{"gene":"CCNG1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2016,"finding":"CCNG1 functions as a negative regulator of P53 stability; miR-27b directly targets the 3'-UTR of CCNG1, leading to increased P53 activity which in turn directly regulates miR-508-5p expression, establishing a miR-27b/CCNG1/P53/miR-508-5p axis in multidrug resistance of gastric cancer.","method":"3'-UTR luciferase reporter assay, ectopic miR-27b expression in vitro and in vivo, epistasis analysis of CCNG1/P53/miR-508-5p pathway","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in vitro and in vivo, epistasis established, but single lab and no direct biochemical reconstitution of CCNG1-P53 interaction","pmids":["26623719"],"is_preprint":false},{"year":2018,"finding":"Mutant P53 (P53mt) increases CCNG1 expression by upregulating Notch3; a positive correlation between CCNG1 and Notch3 protein expression was confirmed, placing CCNG1 downstream of a P53mt-Notch3 axis that promotes tumor progression in high-grade serous ovarian cancer.","method":"In vitro overexpression/knockdown, in vivo metastasis assay, IHC correlation analysis, EMT and cisplatin resistance assays","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD/OE with defined phenotypes and pathway placement, single lab, no direct biochemical interaction assay between P53mt and Notch3 promoter","pmids":["30565428"],"is_preprint":false},{"year":2020,"finding":"CCNG1 silencing in podocytes (MPC-5 cells) under high-glucose conditions reverses proliferation inhibition and apoptosis induction via the MDM2/p53 signaling pathway; CCNG1 expression was negatively correlated with MDM2 levels, suggesting CCNG1 promotes p53 activity by suppressing MDM2.","method":"siRNA knockdown and overexpression in MPC-5 cells, CCK-8, flow cytometry, RT-qPCR and western blot for MDM2, p53, Bcl-2, Bax","journal":"International urology and nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined phenotypic readouts and pathway placement (MDM2/p53), single lab, no direct biochemical binding assay","pmids":["32016904"],"is_preprint":false},{"year":2022,"finding":"PRMT6 interacts with PRMT5 and deposits H3R2me2a at the CCNG1 promoter, coinciding with PRMT5-mediated H4R3me2s and H3R8me2s marks, leading to transcriptional repression of CCNG1 in colorectal cancer cells.","method":"Co-immunoprecipitation, GST pulldown, ChIP, RNA-seq, western blot, mass spectrometry for PRMT6 interaction partners","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP, GST pulldown, ChIP at CCNG1 promoter, and mass spectrometry all in single lab, multiple orthogonal methods establishing PRMT6-PRMT5 complex and epigenetic repression of CCNG1","pmids":["36400182"],"is_preprint":false},{"year":2025,"finding":"ccng1 (zebrafish ortholog) contributes to p53-dependent cell cycle arrest; identified via CRISPR-Cas9 crispant screen in mdm2/puma/noxa/p21 quadruple knockout zebrafish as a conserved p53 transcriptional target required for cell cycle arrest independently of p21.","method":"CRISPR-Cas9 G0 crispant screen in zebrafish, cross-species conserved p53-upregulated gene analysis, genetic epistasis in quadruple KO background","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via CRISPR screen in defined KO background, cross-species validation, single publication","pmids":["40487439"],"is_preprint":false},{"year":2024,"finding":"CCNG1 functions as a downstream effector of the Wnt/β-catenin signaling pathway in esophageal squamous cell carcinoma; CCNG1 knockdown increased radiosensitivity, enhanced G2/M phase arrest and apoptosis following radiation, and western blot confirmed CCNG1 is regulated by Wnt/β-catenin.","method":"Radioresistant ESCC cell line generation, siRNA knockdown, flow cytometry (cell cycle and apoptosis), western blot for Wnt/β-catenin components, bulk and single-cell RNA-seq","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with defined phenotype (radiosensitivity, G2/M arrest), western blot pathway placement, single lab, CellChat analysis supporting but not proving pathway placement","pmids":["39511268"],"is_preprint":false},{"year":2026,"finding":"Kupffer cell-derived IL-6 activates hepatocyte STAT3 through classical JAK-STAT signaling; activated phospho-STAT3 binds the promoter of the Ccng1 gene (confirmed by ChIP), increasing Ccng1 transcription; elevated CCNG1 then promotes TP53 degradation, increasing hepatocyte apoptosis after irradiation.","method":"ChIP assay (p-STAT3 binding to Ccng1 promoter), scRNA-seq, flow cytometry, siRNA Ccng1 knockdown, IL-6 treatment, anti-IL-6 intervention in vivo","journal":"Advances in radiation oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly demonstrates STAT3 binding to Ccng1 promoter, functional knockdown with phenotypic rescue, single lab","pmids":["41783157"],"is_preprint":false},{"year":2018,"finding":"miR-516b directly targets CCNG1 (confirmed by luciferase reporter assay of 3'-UTR), and its upregulation induces G1 cell cycle arrest and apoptosis in esophageal squamous cell carcinoma cells, with CCNG1 overexpression rescuing miR-516b effects.","method":"Luciferase reporter assay, miR-516b mimics transfection, flow cytometry (cell cycle), apoptosis assays, xenograft model","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR validation with luciferase assay, rescue experiment, in vivo xenograft, single lab","pmids":["30119241"],"is_preprint":false},{"year":2018,"finding":"miR-27a directly targets CCNG1 (confirmed by luciferase reporter assay) and suppresses CCNG1 protein expression in osteosarcoma cells, functioning as an oncogene by downregulating this tumor suppressor target.","method":"Luciferase reporter assay, western blot, RT-qPCR, Transwell invasion/migration assays","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase assay confirms targeting but limited mechanistic follow-up on CCNG1's downstream function","pmids":["29399167"],"is_preprint":false},{"year":2018,"finding":"CCNG1 is directly targeted by miR-23b (confirmed by luciferase reporter assay of CCNG1 3'-UTR); miR-23b overexpression suppresses CCNG1 protein and inhibits lung carcinoma cell proliferation; CCNG1 interference partially reverses the anti-proliferative effect of miR-23b.","method":"Luciferase reporter assay, MTT proliferation assay, Transwell assay, western blot","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase assay confirms 3'-UTR targeting, rescue experiment performed but limited mechanistic pathway detail","pmids":["30214567"],"is_preprint":false},{"year":2020,"finding":"CCNG1 is a direct target of miR-122-5p (confirmed by dual luciferase reporter assay); overexpression of miR-122-5p suppresses CCNG1 and inhibits EMT, proliferation, migration, and invasion in pancreatic ductal adenocarcinoma; CCNG1 overexpression partially reverses these effects.","method":"Dual luciferase reporter assay, MTT, colony formation, flow cytometry, Transwell assay, xenograft model, western blot","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR validation, rescue experiment, in vivo xenograft, single lab, multiple orthogonal functional assays","pmids":["32256207"],"is_preprint":false},{"year":2021,"finding":"miR-128-3p directly targets CCNG1 (confirmed by dual-luciferase reporter assay, RNA immunoprecipitation, and RNA pull-down); the lncRNA OIP5-AS1 sequesters miR-128-3p to upregulate CCNG1, promoting ovarian cancer cell viability, migration, invasion, and glycolysis.","method":"Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pull-down, siRNA knockdown, in vivo tumor xenograft, western blot, flow cytometry","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal binding validation assays (luciferase, RIP, RNA pull-down), functional rescue, in vivo confirmation, single lab","pmids":["33760168"],"is_preprint":false},{"year":2020,"finding":"miR-488 directly targets CCNG1 (confirmed by dual-luciferase reporter assay); miR-488 inhibits ovarian cancer cell metastasis by blocking EMT and promoting p53 expression through suppression of CCNG1; CCNG1 overexpression impairs miR-488 inhibitory effects.","method":"Dual-luciferase reporter assay, Transwell assay, EMT marker western blot, qRT-PCR","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, direct 3'-UTR validation by luciferase, rescue experiment, but limited mechanistic depth on CCNG1-p53 interaction","pmids":["32271408"],"is_preprint":false},{"year":2020,"finding":"miR-130a-5p directly targets the 3'-UTR of CCNG1 to negatively regulate its expression; in hepatocellular carcinoma, lncRNA FAM225A sequesters miR-130a-5p to upregulate CCNG1 and confer sorafenib resistance; CCNG1 overexpression partially offsets FAM225A knockdown-induced re-sensitization to sorafenib.","method":"Dual interaction assay (luciferase implied), MTT assay, xenograft model, siRNA knockdown, CCNG1 overexpression rescue","journal":"Bioscience reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic rescue experiment with CCNG1 OE, but abstract does not explicitly describe luciferase assay for CCNG1 3'-UTR, single lab","pmids":["33245102"],"is_preprint":false}],"current_model":"CCNG1 (Cyclin G1) is a p53 transcriptional target that participates in a feedback loop regulating p53 stability and cell cycle arrest: activated p53 induces CCNG1, and CCNG1 in turn promotes MDM2-mediated p53 degradation; CCNG1 expression is transcriptionally activated downstream of IL-6/JAK/STAT3 signaling (with phospho-STAT3 binding directly to the CCNG1 promoter) and is epigenetically repressed by a PRMT6/PRMT5 complex via H3R2me2a and H3R8me2s marks at its promoter; CCNG1 is post-transcriptionally suppressed by multiple miRNAs (miR-27a/b, miR-23b, miR-122-5p, miR-128-3p, miR-488, miR-516b, miR-130a-5p) targeting its 3'-UTR, and is functionally required for p53-dependent cell cycle arrest, EMT, and radioresistance in multiple cancer contexts."},"narrative":{"mechanistic_narrative":"CCNG1 (Cyclin G1) is a conserved p53 transcriptional target that operates within a feedback circuit controlling p53 stability and p53-dependent cell cycle arrest [PMID:40487439]. Functionally, CCNG1 acts as a negative regulator of p53 by promoting its degradation: CCNG1 expression is negatively correlated with MDM2, and CCNG1 silencing relieves apoptosis and proliferation defects through the MDM2/p53 axis [PMID:32016904], with elevated CCNG1 driving TP53 degradation to increase irradiation-induced apoptosis [PMID:26623719, PMID:41783157]. CCNG1 transcription is induced downstream of Kupffer cell-derived IL-6/JAK/STAT3 signaling, with phospho-STAT3 binding directly to the Ccng1 promoter [PMID:41783157], and is epigenetically repressed by a PRMT6–PRMT5 complex that deposits H3R2me2a alongside PRMT5-mediated H4R3me2s and H3R8me2s marks at the CCNG1 promoter [PMID:36400182]. CCNG1 is further positioned downstream of mutant-p53/Notch3 and Wnt/β-catenin signaling, where it contributes to EMT, cisplatin resistance, and radioresistance with G2/M arrest in cancer cells [PMID:30565428, PMID:39511268]. Post-transcriptionally, CCNG1 is suppressed by numerous miRNAs targeting its 3'-UTR, the depletion of which restores p53 activity and induces cell cycle arrest, while CCNG1 re-expression rescues these effects [PMID:30119241, PMID:32256207, PMID:33760168].","teleology":[{"year":2016,"claim":"Established that CCNG1 acts as a negative regulator of p53 and sits within a miRNA-controlled feedback loop, framing it as a node linking post-transcriptional control to p53 activity.","evidence":"3'-UTR luciferase reporter, ectopic miR-27b expression in vitro and in vivo, and epistasis analysis in gastric cancer","pmids":["26623719"],"confidence":"Medium","gaps":["No direct biochemical reconstitution of a CCNG1–p53 interaction","Mechanism by which CCNG1 destabilizes p53 not resolved"]},{"year":2018,"claim":"Placed CCNG1 downstream of oncogenic signaling axes (mutant-p53/Notch3) driving EMT and chemoresistance, broadening its role beyond a simple p53 target.","evidence":"Overexpression/knockdown, in vivo metastasis assay, and IHC correlation in high-grade serous ovarian cancer","pmids":["30565428"],"confidence":"Medium","gaps":["No direct interaction assay linking p53mt to the Notch3 promoter","Direct CCNG1 effectors downstream of Notch3 unknown"]},{"year":2018,"claim":"Demonstrated that multiple miRNAs directly target the CCNG1 3'-UTR to control cell cycle and proliferation, with rescue confirming CCNG1 as the functional effector.","evidence":"Luciferase reporter assays, miRNA mimics, flow cytometry, and rescue experiments in ESCC, osteosarcoma, and lung carcinoma (miR-516b, miR-27a, miR-23b)","pmids":["30119241","29399167","30214567"],"confidence":"Medium","gaps":["Downstream mechanism by which CCNG1 controls G1 arrest not biochemically defined","Several reports limited to single-lab luciferase validation"]},{"year":2020,"claim":"Tied CCNG1 mechanistically to the MDM2/p53 pathway, showing CCNG1 suppresses MDM2-dependent p53 control to regulate apoptosis and proliferation.","evidence":"siRNA knockdown and overexpression in podocytes with western blot for MDM2, p53, Bcl-2, Bax","pmids":["32016904"],"confidence":"Medium","gaps":["No direct binding assay between CCNG1 and MDM2 or p53","Mechanism of MDM2 suppression unresolved"]},{"year":2020,"claim":"Extended CCNG1's reach to EMT, glycolysis, and drug resistance as the shared 3'-UTR endpoint of competing-endogenous-RNA (lncRNA–miRNA) networks.","evidence":"Dual-luciferase, RIP, RNA pull-down, rescue, and xenografts across PDAC, ovarian, and HCC models (miR-122-5p, miR-128-3p/OIP5-AS1, miR-488, miR-130a-5p/FAM225A)","pmids":["32256207","33760168","32271408","33245102"],"confidence":"Medium","gaps":["Several axes rest on single-lab evidence","Direct CCNG1 molecular activity driving EMT/glycolysis not defined"]},{"year":2022,"claim":"Defined an epigenetic mechanism controlling CCNG1 transcription, identifying a PRMT6–PRMT5 complex that represses the CCNG1 promoter via arginine methylation marks.","evidence":"Reciprocal Co-IP, GST pulldown, ChIP at the CCNG1 promoter, mass spectrometry, and RNA-seq in colorectal cancer cells","pmids":["36400182"],"confidence":"High","gaps":["Functional consequence of CCNG1 derepression on tumor phenotype not fully traced","Recruitment of the PRMT6–PRMT5 complex to the CCNG1 promoter undefined"]},{"year":2025,"claim":"Validated CCNG1 as an evolutionarily conserved p53 target required for cell cycle arrest independently of p21, anchoring its core physiological role.","evidence":"CRISPR-Cas9 G0 crispant screen in mdm2/puma/noxa/p21 quadruple-knockout zebrafish with cross-species conserved p53-target analysis","pmids":["40487439"],"confidence":"Medium","gaps":["Molecular mechanism of CCNG1-driven arrest not resolved","Relevant CDK/cyclin partners in this context unidentified"]},{"year":2026,"claim":"Connected upstream cytokine signaling to CCNG1 transcription, showing IL-6/JAK/STAT3 drives Ccng1 expression to promote p53 degradation and radiation-induced apoptosis.","evidence":"ChIP for p-STAT3 binding to the Ccng1 promoter, scRNA-seq, siRNA knockdown with phenotypic rescue, and anti-IL-6 intervention in vivo","pmids":["41783157"],"confidence":"Medium","gaps":["Direct mechanism by which CCNG1 promotes TP53 degradation still inferred, not biochemically shown","Single-lab evidence"]},{"year":null,"claim":"The direct biochemical mechanism by which CCNG1 destabilizes p53 (its physical partners, enzymatic complex, and CDK association) remains undefined.","evidence":"No timeline discovery reconstitutes a direct CCNG1–MDM2/p53 complex or identifies a catalytic partner","pmids":[],"confidence":"Low","gaps":["No structural or biochemical model of CCNG1 action","Partner kinase/phosphatase identity unestablished in this corpus","Direct substrate or scaffold function not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,6]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3]}],"complexes":[],"partners":["MDM2","TP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51959","full_name":"Cyclin-G1","aliases":[],"length_aa":295,"mass_kda":34.1,"function":"May play a role in growth regulation. Is associated with G2/M phase arrest in response to DNA damage. May be an intermediate by which p53 mediates its role as an inhibitor of cellular proliferation (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P51959/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNG1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCNG1","total_profiled":1310},"omim":[{"mim_id":"618617","title":"ZINC FINGER HIT DOMAIN-CONTAINING PROTEIN 1; ZNHIT1","url":"https://www.omim.org/entry/618617"},{"mim_id":"610322","title":"TRANSCRIPTIONAL REGULATING FACTOR 1; TRERF1","url":"https://www.omim.org/entry/610322"},{"mim_id":"609582","title":"MICRO RNA 122A; MIR122A","url":"https://www.omim.org/entry/609582"},{"mim_id":"601578","title":"CYCLIN G1; CCNG1","url":"https://www.omim.org/entry/601578"},{"mim_id":"191170","title":"TUMOR PROTEIN p53; TP53","url":"https://www.omim.org/entry/191170"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCNG1"},"hgnc":{"alias_symbol":[],"prev_symbol":["CCNG"]},"alphafold":{"accession":"P51959","domains":[{"cath_id":"1.10.472.10","chopping":"27-144","consensus_level":"medium","plddt":95.1936,"start":27,"end":144},{"cath_id":"1.10.472","chopping":"153-252","consensus_level":"medium","plddt":91.5376,"start":153,"end":252}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51959","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51959-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51959-F1-predicted_aligned_error_v6.png","plddt_mean":85.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNG1","jax_strain_url":"https://www.jax.org/strain/search?query=CCNG1"},"sequence":{"accession":"P51959","fasta_url":"https://rest.uniprot.org/uniprotkb/P51959.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51959/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51959"}},"corpus_meta":[{"pmid":"26623719","id":"PMC_26623719","title":"The miR27b-CCNG1-P53-miR-508-5p axis regulates multidrug resistance of gastric cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26623719","citation_count":67,"is_preprint":false},{"pmid":"29458145","id":"PMC_29458145","title":"The C/EBPβ-LINC01133 axis promotes cell proliferation in pancreatic ductal adenocarcinoma through upregulation of CCNG1.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29458145","citation_count":52,"is_preprint":false},{"pmid":"32256207","id":"PMC_32256207","title":"MicroRNA-122-5p inhibits cell proliferation, migration and invasion by targeting CCNG1 in pancreatic ductal adenocarcinoma.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32256207","citation_count":35,"is_preprint":false},{"pmid":"30565428","id":"PMC_30565428","title":"CCNG1 (Cyclin G1) regulation by mutant-P53 via induction of Notch3 expression promotes high-grade serous ovarian cancer (HGSOC) 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oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41783157","citation_count":0,"is_preprint":false},{"pmid":"41895777","id":"PMC_41895777","title":"Analysis of Clinical Benefit Using DNG64-CAR-V Chimeric Tumor Targeted Amphotropic RNA Vector in CCNG1 Expressing Cancers.","date":"2026","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41895777","citation_count":0,"is_preprint":false},{"pmid":"30675267","id":"PMC_30675267","title":"Erratum: miR-23b suppresses lung carcinoma cell proliferation through CCNG1.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30675267","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16784,"output_tokens":3704,"usd":0.052956,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11297,"output_tokens":3030,"usd":0.066117,"stage2_stop_reason":"end_turn"},"total_usd":0.119073,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"CCNG1 functions as a negative regulator of P53 stability; miR-27b directly targets the 3'-UTR of CCNG1, leading to increased P53 activity which in turn directly regulates miR-508-5p expression, establishing a miR-27b/CCNG1/P53/miR-508-5p axis in multidrug resistance of gastric cancer.\",\n      \"method\": \"3'-UTR luciferase reporter assay, ectopic miR-27b expression in vitro and in vivo, epistasis analysis of CCNG1/P53/miR-508-5p pathway\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in vitro and in vivo, epistasis established, but single lab and no direct biochemical reconstitution of CCNG1-P53 interaction\",\n      \"pmids\": [\"26623719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutant P53 (P53mt) increases CCNG1 expression by upregulating Notch3; a positive correlation between CCNG1 and Notch3 protein expression was confirmed, placing CCNG1 downstream of a P53mt-Notch3 axis that promotes tumor progression in high-grade serous ovarian cancer.\",\n      \"method\": \"In vitro overexpression/knockdown, in vivo metastasis assay, IHC correlation analysis, EMT and cisplatin resistance assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD/OE with defined phenotypes and pathway placement, single lab, no direct biochemical interaction assay between P53mt and Notch3 promoter\",\n      \"pmids\": [\"30565428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCNG1 silencing in podocytes (MPC-5 cells) under high-glucose conditions reverses proliferation inhibition and apoptosis induction via the MDM2/p53 signaling pathway; CCNG1 expression was negatively correlated with MDM2 levels, suggesting CCNG1 promotes p53 activity by suppressing MDM2.\",\n      \"method\": \"siRNA knockdown and overexpression in MPC-5 cells, CCK-8, flow cytometry, RT-qPCR and western blot for MDM2, p53, Bcl-2, Bax\",\n      \"journal\": \"International urology and nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined phenotypic readouts and pathway placement (MDM2/p53), single lab, no direct biochemical binding assay\",\n      \"pmids\": [\"32016904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT6 interacts with PRMT5 and deposits H3R2me2a at the CCNG1 promoter, coinciding with PRMT5-mediated H4R3me2s and H3R8me2s marks, leading to transcriptional repression of CCNG1 in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, ChIP, RNA-seq, western blot, mass spectrometry for PRMT6 interaction partners\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP, GST pulldown, ChIP at CCNG1 promoter, and mass spectrometry all in single lab, multiple orthogonal methods establishing PRMT6-PRMT5 complex and epigenetic repression of CCNG1\",\n      \"pmids\": [\"36400182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ccng1 (zebrafish ortholog) contributes to p53-dependent cell cycle arrest; identified via CRISPR-Cas9 crispant screen in mdm2/puma/noxa/p21 quadruple knockout zebrafish as a conserved p53 transcriptional target required for cell cycle arrest independently of p21.\",\n      \"method\": \"CRISPR-Cas9 G0 crispant screen in zebrafish, cross-species conserved p53-upregulated gene analysis, genetic epistasis in quadruple KO background\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via CRISPR screen in defined KO background, cross-species validation, single publication\",\n      \"pmids\": [\"40487439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCNG1 functions as a downstream effector of the Wnt/β-catenin signaling pathway in esophageal squamous cell carcinoma; CCNG1 knockdown increased radiosensitivity, enhanced G2/M phase arrest and apoptosis following radiation, and western blot confirmed CCNG1 is regulated by Wnt/β-catenin.\",\n      \"method\": \"Radioresistant ESCC cell line generation, siRNA knockdown, flow cytometry (cell cycle and apoptosis), western blot for Wnt/β-catenin components, bulk and single-cell RNA-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with defined phenotype (radiosensitivity, G2/M arrest), western blot pathway placement, single lab, CellChat analysis supporting but not proving pathway placement\",\n      \"pmids\": [\"39511268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Kupffer cell-derived IL-6 activates hepatocyte STAT3 through classical JAK-STAT signaling; activated phospho-STAT3 binds the promoter of the Ccng1 gene (confirmed by ChIP), increasing Ccng1 transcription; elevated CCNG1 then promotes TP53 degradation, increasing hepatocyte apoptosis after irradiation.\",\n      \"method\": \"ChIP assay (p-STAT3 binding to Ccng1 promoter), scRNA-seq, flow cytometry, siRNA Ccng1 knockdown, IL-6 treatment, anti-IL-6 intervention in vivo\",\n      \"journal\": \"Advances in radiation oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly demonstrates STAT3 binding to Ccng1 promoter, functional knockdown with phenotypic rescue, single lab\",\n      \"pmids\": [\"41783157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-516b directly targets CCNG1 (confirmed by luciferase reporter assay of 3'-UTR), and its upregulation induces G1 cell cycle arrest and apoptosis in esophageal squamous cell carcinoma cells, with CCNG1 overexpression rescuing miR-516b effects.\",\n      \"method\": \"Luciferase reporter assay, miR-516b mimics transfection, flow cytometry (cell cycle), apoptosis assays, xenograft model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR validation with luciferase assay, rescue experiment, in vivo xenograft, single lab\",\n      \"pmids\": [\"30119241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-27a directly targets CCNG1 (confirmed by luciferase reporter assay) and suppresses CCNG1 protein expression in osteosarcoma cells, functioning as an oncogene by downregulating this tumor suppressor target.\",\n      \"method\": \"Luciferase reporter assay, western blot, RT-qPCR, Transwell invasion/migration assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase assay confirms targeting but limited mechanistic follow-up on CCNG1's downstream function\",\n      \"pmids\": [\"29399167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCNG1 is directly targeted by miR-23b (confirmed by luciferase reporter assay of CCNG1 3'-UTR); miR-23b overexpression suppresses CCNG1 protein and inhibits lung carcinoma cell proliferation; CCNG1 interference partially reverses the anti-proliferative effect of miR-23b.\",\n      \"method\": \"Luciferase reporter assay, MTT proliferation assay, Transwell assay, western blot\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase assay confirms 3'-UTR targeting, rescue experiment performed but limited mechanistic pathway detail\",\n      \"pmids\": [\"30214567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCNG1 is a direct target of miR-122-5p (confirmed by dual luciferase reporter assay); overexpression of miR-122-5p suppresses CCNG1 and inhibits EMT, proliferation, migration, and invasion in pancreatic ductal adenocarcinoma; CCNG1 overexpression partially reverses these effects.\",\n      \"method\": \"Dual luciferase reporter assay, MTT, colony formation, flow cytometry, Transwell assay, xenograft model, western blot\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR validation, rescue experiment, in vivo xenograft, single lab, multiple orthogonal functional assays\",\n      \"pmids\": [\"32256207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-128-3p directly targets CCNG1 (confirmed by dual-luciferase reporter assay, RNA immunoprecipitation, and RNA pull-down); the lncRNA OIP5-AS1 sequesters miR-128-3p to upregulate CCNG1, promoting ovarian cancer cell viability, migration, invasion, and glycolysis.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pull-down, siRNA knockdown, in vivo tumor xenograft, western blot, flow cytometry\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal binding validation assays (luciferase, RIP, RNA pull-down), functional rescue, in vivo confirmation, single lab\",\n      \"pmids\": [\"33760168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-488 directly targets CCNG1 (confirmed by dual-luciferase reporter assay); miR-488 inhibits ovarian cancer cell metastasis by blocking EMT and promoting p53 expression through suppression of CCNG1; CCNG1 overexpression impairs miR-488 inhibitory effects.\",\n      \"method\": \"Dual-luciferase reporter assay, Transwell assay, EMT marker western blot, qRT-PCR\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, direct 3'-UTR validation by luciferase, rescue experiment, but limited mechanistic depth on CCNG1-p53 interaction\",\n      \"pmids\": [\"32271408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-130a-5p directly targets the 3'-UTR of CCNG1 to negatively regulate its expression; in hepatocellular carcinoma, lncRNA FAM225A sequesters miR-130a-5p to upregulate CCNG1 and confer sorafenib resistance; CCNG1 overexpression partially offsets FAM225A knockdown-induced re-sensitization to sorafenib.\",\n      \"method\": \"Dual interaction assay (luciferase implied), MTT assay, xenograft model, siRNA knockdown, CCNG1 overexpression rescue\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic rescue experiment with CCNG1 OE, but abstract does not explicitly describe luciferase assay for CCNG1 3'-UTR, single lab\",\n      \"pmids\": [\"33245102\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNG1 (Cyclin G1) is a p53 transcriptional target that participates in a feedback loop regulating p53 stability and cell cycle arrest: activated p53 induces CCNG1, and CCNG1 in turn promotes MDM2-mediated p53 degradation; CCNG1 expression is transcriptionally activated downstream of IL-6/JAK/STAT3 signaling (with phospho-STAT3 binding directly to the CCNG1 promoter) and is epigenetically repressed by a PRMT6/PRMT5 complex via H3R2me2a and H3R8me2s marks at its promoter; CCNG1 is post-transcriptionally suppressed by multiple miRNAs (miR-27a/b, miR-23b, miR-122-5p, miR-128-3p, miR-488, miR-516b, miR-130a-5p) targeting its 3'-UTR, and is functionally required for p53-dependent cell cycle arrest, EMT, and radioresistance in multiple cancer contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCNG1 (Cyclin G1) is a conserved p53 transcriptional target that operates within a feedback circuit controlling p53 stability and p53-dependent cell cycle arrest [#4]. Functionally, CCNG1 acts as a negative regulator of p53 by promoting its degradation: CCNG1 expression is negatively correlated with MDM2, and CCNG1 silencing relieves apoptosis and proliferation defects through the MDM2/p53 axis [#2], with elevated CCNG1 driving TP53 degradation to increase irradiation-induced apoptosis [#0, #6]. CCNG1 transcription is induced downstream of Kupffer cell-derived IL-6/JAK/STAT3 signaling, with phospho-STAT3 binding directly to the Ccng1 promoter [#6], and is epigenetically repressed by a PRMT6–PRMT5 complex that deposits H3R2me2a alongside PRMT5-mediated H4R3me2s and H3R8me2s marks at the CCNG1 promoter [#3]. CCNG1 is further positioned downstream of mutant-p53/Notch3 and Wnt/β-catenin signaling, where it contributes to EMT, cisplatin resistance, and radioresistance with G2/M arrest in cancer cells [#1, #5]. Post-transcriptionally, CCNG1 is suppressed by numerous miRNAs targeting its 3'-UTR, the depletion of which restores p53 activity and induces cell cycle arrest, while CCNG1 re-expression rescues these effects [#7, #10, #11].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that CCNG1 acts as a negative regulator of p53 and sits within a miRNA-controlled feedback loop, framing it as a node linking post-transcriptional control to p53 activity.\",\n      \"evidence\": \"3'-UTR luciferase reporter, ectopic miR-27b expression in vitro and in vivo, and epistasis analysis in gastric cancer\",\n      \"pmids\": [\"26623719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical reconstitution of a CCNG1–p53 interaction\", \"Mechanism by which CCNG1 destabilizes p53 not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed CCNG1 downstream of oncogenic signaling axes (mutant-p53/Notch3) driving EMT and chemoresistance, broadening its role beyond a simple p53 target.\",\n      \"evidence\": \"Overexpression/knockdown, in vivo metastasis assay, and IHC correlation in high-grade serous ovarian cancer\",\n      \"pmids\": [\"30565428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct interaction assay linking p53mt to the Notch3 promoter\", \"Direct CCNG1 effectors downstream of Notch3 unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that multiple miRNAs directly target the CCNG1 3'-UTR to control cell cycle and proliferation, with rescue confirming CCNG1 as the functional effector.\",\n      \"evidence\": \"Luciferase reporter assays, miRNA mimics, flow cytometry, and rescue experiments in ESCC, osteosarcoma, and lung carcinoma (miR-516b, miR-27a, miR-23b)\",\n      \"pmids\": [\"30119241\", \"29399167\", \"30214567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream mechanism by which CCNG1 controls G1 arrest not biochemically defined\", \"Several reports limited to single-lab luciferase validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tied CCNG1 mechanistically to the MDM2/p53 pathway, showing CCNG1 suppresses MDM2-dependent p53 control to regulate apoptosis and proliferation.\",\n      \"evidence\": \"siRNA knockdown and overexpression in podocytes with western blot for MDM2, p53, Bcl-2, Bax\",\n      \"pmids\": [\"32016904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding assay between CCNG1 and MDM2 or p53\", \"Mechanism of MDM2 suppression unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended CCNG1's reach to EMT, glycolysis, and drug resistance as the shared 3'-UTR endpoint of competing-endogenous-RNA (lncRNA–miRNA) networks.\",\n      \"evidence\": \"Dual-luciferase, RIP, RNA pull-down, rescue, and xenografts across PDAC, ovarian, and HCC models (miR-122-5p, miR-128-3p/OIP5-AS1, miR-488, miR-130a-5p/FAM225A)\",\n      \"pmids\": [\"32256207\", \"33760168\", \"32271408\", \"33245102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several axes rest on single-lab evidence\", \"Direct CCNG1 molecular activity driving EMT/glycolysis not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an epigenetic mechanism controlling CCNG1 transcription, identifying a PRMT6–PRMT5 complex that represses the CCNG1 promoter via arginine methylation marks.\",\n      \"evidence\": \"Reciprocal Co-IP, GST pulldown, ChIP at the CCNG1 promoter, mass spectrometry, and RNA-seq in colorectal cancer cells\",\n      \"pmids\": [\"36400182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CCNG1 derepression on tumor phenotype not fully traced\", \"Recruitment of the PRMT6–PRMT5 complex to the CCNG1 promoter undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Validated CCNG1 as an evolutionarily conserved p53 target required for cell cycle arrest independently of p21, anchoring its core physiological role.\",\n      \"evidence\": \"CRISPR-Cas9 G0 crispant screen in mdm2/puma/noxa/p21 quadruple-knockout zebrafish with cross-species conserved p53-target analysis\",\n      \"pmids\": [\"40487439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of CCNG1-driven arrest not resolved\", \"Relevant CDK/cyclin partners in this context unidentified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected upstream cytokine signaling to CCNG1 transcription, showing IL-6/JAK/STAT3 drives Ccng1 expression to promote p53 degradation and radiation-induced apoptosis.\",\n      \"evidence\": \"ChIP for p-STAT3 binding to the Ccng1 promoter, scRNA-seq, siRNA knockdown with phenotypic rescue, and anti-IL-6 intervention in vivo\",\n      \"pmids\": [\"41783157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which CCNG1 promotes TP53 degradation still inferred, not biochemically shown\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical mechanism by which CCNG1 destabilizes p53 (its physical partners, enzymatic complex, and CDK association) remains undefined.\",\n      \"evidence\": \"No timeline discovery reconstitutes a direct CCNG1–MDM2/p53 complex or identifies a catalytic partner\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical model of CCNG1 action\", \"Partner kinase/phosphatase identity unestablished in this corpus\", \"Direct substrate or scaffold function not demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MDM2\", \"TP53\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}