6A-IGF2BP3 interaction confirmed by pulldown and RIP; Trim21-hnRNPA1 ubiquitination mechanism established biochemically; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"37897508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"lncRNA OIP5-AS1 positively regulates cell proliferation by promoting G2/M phase progression in HeLa cells; silencing OIP5-AS1 with siRNA or antisense oligonucleotides causes G2/M arrest without inducing apoptosis.\",\n      \"method\": \"siRNA and antisense oligonucleotide knockdown, cell cycle analysis by flow cytometry, apoptosis analysis\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cell-cycle phenotype using two independent silencing approaches; single lab, single study\",\n      \"pmids\": [\"29277759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Exosome-derived lncRNA OIP5-AS1 (from M2 microglia) binds TXNIP protein and recruits the E3 ubiquitin ligase ITCH to promote TXNIP ubiquitination and proteasomal degradation, reducing TXNIP protein (but not mRNA) levels and inhibiting neuronal pyroptosis after cerebral ischemia/reperfusion injury.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), ubiquitination assay, MCAO/R mouse model and OGD/R cell model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct OIP5-AS1–TXNIP interaction and ITCH recruitment confirmed by pulldown, RIP and Co-IP; ubiquitination and degradation mechanism validated biochemically; in vivo model corroborates\",\n      \"pmids\": [\"38103409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA OIP5-AS1 promotes cataract formation under oxidative stress by acting through HuR: HuR functions as a scaffold that carries both OIP5-AS1 and POLG mRNA, mediating decay of POLG mRNA; reduced POLG lowers mtDNA copy number and mitochondrial membrane potential, increasing ROS and apoptosis of lens epithelial cells. TFAP2A binds the OIP5-AS1 promoter and drives its expression.\",\n      \"method\": \"Ribonucleoprotein immunoprecipitation (RIP)-qPCR (OIP5-AS1–HuR–POLG mRNA complex), chromatin immunoprecipitation (ChIP)-qPCR (TFAP2A at OIP5-AS1 promoter), POLG overexpression rescue, JC-1 staining, flow cytometry, ex vivo cataract model\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — RIP confirms ternary complex; ChIP confirms upstream transcription factor; POLG rescue validates pathway; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"33006594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SUMOylation of IGF2BP2 at K497/K505/K509 (reducible by SENP1) increases IGF2BP2 protein stability by blocking ubiquitin-proteasome degradation; SUMOylated IGF2BP2 enhances stability of lncRNA OIP5-AS1, thereby increasing OIP5-AS1 sponging of miR-495-3p, de-repressing HIF1A and MMP14 and promoting vasculogenic mimicry in glioma.\",\n      \"method\": \"Ni2+-NTA agarose bead pulldown, Co-IP, in vitro SUMOylation assay, immunoprecipitation, immunofluorescence, RIP and luciferase reporter assays, nude mouse xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro SUMOylation assay plus multiple pulldown/IP methods define SUMO modification sites and stability mechanism; functional consequence confirmed in vivo; rigorous single study\",\n      \"pmids\": [\"34345216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL14 suppresses PTC cell proliferation and migration by binding to and inhibiting lncRNA OIP5-AS1 expression (confirmed by RIP and RNA pulldown); OIP5-AS1 in turn acts as a sponge for miR-98 to up-regulate ADAMTS8, activating EGFR and MEK/ERK pathways.\",\n      \"method\": \"RIP assay, RNA pulldown assay, luciferase reporter assay, siRNA/overexpression functional assays, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and pulldown confirm METTL14–OIP5-AS1 interaction; ceRNA axis validated by luciferase; single lab, multiple methods\",\n      \"pmids\": [\"34131102\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OIP5 protein promotes cell proliferation by interacting with NCK2 (confirmed by Co-IP/pulldown), activating AKT/mTORC1 and GSK-3β/β-catenin signaling, and participating in an E2F1 positive-feedback loop; its antisense lncRNA OIP5-AS1 (cyrano) operates as a multifunctional noncoding regulator that (1) sequesters HuR protein away from pro-proliferative target mRNAs, (2) suppresses GAK mRNA stability to prevent aberrant mitosis, (3) drives miR-7 decay via TDMD to promote MYMX-dependent myoblast fusion, (4) binds AKAP1/calcineurin to block DRP1 dephosphorylation and excessive mitochondrial fission, (5) recruits EZH2 to epigenetically silence target genes, (6) stabilizes hnRNPA1 by blocking Trim21-mediated ubiquitination, and (7) recruits the E3 ligase ITCH to ubiquitinate and degrade TXNIP, with context-specific ceRNA activity sponging dozens of miRNAs across cancer, cardiac, and neurological settings.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The OIP5 locus encodes two functionally distinct products: a protein-coding OIP5 transcript that acts as a pro-proliferative oncoprotein, and the antisense long noncoding RNA OIP5-AS1, a multifunctional regulator of RNA stability, miRNA decay, epigenetic silencing, and protein turnover [#0, #6]. The OIP5 protein promotes cell survival and cell-cycle progression across colorectal, gastric, hepatocellular, bladder, and glioblastoma cells, where its loss induces growth inhibition and sub-G1 accumulation [#0, #3]. Mechanistically, OIP5 protein activates AKT signaling through mTORC2 and p38/PTEN, feeding into mTORC1-driven growth and GSK-3\\u03b2/\\u03b2-catenin-driven metastasis [#1], operates in a positive-feedback loop with the E2F1 transcription factor that binds the OIP5 promoter [#2], and engages NCK2 in a direct physical interaction (Co-IP, IP-MS, GST pulldown) that governs spermatogonial stem cell self-renewal via cyclin regulation [#4]. The antisense lncRNA OIP5-AS1 controls gene expression through several biochemically distinct routes: it binds and sequesters the RNA-binding protein HuR to modulate the stability of HuR target mRNAs, including reducing GAK mRNA stability to safeguard mitotic spindle integrity and mediating POLG mRNA decay under oxidative stress [#5, #6, #18]; it directs target RNA-directed decay of miR-7 to de-repress the fusogen MYMX during myogenesis [#7]; it recruits the PRC2 component EZH2 to promoters for epigenetic silencing [#12]; and it controls protein turnover by blocking Trim21-mediated ubiquitination of hnRNPA1 and by recruiting the E3 ligase ITCH to degrade TXNIP [#15, #17]. In the heart, OIP5-AS1 binds AKAP1/calcineurin to prevent DRP1 dephosphorylation and excessive mitochondrial fission, and its loss exacerbates pressure-overload heart failure in a sex-specific manner [#8, #9]. OIP5-AS1 stability is itself controlled by m6A-dependent IGF2BP3 binding and by SUMOylated IGF2BP2 [#15, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that the OIP5 protein-coding gene is required for cancer cell survival, framing it as a candidate oncogene rather than a passenger.\",\n      \"evidence\": \"siRNA knockdown with flow cytometry and growth assays in colorectal and gastric cancer lines\",\n      \"pmids\": [\"20510019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partner or signaling pathway identified\", \"Mechanism of apoptosis induction unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected OIP5 protein to defined oncogenic signaling, showing it activates AKT via mTORC2 and p38/PTEN to drive growth and metastasis programs.\",\n      \"evidence\": \"Kinase profiling, shRNA, orthotopic mouse model and miRNA array in hepatocellular carcinoma\",\n      \"pmids\": [\"28184024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between OIP5 and the kinases not shown\", \"How OIP5 activates these kinases mechanistically is unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed OIP5 protein in a transcriptional circuit by showing E2F1 drives its expression and OIP5 reciprocally stabilizes E2F1, creating a proliferative feedback loop.\",\n      \"evidence\": \"ChIP, luciferase, IP, shRNA and orthotopic tumor model in glioblastoma\",\n      \"pmids\": [\"29547938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which OIP5 stabilizes E2F1 not defined\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the first validated direct protein partner of OIP5, NCK2, linking the interaction to stem cell self-renewal and cyclin control.\",\n      \"evidence\": \"Co-IP, IP-MS and GST pulldown with functional assays in human spermatogonial stem cells\",\n      \"pmids\": [\"37292517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the OIP5\\u2013NCK2 interaction unknown\", \"How the interaction connects to the AKT/E2F1 axes not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the antisense lncRNA OIP5-AS1 as an HuR-binding RNA that sequesters HuR from its target mRNAs, establishing a protein-sponge mode of action.\",\n      \"evidence\": \"MS2-tagging, RIP, RNA pulldown and HuR-target interaction assays\",\n      \"pmids\": [\"26819413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of affected HuR targets not enumerated\", \"Stoichiometry of HuR sequestration unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed OIP5-AS1 controls mitotic fidelity by destabilizing GAK mRNA, with epistasis rescue placing it upstream of GAK in spindle regulation.\",\n      \"evidence\": \"RNA pulldown, proteomics, mRNA stability assay, double-knockdown rescue and spindle immunofluorescence\",\n      \"pmids\": [\"28472763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GAK destabilization is HuR-dependent not directly tested\", \"Other mitotic targets not excluded\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated nuclear OIP5-AS1 acts as a ceRNA for miR-186a-5p to upregulate ZEB1, supporting a cytoplasmic/nuclear miRNA-sponge function in cancer.\",\n      \"evidence\": \"Nuclear fractionation, RIP, dual luciferase and rescue assays in hepatoblastoma\",\n      \"pmids\": [\"29475118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ceRNA stoichiometry not quantified\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established an epigenetic silencing mode in which OIP5-AS1 binds EZH2 and guides it to specific promoters (GSK-3\\u03b2, NLRP6); nuclear localization corroborated the chromatin role.\",\n      \"evidence\": \"ChIP, RIP, nuclear/cytoplasmic fractionation and functional rescue in endothelial and gastric cancer cells\",\n      \"pmids\": [\"30972206\", \"31219209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How OIP5-AS1 confers promoter specificity unknown\", \"PRC2 recruitment generality across genes untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the HuR mechanism to mitochondrial maintenance, showing OIP5-AS1 and POLG mRNA share HuR as a scaffold so OIP5-AS1 promotes POLG decay and oxidative damage in lens cells, with TFAP2A as an upstream driver.\",\n      \"evidence\": \"RIP-qPCR of the ternary complex, ChIP, POLG rescue and ex vivo cataract model\",\n      \"pmids\": [\"33006594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of POLG regulation in other tissues untested\", \"Quantitative balance between HuR sequestration and scaffolding unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed OIP5-AS1 protects cardiomyocytes by sponging miR-29a to de-repress SIRT1 and activate AMPK/PGC1\\u03b1, framing a cardioprotective ceRNA axis.\",\n      \"evidence\": \"Dual-luciferase, RIP, miR-29a and SIRT1-inhibitor rescue in rat MI/R and H9c2 models\",\n      \"pmids\": [\"32468629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous miR-29a sponging stoichiometry unquantified\", \"Single signaling output measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined how OIP5-AS1 levels are set post-transcriptionally, showing m6A-dependent IGF2BP3 binding and SUMOylated IGF2BP2 each stabilize the lncRNA.\",\n      \"evidence\": \"RNA pulldown, RIP, in vitro SUMOylation assay and xenografts in gastric cancer and glioma\",\n      \"pmids\": [\"37897508\", \"34345216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each stabilizer in vivo unclear\", \"Whether the two pathways act in the same cells untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed OIP5-AS1 controls protein turnover, blocking Trim21-mediated ubiquitination of hnRNPA1 to sustain PKM2-driven glycolysis.\",\n      \"evidence\": \"RNA pulldown, RIP, ubiquitination assay and patient-derived xenografts in gastric cancer\",\n      \"pmids\": [\"37897508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface with hnRNPA1/Trim21 not mapped\", \"Whether this is gastric-cancer specific unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed OIP5-AS1 supports proliferation through G2/M progression independent of apoptosis, and identified METTL14 as a negative upstream regulator feeding a miR-98/ADAMTS8/EGFR ceRNA axis.\",\n      \"evidence\": \"siRNA/ASO knockdown with cell-cycle analysis; RIP, pulldown, luciferase and xenografts in papillary thyroid cancer\",\n      \"pmids\": [\"29277759\", \"34131102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between G2/M control and named axes not unified\", \"Single-context ceRNA validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated OIP5-AS1 actively degrades a specific miRNA via TDMD, driving miR-7 decay to de-repress the fusogen MYMX during myoblast fusion.\",\n      \"evidence\": \"qRT-PCR, oligonucleotide site blocker, MYMX luciferase reporter and myotube formation assays in human myogenesis\",\n      \"pmids\": [\"35736212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TDMD machinery components recruited by OIP5-AS1 not identified\", \"Whether TDMD operates in non-muscle contexts untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a physiological in vivo role for OIP5-AS1 in the heart, with global knockout worsening pressure-overload heart failure selectively in females via mitochondrial pathways.\",\n      \"evidence\": \"CRISPR knockout mice, transverse aortic constriction and RNA-seq\",\n      \"pmids\": [\"34142046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of sex specificity unresolved\", \"Direct effector linking knockout to mitochondrial defects not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed OIP5-AS1 can act as a protein scaffold for an E3 ligase, recruiting ITCH to ubiquitinate and degrade TXNIP and thereby suppress neuronal pyroptosis after cerebral ischemia.\",\n      \"evidence\": \"RNA pulldown, RIP, Co-IP, ubiquitination assay and MCAO/R mouse and OGD/R cell models\",\n      \"pmids\": [\"38103409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interfaces among OIP5-AS1, ITCH and TXNIP not mapped\", \"Generality beyond the neuronal/exosome context untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a mitochondrial-fission control mechanism in which Oip5-as1 binds calcineurin to prevent DRP1 Ser637 dephosphorylation, limiting fission during ischemia/reperfusion injury.\",\n      \"evidence\": \"RNA pulldown, RIP, Co-IP, conditional CRISPR knockout and AAV9 overexpression with echocardiography\",\n      \"pmids\": [\"38745296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of AKAP1 binding versus calcineurin binding not fully separated\", \"Direct effect on calcineurin catalytic activity not biochemically isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether the OIP5 protein and its antisense lncRNA OIP5-AS1 are functionally coupled within the same cells, and how the many context-specific OIP5-AS1 mechanisms (HuR sponging, TDMD, EZH2 silencing, E3-ligase scaffolding, calcineurin binding) are selected in a given tissue.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No study integrates OIP5 protein and OIP5-AS1 functions in one system\", \"Determinants of which OIP5-AS1 mechanism dominates per cell type unknown\", \"No structural models for any OIP5/OIP5-AS1 interaction\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 7, 9, 12, 17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [17, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 16]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 17]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NCK2\", \"HuR\", \"EZH2\", \"AKAP1\", \"calcineurin\", \"ITCH\", \"hnRNPA1\", \"IGF2BP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"OIP5","tier":"IDENTITY","verdict":"Identity concern","subtype":"alt_product","uniprot_band":"sparse","rules_fired":"R4","issue":"R4: alt-product term(s) in opening sentences"},"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}