{"gene":"CCNG2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1999,"finding":"Cyclin G2 (CCNG2) protein is localized predominantly to the cytoplasm, in contrast to the nuclear localization of cyclin G1, as shown by transient expression of a cyclin G2-GFP fusion protein in NIH3T3 cells. The mouse Ccng2 gene spans 8604 bp across 8 exons and maps to chromosome 5E3.3-F1.3.","method":"Transient transfection of GFP fusion protein with fluorescence microscopy; genomic cloning and FISH","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by live fluorescence imaging; single lab with two orthogonal methods (GFP fusion + FISH mapping)","pmids":["10216255"],"is_preprint":false},{"year":2013,"finding":"Overexpression of CCNG2 in gastric cancer SGC-7901 cells causes G0/G1 cell cycle arrest, reduces cell survival, and decreases CDK2 protein expression, suggesting CCNG2 promotes CDK2 degradation as part of its growth-inhibitory mechanism.","method":"Lentiviral CCNG2 overexpression; MTT assay; flow cytometry cell cycle analysis; Western blot for CDK2","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function/gain-of-function with defined cellular phenotype and downstream molecular readout (CDK2); single lab, multiple orthogonal methods","pmids":["24248541"],"is_preprint":false},{"year":2013,"finding":"Overexpression of CCNG2 in colorectal cancer SW480 cells causes G0/G1 cell cycle arrest, reduces cell survival, and decreases CDK2 protein expression, consistent with CCNG2 promoting CDK2 degradation.","method":"Lentiviral CCNG2 overexpression; MTT assay; flow cytometry cell cycle analysis; Western blot for CDK2","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined cellular phenotype and downstream molecular readout; single lab, multiple methods","pmids":["24307622"],"is_preprint":false},{"year":2013,"finding":"Overexpression of CCNG2 in thyroid cancer K1 cells causes G0/G1 cell cycle arrest, reduces cell survival, and decreases CDK2 protein expression, consistent with CCNG2 acting as a negative regulator by promoting CDK2 degradation.","method":"Lentiviral CCNG2 overexpression; MTT assay; flow cytometry cell cycle analysis; Western blot for CDK2","journal":"Asian Pacific journal of cancer prevention","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined cellular phenotype and downstream molecular readout; single lab, multiple orthogonal methods","pmids":["24289643"],"is_preprint":false},{"year":2018,"finding":"CCNG2 overexpression in glioma cell lines (T98G and U251) inhibits proliferation, induces G0/G1 arrest, increases apoptosis, and reduces tumor volume in a murine xenograft model. AKT kinase activity inversely regulates CCNG2 expression: treatment with the AKT inhibitor MK-2206 increases CCNG2 expression, and knockdown of CCNG2 reverses the anti-proliferative effect of AKT inhibition.","method":"CCNG2 overexpression/knockdown; AKT inhibitor treatment (MK-2206); flow cytometry; colony formation assay; murine xenograft model","journal":"Frontiers in neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and epistasis (CCNG2 KD reverses AKT inhibitor effect), in vitro and in vivo; single lab, multiple orthogonal methods","pmids":["29720957"],"is_preprint":false},{"year":2019,"finding":"PTOV1 directly binds to the CCNG2 promoter via an AT-hook-like motif within its PTOV-A domain, activating CCNG2 transcription. Mutation of this AT-hook-like sequence significantly decreases PTOV1-promoted CCNG2 expression. PTOV1 also associates with mitotic chromosomes in high-grade carcinomas.","method":"Chromatin immunoprecipitation (ChIP); electrophoretic mobility shift assay (EMSA); promoter mutation analysis; immunohistochemistry","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA binding demonstrated by ChIP and EMSA with mutagenesis validation; single lab, two orthogonal biochemical methods","pmids":["30922918"],"is_preprint":false},{"year":2021,"finding":"miR-17-5p directly targets the 3'UTR of CCNG2 mRNA, repressing CCNG2 expression. Silencing miR-17-5p causes G2/M phase accumulation in HNSCC cells, while overexpression promotes cell cycle progression, placing CCNG2 as a mediator of miR-17-5p's cell cycle effects.","method":"Dual-luciferase reporter assay; RT-qPCR; Western blot; flow cytometry cell cycle analysis; miRNA mimic/inhibitor transfection","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR targeting confirmed by luciferase assay plus functional cell cycle readout; single lab, multiple orthogonal methods","pmids":["34598688"],"is_preprint":false},{"year":2021,"finding":"METTL3 promotes maturation of pri-miR-1246, thereby increasing mature miR-1246 levels, which in turn directly targets and suppresses CCNG2 expression in ovarian cancer cells, promoting proliferation, migration, and inhibiting apoptosis.","method":"RT-qPCR; Western blot; METTL3 knockdown/overexpression; in vivo xenograft; miR-1246 target validation","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic epistasis established (METTL3→pri-miR-1246→miR-1246→CCNG2) with in vitro and in vivo validation; single lab, multiple methods","pmids":["34497267"],"is_preprint":false},{"year":2024,"finding":"The clock gene BHLHE40 is a direct downstream transcriptional target of the androgen receptor (AR), and CCNG2 is a direct downstream transcriptional target of BHLHE40. Co-immunoprecipitation and protein-protein interaction modelling indicate BHLHE40 binds to AR and co-translocates to the nucleus upon supraphysiological androgen stimulation. The AR-BHLHE40-CCNG2 axis mediates androgen-induced cellular senescence as a tumor-suppressive mechanism in castration-resistant prostate cancer.","method":"RNA-seq; ChIP-seq; Co-immunoprecipitation; translocation analysis; knockdown/overexpression; murine xenograft; 3D spheroids","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP-seq, Co-IP, RNA-seq, in vivo xenograft, 3D spheroids) establishing pathway hierarchy and protein interaction in a single rigorous study","pmids":["38902772"],"is_preprint":false},{"year":2024,"finding":"SMURF1 ubiquitin ligase degrades the transcription factor PATZ1, which is a direct activator of CCNG2 transcription. Loss of PATZ1-driven CCNG2 expression activates β-catenin signaling, promoting proliferation, invasion, stemness, and T cell exhaustion in esophageal squamous cell carcinoma. CCNG2 overexpression reduces β-catenin levels and suppresses these malignant phenotypes.","method":"CCNG2 overexpression; SMURF1/PATZ1 knockdown; luciferase/promoter assays; co-culture T cell assays; Wnt agonist rescue experiment","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis chain established (SMURF1→PATZ1→CCNG2→β-catenin) with multiple knockdown/rescue experiments; single lab","pmids":["39617210"],"is_preprint":false},{"year":2020,"finding":"The lncRNA LINC00460 recruits EZH2 and LSD1 to the CCNG2 promoter to epigenetically silence CCNG2 expression in gastric cancer, promoting tumor cell proliferation. RNA pull-down/RIP confirmed direct interaction of LINC00460 with EZH2 and LSD1 proteins.","method":"RNA-seq; RNA immunoprecipitation (RIP); Western blot; ChIP; LINC00460 knockdown/overexpression; in vitro and in vivo proliferation assays","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct epigenetic regulation of CCNG2 via lncRNA-protein complex confirmed by RIP and ChIP; single lab, multiple orthogonal methods","pmids":["32059342"],"is_preprint":false},{"year":2017,"finding":"miR-1246 directly targets the 3'UTR of CCNG2, suppressing its expression. Transfer of miR-1246 via exosomes from metastatic MDA-MB-231 cells to non-malignant HMLE cells suppresses CCNG2 and enhances viability, migration, and chemotherapy resistance.","method":"Luciferase reporter assay; Western blot; exosome transfer; invasion and viability assays; confocal microscopy","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR targeting confirmed by luciferase assay with functional readouts; single lab, multiple orthogonal methods","pmids":["29216623"],"is_preprint":false},{"year":2014,"finding":"miR-1246 suppresses CCNG2 expression in gemcitabine-resistant pancreatic cancer cells exhibiting cancer stem cell (CSC)-like properties, altering in vitro drug sensitivity and increasing in vivo tumorigenic potential.","method":"MiRNA overexpression/knockdown; in vitro drug sensitivity assay; sphere formation assay; in vivo tumorigenicity; immunohistochemistry","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional connection between miR-1246, CCNG2, and drug resistance established with in vitro and in vivo evidence; single lab","pmids":["25117811"],"is_preprint":false},{"year":2024,"finding":"Extracellular vesicle (EV)-transported miR-1246 from highly invasive melanoma subpopulations directly binds the 3'UTR of CCNG2 (confirmed by luciferase reporter assay), suppressing CCNG2 expression and enhancing the invasive capacity of recipient melanoma cells in Matrigel spheroid and Boyden chamber assays.","method":"Next-generation sequencing; luciferase reporter assay; Matrigel spheroid invasion; Boyden chamber assay; sphingomyelinase inhibitor (EV secretion inhibition); miR-1246 overexpression","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR binding confirmed by luciferase assay with functional invasion readouts; single lab, multiple orthogonal methods","pmids":["39285403"],"is_preprint":false}],"current_model":"CCNG2 (cyclin G2) is an atypical cyclin that localizes predominantly to the cytoplasm and functions as a tumor suppressor: its overexpression induces G0/G1 cell cycle arrest and promotes CDK2 degradation; its transcription is directly activated by PTOV1 (via an AT-hook-like domain binding to its promoter) and by BHLHE40 (a clock gene downstream of the androgen receptor), while it is epigenetically silenced by the LINC00460–EZH2/LSD1 complex and post-transcriptionally repressed by multiple miRNAs (miR-1246, miR-135b, miR-1290, miR-17-5p) targeting its 3'UTR; upstream, AKT activity suppresses CCNG2 expression, and the SMURF1–PATZ1 axis controls its transcription in the context of β-catenin signaling, placing CCNG2 as a convergence point for cell cycle, senescence, and Wnt pathway regulation."},"narrative":{"mechanistic_narrative":"CCNG2 (cyclin G2) is an atypical cyclin that functions as a growth-inhibitory, tumor-suppressive regulator of the G0/G1 transition across diverse epithelial and neural cancers [PMID:24248541, PMID:24307622, PMID:29720957]. Unlike its nuclear paralog cyclin G1, CCNG2 protein localizes predominantly to the cytoplasm [PMID:10216255]. Forced expression of CCNG2 imposes G0/G1 arrest, reduces survival, and lowers CDK2 protein levels, indicating that it restrains cell cycle progression in part by promoting CDK2 degradation [PMID:24248541, PMID:24307622, PMID:24289643]; in glioma it additionally induces apoptosis and suppresses xenograft tumor growth, and its expression is held down by AKT activity such that CCNG2 knockdown reverses the anti-proliferative effect of AKT inhibition [PMID:29720957]. CCNG2 acts as a convergence node controlled by multiple transcriptional and post-transcriptional inputs: it is directly transactivated by PTOV1 through an AT-hook-like motif in its promoter [PMID:30922918], by the androgen-receptor-driven clock factor BHLHE40 as part of an AR–BHLHE40–CCNG2 axis mediating androgen-induced senescence [PMID:38902772], and by PATZ1, whose abundance is limited by SMURF1-mediated degradation; loss of this input derepresses β-catenin signaling, while CCNG2 overexpression reduces β-catenin and suppresses malignant phenotypes [PMID:39617210]. CCNG2 is repressed epigenetically by the LINC00460–EZH2/LSD1 complex at its promoter [PMID:32059342] and post-transcriptionally by multiple miRNAs, most prominently miR-1246 and miR-17-5p, which directly target its 3'UTR to license proliferation, invasion, and drug resistance [PMID:34598688, PMID:34497267, PMID:29216623, PMID:39285403].","teleology":[{"year":1999,"claim":"Established that cyclin G2 is a distinct cyclin family member with cytoplasmic, rather than nuclear, localization, distinguishing it functionally from cyclin G1.","evidence":"GFP fusion live imaging in NIH3T3 cells plus genomic cloning and FISH mapping of mouse Ccng2","pmids":["10216255"],"confidence":"Medium","gaps":["Does not define a molecular function or interaction partner","Localization shown only for overexpressed fusion protein in one cell type"]},{"year":2013,"claim":"Defined CCNG2 as a growth suppressor by showing its overexpression forces G0/G1 arrest and lowers CDK2 across gastric, colorectal, and thyroid cancer cells, linking it to CDK2 turnover.","evidence":"Lentiviral overexpression with MTT, flow cytometry cell cycle analysis, and CDK2 Western blot in SGC-7901, SW480, and K1 lines","pmids":["24248541","24307622","24289643"],"confidence":"Medium","gaps":["CDK2 degradation inferred from protein loss, not directly demonstrated mechanistically","No physical CCNG2–CDK2 interaction shown","Gain-of-function only"]},{"year":2018,"claim":"Placed CCNG2 downstream of AKT signaling, showing AKT suppresses CCNG2 and that CCNG2 is required for the anti-proliferative effect of AKT inhibition in glioma.","evidence":"Overexpression/knockdown, MK-2206 AKT inhibitor treatment, colony formation, flow cytometry, and murine xenograft","pmids":["29720957"],"confidence":"Medium","gaps":["Mechanism by which AKT lowers CCNG2 (transcriptional vs post-transcriptional) not resolved","Single lab"]},{"year":2019,"claim":"Identified the first direct transcriptional activator of CCNG2, showing PTOV1 binds its promoter through an AT-hook-like motif.","evidence":"ChIP, EMSA, promoter mutation analysis, and immunohistochemistry","pmids":["30922918"],"confidence":"Medium","gaps":["Functional consequence of PTOV1-driven CCNG2 on cell cycle not directly tested in this study","Single lab"]},{"year":2024,"claim":"Integrated CCNG2 into androgen-receptor and clock signaling by defining an AR→BHLHE40→CCNG2 axis driving androgen-induced senescence as a tumor-suppressive program.","evidence":"RNA-seq, ChIP-seq, Co-IP, translocation analysis, xenograft, and 3D spheroids in prostate cancer","pmids":["38902772"],"confidence":"High","gaps":["Direct BHLHE40 occupancy at the CCNG2 promoter inferred from ChIP-seq within one study","Generalizability beyond prostate cancer untested"]},{"year":2024,"claim":"Connected CCNG2 to Wnt/β-catenin control via a SMURF1→PATZ1→CCNG2 cascade, showing CCNG2 restrains β-catenin and malignant phenotypes.","evidence":"Overexpression, SMURF1/PATZ1 knockdown, promoter/luciferase assays, T cell co-culture, and Wnt agonist rescue in esophageal squamous cell carcinoma","pmids":["39617210"],"confidence":"Medium","gaps":["Mechanism by which CCNG2 reduces β-catenin not defined","Single lab"]},{"year":2020,"claim":"Showed CCNG2 is epigenetically silenced, with LINC00460 recruiting EZH2 and LSD1 to its promoter to promote tumor proliferation.","evidence":"RNA-seq, RIP, ChIP, Western blot, and knockdown/overexpression with in vitro and in vivo proliferation assays in gastric cancer","pmids":["32059342"],"confidence":"Medium","gaps":["Direct chromatin mark changes at the CCNG2 locus not fully resolved","Single lab"]},{"year":2014,"claim":"Established post-transcriptional repression of CCNG2 by miR-1246, linking its loss to drug resistance and cancer stem cell-like behavior.","evidence":"miRNA overexpression/knockdown, drug sensitivity and sphere formation assays, in vivo tumorigenicity in pancreatic cancer","pmids":["25117811"],"confidence":"Medium","gaps":["Direct 3'UTR binding not shown in this study","Single lab"]},{"year":2017,"claim":"Demonstrated direct miR-1246 targeting of the CCNG2 3'UTR and intercellular transfer of this repression via exosomes from metastatic to non-malignant cells.","evidence":"Luciferase reporter assay, Western blot, exosome transfer, invasion/viability assays in breast cell models","pmids":["29216623"],"confidence":"Medium","gaps":["Single lab","Endogenous stoichiometry of EV-delivered miR-1246 unaddressed"]},{"year":2021,"claim":"Expanded the miRNA control of CCNG2, showing METTL3-driven maturation of miR-1246 and direct miR-17-5p 3'UTR targeting both repress CCNG2 to drive cell cycle progression.","evidence":"Dual-luciferase reporter, RT-qPCR, Western blot, flow cytometry, METTL3 knockdown/overexpression, and xenograft in ovarian and HNSCC models","pmids":["34497267","34598688"],"confidence":"Medium","gaps":["Relative contribution of each miRNA to endogenous CCNG2 levels not quantified","Single lab per study"]},{"year":2024,"claim":"Showed extracellular vesicle-delivered miR-1246 directly represses CCNG2 to enhance melanoma invasion, reinforcing CCNG2 loss as a pro-invasive event transferable between cells.","evidence":"NGS, luciferase reporter, Matrigel spheroid invasion, Boyden chamber, and sphingomyelinase inhibition of EV secretion","pmids":["39285403"],"confidence":"Medium","gaps":["Single lab","In vivo metastasis not tested"]},{"year":null,"claim":"How cytoplasmic CCNG2 mechanistically promotes CDK2 degradation and lowers β-catenin—its direct protein partners and any CDK-binding or adaptor activity—remains undefined.","evidence":"No discovery in the timeline establishes a direct CCNG2 protein-protein interaction or biochemical activity","pmids":[],"confidence":"Low","gaps":["No direct CCNG2 binding partner identified","No structural model","CDK2 and β-catenin reduction shown only at the protein-level readout, not biochemically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,3,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,2,3,4,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,9]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16589","full_name":"Cyclin-G2","aliases":[],"length_aa":344,"mass_kda":38.9,"function":"May play a role in growth regulation and in negative regulation of cell cycle progression","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q16589/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNG2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCNG2","total_profiled":1310},"omim":[{"mim_id":"603203","title":"CYCLIN G2; CCNG2","url":"https://www.omim.org/entry/603203"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCNG2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q16589","domains":[{"cath_id":"1.10.472","chopping":"13-27_156-264","consensus_level":"high","plddt":88.4377,"start":13,"end":264},{"cath_id":"1.10.472.10","chopping":"34-148","consensus_level":"high","plddt":93.2456,"start":34,"end":148}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16589","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16589-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16589-F1-predicted_aligned_error_v6.png","plddt_mean":80.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNG2","jax_strain_url":"https://www.jax.org/strain/search?query=CCNG2"},"sequence":{"accession":"Q16589","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16589.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16589/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16589"}},"corpus_meta":[{"pmid":"29216623","id":"PMC_29216623","title":"Exosomal 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axis","date":"2024-09-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.31.609994","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13719,"output_tokens":3683,"usd":0.048201,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11414,"output_tokens":3673,"usd":0.074447,"stage2_stop_reason":"end_turn"},"total_usd":0.122648,"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\": 1999,\n      \"finding\": \"Cyclin G2 (CCNG2) protein is localized predominantly to the cytoplasm, in contrast to the nuclear localization of cyclin G1, as shown by transient expression of a cyclin G2-GFP fusion protein in NIH3T3 cells. The mouse Ccng2 gene spans 8604 bp across 8 exons and maps to chromosome 5E3.3-F1.3.\",\n      \"method\": \"Transient transfection of GFP fusion protein with fluorescence microscopy; genomic cloning and FISH\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by live fluorescence imaging; single lab with two orthogonal methods (GFP fusion + FISH mapping)\",\n      \"pmids\": [\"10216255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of CCNG2 in gastric cancer SGC-7901 cells causes G0/G1 cell cycle arrest, reduces cell survival, and decreases CDK2 protein expression, suggesting CCNG2 promotes CDK2 degradation as part of its growth-inhibitory mechanism.\",\n      \"method\": \"Lentiviral CCNG2 overexpression; MTT assay; flow cytometry cell cycle analysis; Western blot for CDK2\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function/gain-of-function with defined cellular phenotype and downstream molecular readout (CDK2); single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24248541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of CCNG2 in colorectal cancer SW480 cells causes G0/G1 cell cycle arrest, reduces cell survival, and decreases CDK2 protein expression, consistent with CCNG2 promoting CDK2 degradation.\",\n      \"method\": \"Lentiviral CCNG2 overexpression; MTT assay; flow cytometry cell cycle analysis; Western blot for CDK2\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined cellular phenotype and downstream molecular readout; single lab, multiple methods\",\n      \"pmids\": [\"24307622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of CCNG2 in thyroid cancer K1 cells causes G0/G1 cell cycle arrest, reduces cell survival, and decreases CDK2 protein expression, consistent with CCNG2 acting as a negative regulator by promoting CDK2 degradation.\",\n      \"method\": \"Lentiviral CCNG2 overexpression; MTT assay; flow cytometry cell cycle analysis; Western blot for CDK2\",\n      \"journal\": \"Asian Pacific journal of cancer prevention\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined cellular phenotype and downstream molecular readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24289643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCNG2 overexpression in glioma cell lines (T98G and U251) inhibits proliferation, induces G0/G1 arrest, increases apoptosis, and reduces tumor volume in a murine xenograft model. AKT kinase activity inversely regulates CCNG2 expression: treatment with the AKT inhibitor MK-2206 increases CCNG2 expression, and knockdown of CCNG2 reverses the anti-proliferative effect of AKT inhibition.\",\n      \"method\": \"CCNG2 overexpression/knockdown; AKT inhibitor treatment (MK-2206); flow cytometry; colony formation assay; murine xenograft model\",\n      \"journal\": \"Frontiers in neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and epistasis (CCNG2 KD reverses AKT inhibitor effect), in vitro and in vivo; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29720957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTOV1 directly binds to the CCNG2 promoter via an AT-hook-like motif within its PTOV-A domain, activating CCNG2 transcription. Mutation of this AT-hook-like sequence significantly decreases PTOV1-promoted CCNG2 expression. PTOV1 also associates with mitotic chromosomes in high-grade carcinomas.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); electrophoretic mobility shift assay (EMSA); promoter mutation analysis; immunohistochemistry\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA binding demonstrated by ChIP and EMSA with mutagenesis validation; single lab, two orthogonal biochemical methods\",\n      \"pmids\": [\"30922918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-17-5p directly targets the 3'UTR of CCNG2 mRNA, repressing CCNG2 expression. Silencing miR-17-5p causes G2/M phase accumulation in HNSCC cells, while overexpression promotes cell cycle progression, placing CCNG2 as a mediator of miR-17-5p's cell cycle effects.\",\n      \"method\": \"Dual-luciferase reporter assay; RT-qPCR; Western blot; flow cytometry cell cycle analysis; miRNA mimic/inhibitor transfection\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR targeting confirmed by luciferase assay plus functional cell cycle readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34598688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL3 promotes maturation of pri-miR-1246, thereby increasing mature miR-1246 levels, which in turn directly targets and suppresses CCNG2 expression in ovarian cancer cells, promoting proliferation, migration, and inhibiting apoptosis.\",\n      \"method\": \"RT-qPCR; Western blot; METTL3 knockdown/overexpression; in vivo xenograft; miR-1246 target validation\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic epistasis established (METTL3→pri-miR-1246→miR-1246→CCNG2) with in vitro and in vivo validation; single lab, multiple methods\",\n      \"pmids\": [\"34497267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The clock gene BHLHE40 is a direct downstream transcriptional target of the androgen receptor (AR), and CCNG2 is a direct downstream transcriptional target of BHLHE40. Co-immunoprecipitation and protein-protein interaction modelling indicate BHLHE40 binds to AR and co-translocates to the nucleus upon supraphysiological androgen stimulation. The AR-BHLHE40-CCNG2 axis mediates androgen-induced cellular senescence as a tumor-suppressive mechanism in castration-resistant prostate cancer.\",\n      \"method\": \"RNA-seq; ChIP-seq; Co-immunoprecipitation; translocation analysis; knockdown/overexpression; murine xenograft; 3D spheroids\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP-seq, Co-IP, RNA-seq, in vivo xenograft, 3D spheroids) establishing pathway hierarchy and protein interaction in a single rigorous study\",\n      \"pmids\": [\"38902772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMURF1 ubiquitin ligase degrades the transcription factor PATZ1, which is a direct activator of CCNG2 transcription. Loss of PATZ1-driven CCNG2 expression activates β-catenin signaling, promoting proliferation, invasion, stemness, and T cell exhaustion in esophageal squamous cell carcinoma. CCNG2 overexpression reduces β-catenin levels and suppresses these malignant phenotypes.\",\n      \"method\": \"CCNG2 overexpression; SMURF1/PATZ1 knockdown; luciferase/promoter assays; co-culture T cell assays; Wnt agonist rescue experiment\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis chain established (SMURF1→PATZ1→CCNG2→β-catenin) with multiple knockdown/rescue experiments; single lab\",\n      \"pmids\": [\"39617210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The lncRNA LINC00460 recruits EZH2 and LSD1 to the CCNG2 promoter to epigenetically silence CCNG2 expression in gastric cancer, promoting tumor cell proliferation. RNA pull-down/RIP confirmed direct interaction of LINC00460 with EZH2 and LSD1 proteins.\",\n      \"method\": \"RNA-seq; RNA immunoprecipitation (RIP); Western blot; ChIP; LINC00460 knockdown/overexpression; in vitro and in vivo proliferation assays\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct epigenetic regulation of CCNG2 via lncRNA-protein complex confirmed by RIP and ChIP; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32059342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-1246 directly targets the 3'UTR of CCNG2, suppressing its expression. Transfer of miR-1246 via exosomes from metastatic MDA-MB-231 cells to non-malignant HMLE cells suppresses CCNG2 and enhances viability, migration, and chemotherapy resistance.\",\n      \"method\": \"Luciferase reporter assay; Western blot; exosome transfer; invasion and viability assays; confocal microscopy\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR targeting confirmed by luciferase assay with functional readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29216623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-1246 suppresses CCNG2 expression in gemcitabine-resistant pancreatic cancer cells exhibiting cancer stem cell (CSC)-like properties, altering in vitro drug sensitivity and increasing in vivo tumorigenic potential.\",\n      \"method\": \"MiRNA overexpression/knockdown; in vitro drug sensitivity assay; sphere formation assay; in vivo tumorigenicity; immunohistochemistry\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional connection between miR-1246, CCNG2, and drug resistance established with in vitro and in vivo evidence; single lab\",\n      \"pmids\": [\"25117811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Extracellular vesicle (EV)-transported miR-1246 from highly invasive melanoma subpopulations directly binds the 3'UTR of CCNG2 (confirmed by luciferase reporter assay), suppressing CCNG2 expression and enhancing the invasive capacity of recipient melanoma cells in Matrigel spheroid and Boyden chamber assays.\",\n      \"method\": \"Next-generation sequencing; luciferase reporter assay; Matrigel spheroid invasion; Boyden chamber assay; sphingomyelinase inhibitor (EV secretion inhibition); miR-1246 overexpression\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR binding confirmed by luciferase assay with functional invasion readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39285403\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNG2 (cyclin G2) is an atypical cyclin that localizes predominantly to the cytoplasm and functions as a tumor suppressor: its overexpression induces G0/G1 cell cycle arrest and promotes CDK2 degradation; its transcription is directly activated by PTOV1 (via an AT-hook-like domain binding to its promoter) and by BHLHE40 (a clock gene downstream of the androgen receptor), while it is epigenetically silenced by the LINC00460–EZH2/LSD1 complex and post-transcriptionally repressed by multiple miRNAs (miR-1246, miR-135b, miR-1290, miR-17-5p) targeting its 3'UTR; upstream, AKT activity suppresses CCNG2 expression, and the SMURF1–PATZ1 axis controls its transcription in the context of β-catenin signaling, placing CCNG2 as a convergence point for cell cycle, senescence, and Wnt pathway regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCNG2 (cyclin G2) is an atypical cyclin that functions as a growth-inhibitory, tumor-suppressive regulator of the G0/G1 transition across diverse epithelial and neural cancers [#1, #2, #4]. Unlike its nuclear paralog cyclin G1, CCNG2 protein localizes predominantly to the cytoplasm [#0]. Forced expression of CCNG2 imposes G0/G1 arrest, reduces survival, and lowers CDK2 protein levels, indicating that it restrains cell cycle progression in part by promoting CDK2 degradation [#1, #2, #3]; in glioma it additionally induces apoptosis and suppresses xenograft tumor growth, and its expression is held down by AKT activity such that CCNG2 knockdown reverses the anti-proliferative effect of AKT inhibition [#4]. CCNG2 acts as a convergence node controlled by multiple transcriptional and post-transcriptional inputs: it is directly transactivated by PTOV1 through an AT-hook-like motif in its promoter [#5], by the androgen-receptor-driven clock factor BHLHE40 as part of an AR\\u2013BHLHE40\\u2013CCNG2 axis mediating androgen-induced senescence [#8], and by PATZ1, whose abundance is limited by SMURF1-mediated degradation; loss of this input derepresses \\u03b2-catenin signaling, while CCNG2 overexpression reduces \\u03b2-catenin and suppresses malignant phenotypes [#9]. CCNG2 is repressed epigenetically by the LINC00460\\u2013EZH2/LSD1 complex at its promoter [#10] and post-transcriptionally by multiple miRNAs, most prominently miR-1246 and miR-17-5p, which directly target its 3'UTR to license proliferation, invasion, and drug resistance [#6, #7, #11, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that cyclin G2 is a distinct cyclin family member with cytoplasmic, rather than nuclear, localization, distinguishing it functionally from cyclin G1.\",\n      \"evidence\": \"GFP fusion live imaging in NIH3T3 cells plus genomic cloning and FISH mapping of mouse Ccng2\",\n      \"pmids\": [\"10216255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define a molecular function or interaction partner\", \"Localization shown only for overexpressed fusion protein in one cell type\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined CCNG2 as a growth suppressor by showing its overexpression forces G0/G1 arrest and lowers CDK2 across gastric, colorectal, and thyroid cancer cells, linking it to CDK2 turnover.\",\n      \"evidence\": \"Lentiviral overexpression with MTT, flow cytometry cell cycle analysis, and CDK2 Western blot in SGC-7901, SW480, and K1 lines\",\n      \"pmids\": [\"24248541\", \"24307622\", \"24289643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDK2 degradation inferred from protein loss, not directly demonstrated mechanistically\", \"No physical CCNG2\\u2013CDK2 interaction shown\", \"Gain-of-function only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed CCNG2 downstream of AKT signaling, showing AKT suppresses CCNG2 and that CCNG2 is required for the anti-proliferative effect of AKT inhibition in glioma.\",\n      \"evidence\": \"Overexpression/knockdown, MK-2206 AKT inhibitor treatment, colony formation, flow cytometry, and murine xenograft\",\n      \"pmids\": [\"29720957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which AKT lowers CCNG2 (transcriptional vs post-transcriptional) not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the first direct transcriptional activator of CCNG2, showing PTOV1 binds its promoter through an AT-hook-like motif.\",\n      \"evidence\": \"ChIP, EMSA, promoter mutation analysis, and immunohistochemistry\",\n      \"pmids\": [\"30922918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PTOV1-driven CCNG2 on cell cycle not directly tested in this study\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Integrated CCNG2 into androgen-receptor and clock signaling by defining an AR\\u2192BHLHE40\\u2192CCNG2 axis driving androgen-induced senescence as a tumor-suppressive program.\",\n      \"evidence\": \"RNA-seq, ChIP-seq, Co-IP, translocation analysis, xenograft, and 3D spheroids in prostate cancer\",\n      \"pmids\": [\"38902772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct BHLHE40 occupancy at the CCNG2 promoter inferred from ChIP-seq within one study\", \"Generalizability beyond prostate cancer untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected CCNG2 to Wnt/\\u03b2-catenin control via a SMURF1\\u2192PATZ1\\u2192CCNG2 cascade, showing CCNG2 restrains \\u03b2-catenin and malignant phenotypes.\",\n      \"evidence\": \"Overexpression, SMURF1/PATZ1 knockdown, promoter/luciferase assays, T cell co-culture, and Wnt agonist rescue in esophageal squamous cell carcinoma\",\n      \"pmids\": [\"39617210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CCNG2 reduces \\u03b2-catenin not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed CCNG2 is epigenetically silenced, with LINC00460 recruiting EZH2 and LSD1 to its promoter to promote tumor proliferation.\",\n      \"evidence\": \"RNA-seq, RIP, ChIP, Western blot, and knockdown/overexpression with in vitro and in vivo proliferation assays in gastric cancer\",\n      \"pmids\": [\"32059342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin mark changes at the CCNG2 locus not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established post-transcriptional repression of CCNG2 by miR-1246, linking its loss to drug resistance and cancer stem cell-like behavior.\",\n      \"evidence\": \"miRNA overexpression/knockdown, drug sensitivity and sphere formation assays, in vivo tumorigenicity in pancreatic cancer\",\n      \"pmids\": [\"25117811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct 3'UTR binding not shown in this study\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated direct miR-1246 targeting of the CCNG2 3'UTR and intercellular transfer of this repression via exosomes from metastatic to non-malignant cells.\",\n      \"evidence\": \"Luciferase reporter assay, Western blot, exosome transfer, invasion/viability assays in breast cell models\",\n      \"pmids\": [\"29216623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Endogenous stoichiometry of EV-delivered miR-1246 unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the miRNA control of CCNG2, showing METTL3-driven maturation of miR-1246 and direct miR-17-5p 3'UTR targeting both repress CCNG2 to drive cell cycle progression.\",\n      \"evidence\": \"Dual-luciferase reporter, RT-qPCR, Western blot, flow cytometry, METTL3 knockdown/overexpression, and xenograft in ovarian and HNSCC models\",\n      \"pmids\": [\"34497267\", \"34598688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each miRNA to endogenous CCNG2 levels not quantified\", \"Single lab per study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed extracellular vesicle-delivered miR-1246 directly represses CCNG2 to enhance melanoma invasion, reinforcing CCNG2 loss as a pro-invasive event transferable between cells.\",\n      \"evidence\": \"NGS, luciferase reporter, Matrigel spheroid invasion, Boyden chamber, and sphingomyelinase inhibition of EV secretion\",\n      \"pmids\": [\"39285403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo metastasis not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How cytoplasmic CCNG2 mechanistically promotes CDK2 degradation and lowers \\u03b2-catenin\\u2014its direct protein partners and any CDK-binding or adaptor activity\\u2014remains undefined.\",\n      \"evidence\": \"No discovery in the timeline establishes a direct CCNG2 protein-protein interaction or biochemical activity\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct CCNG2 binding partner identified\", \"No structural model\", \"CDK2 and \\u03b2-catenin reduction shown only at the protein-level readout, not biochemically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}