{"gene":"GTF3C2","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1994,"finding":"GTF3C2 (KIAA0004) was first identified as a novel human gene by cDNA cloning from human immature myeloid cell line KG-1, with its coding sequence predicted from analysis of randomly sampled cDNA clones.","method":"cDNA library screening, sequence analysis","journal":"DNA research","confidence":"Medium","confidence_rationale":"Tier 2 — original gene identification by direct cDNA cloning and sequencing","pmids":["7584026"],"is_preprint":false},{"year":2000,"finding":"TFIIIC110 (GTF3C2), a subunit of human TFIIIC2, physically interacts with NF1 protein family members; NF1 binds specifically to two subunits of TFIIIC2 (TFIIIC220 and TFIIIC110/GTF3C2) and this interaction facilitates accurate termination and multiple-round reinitiation of transcription by RNA polymerase III on the VA1 gene template.","method":"Protein purification, peptide sequence analysis, co-immunoprecipitation, immunodepletion, in vitro transcription assay, mutational analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical purification to homogeneity, reciprocal interaction confirmation, functional in vitro assay with mutants","pmids":["11118217"],"is_preprint":false},{"year":2004,"finding":"TFIIIC110 (GTF3C2) levels are not increased upon MVM parvovirus infection or NS1 expression in mouse fibroblasts, even though SINE (B1 and B2) transcripts are elevated, indicating that upregulation of SINE expression is not driven by increased GTF3C2/TFIIIC110 levels.","method":"Differential display, primer extension, Western blot, transient transfection","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein level measurement with functional context, single study","pmids":["15351211"],"is_preprint":false},{"year":2005,"finding":"Multiple alternative promoters for the GTF3C2 gene were identified in genome-wide analysis of human transcriptional start sites, indicating that GTF3C2 expression is subject to complex transcriptional regulation through multiple promoter usage.","method":"5'-end sequencing of full-length cDNAs from 164 oligo-cap libraries, bioinformatic clustering of transcriptional start sites","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide empirical mapping of TSSs with large-scale sequencing","pmids":["16344560"],"is_preprint":false},{"year":2006,"finding":"GTF3C2 (TFIIIC110) was detected as a phosphoprotein in EGF-stimulated HeLa cells with specific phosphorylation sites identified by mass spectrometry, indicating that GTF3C2 undergoes dynamic phosphorylation in response to growth factor signaling.","method":"Large-scale phosphoproteomics by LC-MS/MS in EGF-stimulated HeLa cells","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — high-throughput MS-based phosphosite identification with temporal dynamics, but no site-specific functional validation for GTF3C2","pmids":["17081983"],"is_preprint":false},{"year":2006,"finding":"Induced expression of TFIIIC110 (GTF3C2) in HeLa and HEK293 cells showed that the protein enters the nucleus, binds other TFIIIC subunits, and is recruited to tRNA and 5S rRNA gene loci in vivo, but overexpression alone has little to no effect on RNA polymerase III transcript levels, arguing against a simple model in which TFIIIC110 induction is sufficient to activate Pol III transcription.","method":"Transient transfection, stable doxycycline-inducible cell lines, chromatin immunoprecipitation (ChIP), RT-PCR","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 — inducible expression system, ChIP at endogenous gene loci, multiple cell lines, rigorous controls","pmids":["16822860"],"is_preprint":false},{"year":2010,"finding":"mTOR kinase associates with TFIIIC (the complex containing GTF3C2/TFIIIC110) and is recruited to tRNA and 5S rRNA gene loci through a TOR signaling motif in TFIIIC; this interaction connects the mTOR nutrient-sensing pathway directly to RNA polymerase III-dependent transcription.","method":"Co-immunoprecipitation, ChIP, proximity ligation assay, in vitro kinase assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including proximity ligation, ChIP, and in vitro kinase assay; replicated across conditions","pmids":["20543138"],"is_preprint":false},{"year":2010,"finding":"In Leishmania-infected macrophages, the surface protease gp63 of Leishmania activates the thrombin receptor PAR1, raising cytosolic Ca2+ and thereby activating μ-calpain, which proteolytically degrades TFIIIC110 (GTF3C2) to inhibit expression of B-box-containing non-coding RNA genes transcribed by RNA polymerase III.","method":"Western blot, protease inhibitor experiments, Ca2+ measurements, RNA analysis, avirulent strain controls","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multi-step pathway dissection with pharmacological inhibitors, genetic controls (avirulent gp63-negative strains), and direct protein level measurement","pmids":["21149457"],"is_preprint":false},{"year":2010,"finding":"In alternatively activated M2 macrophages, Leishmania requires both surface gp63 and LPG to down-regulate TFIIIC110 (GTF3C2), thereby repressing B-box-containing Pol III-transcribed ncRNA gene promoters; this effect is selective for M2 macrophages and correlates with permissiveness to Leishmania infection.","method":"Western blot, RNA analysis, pharmacological and genetic dissection with defined Leishmania surface mutants","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — genetic dissection using defined mutant parasites, multiple macrophage polarization states compared; single lab","pmids":["21165676"],"is_preprint":false},{"year":2015,"finding":"GTF3C2 was identified as a protein interaction partner in large-scale affinity-purification mass spectrometry (BioPlex) of HEK293T cells, placing it within protein communities consistent with its role in the RNA Pol III transcription machinery.","method":"High-throughput AP-MS (BioPlex), 2,594 bait proteins","journal":"Cell","confidence":"Low","confidence_rationale":"Tier 3 — large-scale AP-MS, no direct functional validation specific to GTF3C2","pmids":["26186194"],"is_preprint":false},{"year":2017,"finding":"GTF3C2 was identified within protein communities in BioPlex 2.0, the largest AP-MS human interactome, consistent with its membership in the TFIIIC complex.","method":"High-throughput AP-MS (BioPlex 2.0), >25% of protein-coding genes as baits","journal":"Nature","confidence":"Low","confidence_rationale":"Tier 3 — large-scale AP-MS dataset; no GTF3C2-specific functional validation","pmids":["28514442"],"is_preprint":false},{"year":2020,"finding":"Sp1 transcription factor directly controls GTF3C2 expression by binding to Sp1 sites in the GTF3C2 promoter 2 (GTF3C2P2) and promoting occupancy of TBP, TFIIAα, and p300 at this promoter; Sp1 knockdown reduces GTF3C2 expression and Pol III-directed transcription, while Sp1 overexpression enhances them, linking Sp1 to Pol III transcription via GTF3C2.","method":"Reporter gene assay, ChIP, shRNA knockdown, overexpression, RT-PCR, Western blot in HeLa, 293T, and SaOS2 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, reporter assay, gain- and loss-of-function) in multiple cell lines","pmids":["32115405"],"is_preprint":false},{"year":2021,"finding":"GTF3C2 was identified in the BioPlex 3.0 proteome-scale interaction network and its interactions were found to differ between 293T and HCT116 cell lines, suggesting cell-type-specific regulation of TFIIIC complex assembly.","method":"AP-MS (BioPlex 3.0), two-cell-line comparison","journal":"Cell","confidence":"Low","confidence_rationale":"Tier 3 — large-scale AP-MS; no GTF3C2-specific functional validation","pmids":["33961781"],"is_preprint":false},{"year":2022,"finding":"GATA4 promotes RNA polymerase III-directed transcription and tumor cell proliferation by activating Sp1 gene transcription (via GATA4 binding to the Sp1 promoter), which in turn activates BRF1 and GTF3C2 expression; GATA4 depletion reduces GTF3C2 expression and decreases Pol III machinery occupancy at Pol III target gene loci.","method":"ChIP, RT-PCR, Western blot, promoter reporter assays, shRNA knockdown, cell proliferation assays in SaOS2 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — epistasis established with ChIP at endogenous loci, multiple orthogonal methods, pathway ordering defined","pmids":["35038452"],"is_preprint":false},{"year":2023,"finding":"TFAP2A (AP-2α) transcription factor activates GTF3C2 expression as part of a program promoting Pol III-directed transcription; TFAP2A was found to positively modulate assembly of the Pol III transcription machinery at Pol III target genes, with GTF3C2 being one of the Pol III transcription-related factors whose expression is induced by TFAP2A.","method":"ChIP, RT-PCR, Western blot, shRNA knockdown, cell proliferation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and functional knockdown, multiple factors examined; GTF3C2 is one of several targets and not the sole focus","pmids":["36707053"],"is_preprint":false},{"year":2024,"finding":"GTF3C2 accumulates in the nucleus of pulmonary microvascular endothelial cells (PMVECs) treated with IL-1β and TNF-α (cytokines released by HP-PRRSV-infected macrophages) and regulates transcription of claudin-8 and claudin-4 tight junction proteins, thereby contributing to endothelial barrier disruption in acute lung injury.","method":"Nuclear fractionation, transcription factor binding analysis, cytokine treatment, Transwell barrier assay, gene expression analysis in porcine PMVECs","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — nuclear accumulation confirmed by fractionation, functional link to tight junction gene regulation established, but GTF3C2-specific mechanistic details (e.g. direct DNA binding validation) limited","pmids":["38806818"],"is_preprint":false},{"year":2025,"finding":"GTF3C2 promotes hepatocellular carcinoma cell proliferation by transcriptionally activating USP21 (ubiquitin-specific peptidase 21), which subsequently stabilizes MEK2 protein and activates the ERK1/2 signaling pathway; GTF3C2 knockdown suppressed proliferation in vitro and tumor growth in vivo, while co-overexpression of USP21 and MEK2 rescued proliferation inhibited by GTF3C2 knockdown.","method":"Luciferase reporter assay, RT-qPCR, Western blot, CCK-8/EdU/colony formation assays, shRNA knockdown, overexpression, subcutaneous xenograft mouse model","journal":"Journal of clinical and translational hepatology","confidence":"High","confidence_rationale":"Tier 2 — reporter assay establishes direct transcriptional activation, epistasis rescue experiments define pathway order, in vivo validation","pmids":["40385937"],"is_preprint":false}],"current_model":"GTF3C2 (TFIIIC110) is the 110 kDa subunit of the TFIIIC2 complex that binds B-box promoter elements and is required for RNA polymerase III transcription of tRNA, 5S rRNA, and other non-coding RNA genes; its expression is transcriptionally controlled by Sp1 (itself activated by GATA4 and TFAP2A) binding to the GTF3C2P2 promoter, it physically interacts with NF1 to support accurate termination and reinitiation of Pol III transcription, it associates with mTOR via a TOR signaling motif in TFIIIC to couple nutrient sensing to Pol III output, it is proteolytically degraded by calpain downstream of Leishmania gp63/PAR1/Ca2+ signaling to suppress ncRNA transcription in macrophages, it accumulates in the nucleus of endothelial cells in response to inflammatory cytokines to regulate claudin tight junction gene transcription, and it drives hepatocellular carcinoma proliferation by transcriptionally activating USP21 to stabilize MEK2 and activate ERK1/2 signaling."},"narrative":{"teleology":[{"year":1994,"claim":"Identification of GTF3C2 as a novel human gene provided the molecular entry point for studying its function in transcription.","evidence":"cDNA cloning from KG-1 myeloid cell line with full-length sequencing","pmids":["7584026"],"confidence":"Medium","gaps":["No function assigned at this stage","Relationship to Pol III machinery not yet established"]},{"year":2000,"claim":"Demonstration that NF1 physically interacts with TFIIIC110 and TFIIIC220 and that this interaction supports accurate termination and reinitiation of Pol III transcription established GTF3C2 as a functional hub within the TFIIIC2 complex.","evidence":"Protein purification, co-immunoprecipitation, immunodepletion, and in vitro transcription on VA1 template with mutational analysis","pmids":["11118217"],"confidence":"High","gaps":["Structural basis of NF1–TFIIIC110 interaction undefined","In vivo relevance of NF1–TFIIIC interaction at endogenous Pol III loci not tested"]},{"year":2006,"claim":"Showing that induced GTF3C2 enters the nucleus, binds other TFIIIC subunits, and occupies tRNA and 5S rRNA loci — yet fails to increase Pol III transcript levels — demonstrated that TFIIIC110 abundance alone is not rate-limiting for Pol III transcription.","evidence":"Doxycycline-inducible expression, ChIP at endogenous Pol III gene loci, RT-PCR in HeLa and HEK293 cells","pmids":["16822860"],"confidence":"High","gaps":["Identity of the rate-limiting cofactors required alongside GTF3C2 not established","Post-translational regulation of endogenous GTF3C2 not addressed"]},{"year":2010,"claim":"Discovery that mTOR associates with TFIIIC through a TOR signaling motif and is recruited to Pol III gene loci linked nutrient/growth-factor sensing directly to the TFIIIC complex containing GTF3C2.","evidence":"Co-immunoprecipitation, ChIP, proximity ligation assay, in vitro kinase assay","pmids":["20543138"],"confidence":"High","gaps":["Whether mTOR directly phosphorylates GTF3C2 or other TFIIIC subunits at specific sites not resolved","Functional consequence of mTOR–TFIIIC interaction on individual Pol III target gene output not quantified"]},{"year":2010,"claim":"Leishmania gp63 activates a PAR1/Ca²⁺/μ-calpain cascade that proteolytically degrades GTF3C2, suppressing B-box ncRNA transcription — the first demonstration that pathogen-induced GTF3C2 destruction modulates Pol III output in innate immune cells.","evidence":"Western blot, Ca²⁺ measurements, protease inhibitor experiments, avirulent gp63-negative parasite controls in macrophages; extended to M2-polarized macrophages with LPG/gp63 mutant parasites","pmids":["21149457","21165676"],"confidence":"High","gaps":["Specific calpain cleavage site(s) on GTF3C2 not mapped","Whether GTF3C2 degradation is necessary and sufficient for Leishmania intracellular survival not formally tested"]},{"year":2020,"claim":"Identification of Sp1 as a direct transcriptional activator of GTF3C2 via the GTF3C2P2 promoter established a transcription-factor cascade controlling Pol III output through GTF3C2 expression levels.","evidence":"ChIP, reporter assay, shRNA knockdown and overexpression in HeLa, 293T, and SaOS2 cells","pmids":["32115405"],"confidence":"High","gaps":["Relative contributions of alternative GTF3C2 promoters to total expression unknown","Signal transduction events upstream of Sp1 that regulate GTF3C2 not fully mapped"]},{"year":2022,"claim":"Placing GATA4 upstream of Sp1 and subsequently GTF3C2 extended the regulatory hierarchy controlling Pol III transcription and linked oncogenic GATA4 activity to GTF3C2 expression and tumor cell proliferation.","evidence":"ChIP at endogenous loci, reporter assays, shRNA epistasis, cell proliferation assays in SaOS2 cells","pmids":["35038452"],"confidence":"High","gaps":["Whether GATA4–Sp1–GTF3C2 axis operates in non-transformed tissues not tested","Direct comparison of GATA4 versus TFAP2A contribution to GTF3C2 levels not performed"]},{"year":2024,"claim":"Nuclear accumulation of GTF3C2 in cytokine-stimulated endothelial cells and its regulation of claudin-8 and claudin-4 transcription revealed a non-canonical role for GTF3C2 in tight junction gene control and barrier function.","evidence":"Nuclear fractionation, transcription factor binding analysis, Transwell barrier assay in porcine PMVECs treated with IL-1β and TNF-α","pmids":["38806818"],"confidence":"Medium","gaps":["Whether GTF3C2 binds claudin promoters directly or acts through Pol III-independent intermediates not resolved","Mechanism of cytokine-induced nuclear accumulation of GTF3C2 unknown","Replication in human endothelial cells needed"]},{"year":2025,"claim":"GTF3C2 transcriptionally activates USP21, which stabilizes MEK2 and activates ERK1/2 signaling to drive hepatocellular carcinoma proliferation — the first defined oncogenic mechanism for GTF3C2 beyond general Pol III transcription enhancement.","evidence":"Luciferase reporter, shRNA/overexpression epistasis rescue, EdU/colony formation assays, subcutaneous xenograft in mice","pmids":["40385937"],"confidence":"High","gaps":["Whether GTF3C2 activates USP21 through canonical Pol III or Pol II promoter elements not established","Mutational mapping of GTF3C2 domains required for USP21 activation absent","Relevance to other cancer types not explored"]},{"year":null,"claim":"Key open questions include the structural basis of GTF3C2 within the TFIIIC2 holocomplex, the identity of its direct DNA-binding domains versus those contributed by other TFIIIC subunits, the complete catalog of post-translational modifications that regulate its activity, and whether its non-canonical gene-regulatory roles (claudin genes, USP21) proceed through Pol III or Pol II mechanisms.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of human TFIIIC2 with GTF3C2 resolved","Genome-wide occupancy of GTF3C2 independent of other TFIIIC subunits not mapped","Functional significance of EGF-induced phosphorylation sites on GTF3C2 not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,5,11,13,16]},{"term_id":"GO:0140223","term_label":"general transcription initiation factor activity","supporting_discovery_ids":[1,5,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,15]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,6,11,13,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16]}],"complexes":["TFIIIC2"],"partners":["GTF3C1","NF1","MTOR","SP1","USP21"],"other_free_text":[]},"mechanistic_narrative":"GTF3C2 (TFIIIC110) is a core subunit of the human TFIIIC2 complex that recognizes B-box promoter elements and is essential for RNA polymerase III transcription of tRNA, 5S rRNA, and other non-coding RNA genes. GTF3C2 enters the nucleus, assembles with other TFIIIC subunits, and is recruited to Pol III gene loci, yet its overexpression alone is insufficient to activate Pol III transcription, indicating that TFIIIC2 complex integrity and additional regulatory inputs are required [PMID:16822860]; these inputs include physical association of the TFIIIC complex with mTOR, which couples nutrient sensing to Pol III output [PMID:20543138], interaction with NF1 to support accurate termination and reinitiation [PMID:11118217], and transcriptional control of GTF3C2 itself by Sp1 (activated upstream by GATA4 and TFAP2A) [PMID:32115405, PMID:35038452]. GTF3C2 is subject to proteolytic degradation by μ-calpain downstream of Leishmania gp63/PAR1/Ca²⁺ signaling in macrophages, which suppresses B-box-dependent ncRNA transcription and promotes pathogen survival [PMID:21149457]. Beyond canonical Pol III targets, GTF3C2 drives hepatocellular carcinoma proliferation by transcriptionally activating USP21 to stabilize MEK2 and engage ERK1/2 signaling, and it accumulates in the nucleus of cytokine-stimulated endothelial cells where it regulates claudin tight junction gene transcription [PMID:40385937, PMID:38806818]."},"prefetch_data":{"uniprot":{"accession":"Q8WUA4","full_name":"General transcription factor 3C polypeptide 2","aliases":["TF3C-beta","Transcription factor IIIC 110 kDa subunit","TFIIIC 110 kDa subunit","TFIIIC110","Transcription factor IIIC subunit beta"],"length_aa":911,"mass_kda":100.7,"function":"Required for RNA polymerase III-mediated transcription. Component of TFIIIC that initiates transcription complex assembly on tRNA and is required for transcription of 5S rRNA and other stable nuclear and cytoplasmic RNAs. May play a direct role in stabilizing interactions of TFIIIC2 with TFIIIC1","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8WUA4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GTF3C2","classification":"Common Essential","n_dependent_lines":834,"n_total_lines":1208,"dependency_fraction":0.6903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GTF3C2","total_profiled":1310},"omim":[{"mim_id":"604883","title":"GENERAL TRANSCRIPTION FACTOR 3C, POLYPEPTIDE 2; GTF3C2","url":"https://www.omim.org/entry/604883"}],"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/GTF3C2"},"hgnc":{"alias_symbol":["KIAA0011","TFIIIC110"],"prev_symbol":[]},"alphafold":{"accession":"Q8WUA4","domains":[{"cath_id":"2.130.10.10","chopping":"320-764_785-822_840-888","consensus_level":"medium","plddt":92.4121,"start":320,"end":888}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUA4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUA4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUA4-F1-predicted_aligned_error_v6.png","plddt_mean":72.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GTF3C2","jax_strain_url":"https://www.jax.org/strain/search?query=GTF3C2"},"sequence":{"accession":"Q8WUA4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUA4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUA4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUA4"}},"corpus_meta":[{"pmid":"25602801","id":"PMC_25602801","title":"Clinical, 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(pulldown, immunodepletion, mutagenesis, in vitro transcription assay), single lab but strong mechanistic validation\",\n      \"pmids\": [\"11118217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TFIIIC110 (GTF3C2), when overexpressed, enters the nucleus, binds other TFIIIC subunits, and is recruited to tRNA and 5S rRNA gene loci in vivo; however, increasing TFIIIC110 alone is insufficient to upregulate Pol III transcription, arguing against a model of regulation solely through TFIIIC110 induction.\",\n      \"method\": \"Transient and stable doxycycline-inducible overexpression in HeLa and HEK293 cells, chromatin immunoprecipitation (ChIP) at tRNA/5S rRNA genes, nuclear localization confirmed by imaging\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function with ChIP and localization assays, single lab with multiple methods but limited mechanistic depth beyond negative result\",\n      \"pmids\": [\"16822860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TFIIIC110 (GTF3C2) is degraded by μ-calpain in macrophages following Leishmania infection; this degradation is triggered via the gp63/PAR1/Ca2+/calpain axis and results in repression of B-box-containing Pol III-transcribed non-coding RNA genes (Alu RNA, 7SL RNA, vault RNA, B2 RNA).\",\n      \"method\": \"Leishmania infection of macrophages, calpain inhibitor experiments, PAR1 inhibition, Western blot for TFIIIC110 levels, non-coding RNA expression assays, use of avirulent gp63-negative Leishmania as control\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal perturbations (pathogen mutant, kinase/protease inhibitors, genetic knockdown context), clear mechanistic pathway established with functional readout\",\n      \"pmids\": [\"21149457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In alternatively polarized M2 macrophages, Leishmania surface gp63 and LPG cooperate to down-regulate TFIIIC110 (GTF3C2), repressing B-box-containing Pol III-transcribed ncRNA genes and permitting intracellular infection.\",\n      \"method\": \"M2 macrophage polarization, Leishmania infection with surface molecule blocking, Western blot for TFIIIC110, ncRNA expression assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — replicated mechanistic finding from same group extending prior work to M2 macrophages with additional surface molecule dissection\",\n      \"pmids\": [\"21165676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sp1 transcription factor binds the GTF3C2 promoter 2 (GTF3C2P2) and activates GTF3C2 expression; Sp1 also promotes occupancy of TBP, TFIIAα, and p300 at GTF3C2P2, thereby up-regulating Pol III-directed transcription and cancer cell proliferation. FLNA represses this pathway by suppressing Sp1 expression.\",\n      \"method\": \"shRNA knockdown and overexpression of Sp1 and FLNA in HeLa, 293T, SaOS2 cells; luciferase reporter assays with GTF3C2P2; ChIP for Sp1, TBP, TFIIAα, p300 at GTF3C2P2; RT-qPCR and Western blot for GTF3C2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reporter assays plus ChIP plus loss/gain-of-function, multiple cell lines, mechanistic pathway from FLNA through Sp1 to GTF3C2 established\",\n      \"pmids\": [\"32115405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GATA4 activates GTF3C2 expression indirectly via Sp1 (GATA4 binds the Sp1 promoter to activate Sp1, which then binds the GTF3C2 promoter); GATA4 depletion reduces occupancy of Pol III transcription machinery at Pol III gene loci, decreasing Pol III transcription and cell proliferation. This defines an FLNA/GATA4/Sp1/GTF3C2 axis.\",\n      \"method\": \"siRNA knockdown of GATA4 in SaOS2 cells, ChIP at Pol III gene loci and Sp1/GTF3C2 promoters, RT-qPCR and Western blot for GTF3C2 and BRF1, cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus KD with functional readout, single lab, mechanistic pathway placement\",\n      \"pmids\": [\"35038452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TFAP2A (AP-2α) activates GTF3C2 expression and promotes assembly of Pol III transcription machinery at Pol III gene loci; TFAP2A silencing reduces GTF3C2 levels and Pol III-directed transcription, inhibiting cell proliferation.\",\n      \"method\": \"ChIP at Pol III-transcribed gene loci, siRNA knockdown of TFAP2A, RT-qPCR and Western blot for GTF3C2, BRF1, c-MYC; cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus loss-of-function with defined proliferative phenotype, single lab\",\n      \"pmids\": [\"36707053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GTF3C2 accumulates in the nucleus of pulmonary microvascular endothelial cells in response to IL-1β and TNF-α signaling (induced by HP-PRRSV infection) and regulates transcription of claudin-8 and claudin-4, thereby controlling endothelial barrier permeability.\",\n      \"method\": \"Nuclear fractionation and immunofluorescence of PMVECs; cytokine addition/blocking experiments; siRNA knockdown of GTF3C2 with claudin-8/claudin-4 expression readout; Transwell permeability assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — nuclear localization by fractionation plus loss-of-function with defined barrier phenotype, single lab\",\n      \"pmids\": [\"38806818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GTF3C2 promotes hepatocellular carcinoma cell proliferation by transcriptionally activating USP21, which subsequently increases MEK2 protein levels and ERK1/2 phosphorylation; overexpression of USP21 and MEK2 rescues the proliferation defect caused by GTF3C2 knockdown.\",\n      \"method\": \"Luciferase reporter assay for USP21 promoter activity; shRNA knockdown and overexpression of GTF3C2 in Hep3B, HCCLM3, SNU449, Huh7 cells; Western blot for USP21, MEK2, p-ERK1/2; CCK-8, EdU, colony formation assays; subcutaneous xenograft in nude mice\",\n      \"journal\": \"Journal of clinical and translational hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay plus rescue experiment plus in vivo xenograft, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40385937\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF3C2 (TFIIIC110) is a subunit of the TFIIIC2 complex required for RNA polymerase III-directed transcription of tRNA, 5S rRNA, and B-box-containing non-coding RNA genes; its expression is transcriptionally activated by Sp1 (itself regulated by the FLNA/GATA4 and TFAP2A axes), its protein can be proteolytically degraded by μ-calpain (via a Leishmania gp63/PAR1/Ca²⁺ pathway) to repress Pol III transcription, and beyond its canonical Pol III role it can also act as a nuclear transcriptional activator of USP21 to drive MEK2/ERK1/2 signaling and HCC cell proliferation, as well as regulate claudin gene transcription to control endothelial barrier integrity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\n- [1] (PMID:25602801): GTF3C2-ALK fusion mentioned as one of many ALK fusions in Spitz tumors. GTF3C2 is just a fusion partner, not studied mechanistically. EXCLUDE (no mechanistic finding about GTF3C2 protein itself).\n- [2] (PMID:33540684): GTF3C2 mentioned as one of 9 genes in expression clustering. Pure expression/prognostic. EXCLUDE.\n- [3] (PMID:15351211): About TFIIIC110 (GTF3C2 paralogue TFIIIC110 = GTF3C1? Actually TFIIIC110 = GTF3C2 based on corpus context). Need to check: TFIIIC110 is the 110 kDa subunit. GTF3C2 is the beta 110 kDa subunit per paper [8]. KEEP for mechanism about TFIIIC110/GTF3C2.\n- [4] (PMID:11118217): About NF1 interacting with TFIIIC220 and TFIIIC110 (GTF3C2). KEEP.\n- [5] (PMID:36045381): GTF3C2 mentioned as a fusion partner in prostate cancer SVs. No mechanistic study of GTF3C2. EXCLUDE.\n- [6] (PMID:21149457): Mechanistic study of TFIIIC110 (GTF3C2) degradation by calpain in Leishmania infection. KEEP.\n- [7] (PMID:29194616): Bioinformatics/expression analysis; GTF3C2 as a regulatory hub by computational inference. EXCLUDE (Tier 4).\n- [8] (PMID:26725916): Bioinformatics/PPI network; GTF3C2 identified as TF by computational analysis. EXCLUDE.\n- [9] (PMID:21165676): Mechanistic follow-up showing TFIIIC110 (GTF3C2) down-regulation by Leishmania in M2 macrophages. KEEP.\n- [10] (PMID:32115405): Direct mechanistic study of Sp1 controlling GTF3C2 expression and Pol III transcription. KEEP.\n- [11] (PMID:35038452): GATA4/Sp1 axis controlling GTF3C2 and Pol III transcription. KEEP.\n- [12] (PMID:16822860): Direct experimental test of TFIIIC110 (GTF3C2) function in Pol III transcription. KEEP.\n- [13] (PMID:38806818): GTF3C2 identified as a transcription factor regulating claudin-8 and claudin-4 in PMVECs. KEEP.\n- [14] (PMID:36550445): GTF3C2 knockdown suppresses cell proliferation (functional). KEEP.\n- [15] (PMID:38444194): GTF3C2 as ALK fusion partner in Spitz melanoma. No mechanistic study. EXCLUDE.\n- [16] (PMID:38941542): GTF3C2 as ALK fusion partner. No mechanistic study. EXCLUDE.\n- [17] (PMID:36707053): TFAP2A activates GTF3C2 expression to promote Pol III transcription. KEEP.\n- [18] (PMID:40385937): Direct mechanistic study of GTF3C2 in HCC via USP21/MEK2/ERK1/2. KEEP.\n- [19] (PMID:41533020): Bioinformatics/computational. GTF3C2 as TF in network. EXCLUDE.\n- [20] (PMID:41149858): GTF3C2-AS1 — this is the antisense transcript, NOT GTF3C2 protein. EXCLUDE (case B).\n\n**Additional gene2pubmed papers:**\n- PMID:17081983: Large-scale phosphoproteomics; GTF3C2 detected as phosphorylated. KEEP (phosphorylation site identification).\n- PMID:12477932: MGC cDNA sequencing. EXCLUDE (no mechanistic finding).\n- PMID:16964243: Large-scale phosphoproteomics. KEEP if GTF3C2 specifically mentioned — general methodology paper, GTF3C2 likely in dataset. Low priority.\n- PMID:26186194: BioPlex interactome; GTF3C2 interactions identified by AP-MS. KEEP.\n- PMID:28514442: BioPlex 2.0. KEEP.\n- PMID:26496610: Quantitative interactome. KEEP if GTF3C2 included.\n- PMID:32296183: HuRI interactome. KEEP.\n- PMID:33961781: BioPlex 3.0. KEEP.\n- PMID:22939629: Census of human protein complexes. KEEP.\n- PMID:21873635: GO annotation propagation. EXCLUDE (computational).\n- PMID:15489334: MGC. EXCLUDE.\n- PMID:20360068: MitoCheck - chromosome segregation complexes. May include TFIIIC. Low relevance.\n- PMID:16344560: Alternative promoters; GTF3C2 promoters identified. KEEP.\n- PMID:34079125: BioID cell map. KEEP if GTF3C2 localized.\n- PMID:25281560: BioID for chromatin proteins. May include GTF3C2. Low specificity.\n- PMID:27173435: Ciliary proteome. Unlikely GTF3C2-specific. EXCLUDE.\n- PMID:21988832: Human liver interactome. May include GTF3C2 interactions. Low specificity.\n- PMID:7584026: KIAA cDNA cloning - first identification. KEEP.\n- PMID:24332808: PRP19/ATR. No GTF3C2 relevance apparent. EXCLUDE.\n- PMID:30804502: BRCA1-BARD1. No GTF3C2. EXCLUDE.\n- PMID:32416067: BET inhibitors. No GTF3C2. EXCLUDE.\n- PMID:21549307: SMARCAD1. No GTF3C2. EXCLUDE.\n- PMID:32877691: Mitochondrial BioID. No GTF3C2. EXCLUDE.\n- PMID:30554943: BET interactome. No GTF3C2. EXCLUDE.\n- PMID:29117863: TRIM25. No GTF3C2. EXCLUDE.\n- PMID:25720964: FBXW7/HSF1. No GTF3C2. EXCLUDE.\n- PMID:20543138: mTOR/TFIIIC association. KEEP — mTOR interacts with TFIIIC (which includes GTF3C2/TFIIIC110).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"GTF3C2 (KIAA0004) was first identified as a novel human gene by cDNA cloning from human immature myeloid cell line KG-1, with its coding sequence predicted from analysis of randomly sampled cDNA clones.\",\n      \"method\": \"cDNA library screening, sequence analysis\",\n      \"journal\": \"DNA research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — original gene identification by direct cDNA cloning and sequencing\",\n      \"pmids\": [\"7584026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TFIIIC110 (GTF3C2), a subunit of human TFIIIC2, physically interacts with NF1 protein family members; NF1 binds specifically to two subunits of TFIIIC2 (TFIIIC220 and TFIIIC110/GTF3C2) and this interaction facilitates accurate termination and multiple-round reinitiation of transcription by RNA polymerase III on the VA1 gene template.\",\n      \"method\": \"Protein purification, peptide sequence analysis, co-immunoprecipitation, immunodepletion, in vitro transcription assay, mutational analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical purification to homogeneity, reciprocal interaction confirmation, functional in vitro assay with mutants\",\n      \"pmids\": [\"11118217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TFIIIC110 (GTF3C2) levels are not increased upon MVM parvovirus infection or NS1 expression in mouse fibroblasts, even though SINE (B1 and B2) transcripts are elevated, indicating that upregulation of SINE expression is not driven by increased GTF3C2/TFIIIC110 levels.\",\n      \"method\": \"Differential display, primer extension, Western blot, transient transfection\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein level measurement with functional context, single study\",\n      \"pmids\": [\"15351211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Multiple alternative promoters for the GTF3C2 gene were identified in genome-wide analysis of human transcriptional start sites, indicating that GTF3C2 expression is subject to complex transcriptional regulation through multiple promoter usage.\",\n      \"method\": \"5'-end sequencing of full-length cDNAs from 164 oligo-cap libraries, bioinformatic clustering of transcriptional start sites\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide empirical mapping of TSSs with large-scale sequencing\",\n      \"pmids\": [\"16344560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GTF3C2 (TFIIIC110) was detected as a phosphoprotein in EGF-stimulated HeLa cells with specific phosphorylation sites identified by mass spectrometry, indicating that GTF3C2 undergoes dynamic phosphorylation in response to growth factor signaling.\",\n      \"method\": \"Large-scale phosphoproteomics by LC-MS/MS in EGF-stimulated HeLa cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — high-throughput MS-based phosphosite identification with temporal dynamics, but no site-specific functional validation for GTF3C2\",\n      \"pmids\": [\"17081983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Induced expression of TFIIIC110 (GTF3C2) in HeLa and HEK293 cells showed that the protein enters the nucleus, binds other TFIIIC subunits, and is recruited to tRNA and 5S rRNA gene loci in vivo, but overexpression alone has little to no effect on RNA polymerase III transcript levels, arguing against a simple model in which TFIIIC110 induction is sufficient to activate Pol III transcription.\",\n      \"method\": \"Transient transfection, stable doxycycline-inducible cell lines, chromatin immunoprecipitation (ChIP), RT-PCR\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — inducible expression system, ChIP at endogenous gene loci, multiple cell lines, rigorous controls\",\n      \"pmids\": [\"16822860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"mTOR kinase associates with TFIIIC (the complex containing GTF3C2/TFIIIC110) and is recruited to tRNA and 5S rRNA gene loci through a TOR signaling motif in TFIIIC; this interaction connects the mTOR nutrient-sensing pathway directly to RNA polymerase III-dependent transcription.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, proximity ligation assay, in vitro kinase assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including proximity ligation, ChIP, and in vitro kinase assay; replicated across conditions\",\n      \"pmids\": [\"20543138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Leishmania-infected macrophages, the surface protease gp63 of Leishmania activates the thrombin receptor PAR1, raising cytosolic Ca2+ and thereby activating μ-calpain, which proteolytically degrades TFIIIC110 (GTF3C2) to inhibit expression of B-box-containing non-coding RNA genes transcribed by RNA polymerase III.\",\n      \"method\": \"Western blot, protease inhibitor experiments, Ca2+ measurements, RNA analysis, avirulent strain controls\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-step pathway dissection with pharmacological inhibitors, genetic controls (avirulent gp63-negative strains), and direct protein level measurement\",\n      \"pmids\": [\"21149457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In alternatively activated M2 macrophages, Leishmania requires both surface gp63 and LPG to down-regulate TFIIIC110 (GTF3C2), thereby repressing B-box-containing Pol III-transcribed ncRNA gene promoters; this effect is selective for M2 macrophages and correlates with permissiveness to Leishmania infection.\",\n      \"method\": \"Western blot, RNA analysis, pharmacological and genetic dissection with defined Leishmania surface mutants\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic dissection using defined mutant parasites, multiple macrophage polarization states compared; single lab\",\n      \"pmids\": [\"21165676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GTF3C2 was identified as a protein interaction partner in large-scale affinity-purification mass spectrometry (BioPlex) of HEK293T cells, placing it within protein communities consistent with its role in the RNA Pol III transcription machinery.\",\n      \"method\": \"High-throughput AP-MS (BioPlex), 2,594 bait proteins\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — large-scale AP-MS, no direct functional validation specific to GTF3C2\",\n      \"pmids\": [\"26186194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GTF3C2 was identified within protein communities in BioPlex 2.0, the largest AP-MS human interactome, consistent with its membership in the TFIIIC complex.\",\n      \"method\": \"High-throughput AP-MS (BioPlex 2.0), >25% of protein-coding genes as baits\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — large-scale AP-MS dataset; no GTF3C2-specific functional validation\",\n      \"pmids\": [\"28514442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sp1 transcription factor directly controls GTF3C2 expression by binding to Sp1 sites in the GTF3C2 promoter 2 (GTF3C2P2) and promoting occupancy of TBP, TFIIAα, and p300 at this promoter; Sp1 knockdown reduces GTF3C2 expression and Pol III-directed transcription, while Sp1 overexpression enhances them, linking Sp1 to Pol III transcription via GTF3C2.\",\n      \"method\": \"Reporter gene assay, ChIP, shRNA knockdown, overexpression, RT-PCR, Western blot in HeLa, 293T, and SaOS2 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, reporter assay, gain- and loss-of-function) in multiple cell lines\",\n      \"pmids\": [\"32115405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GTF3C2 was identified in the BioPlex 3.0 proteome-scale interaction network and its interactions were found to differ between 293T and HCT116 cell lines, suggesting cell-type-specific regulation of TFIIIC complex assembly.\",\n      \"method\": \"AP-MS (BioPlex 3.0), two-cell-line comparison\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — large-scale AP-MS; no GTF3C2-specific functional validation\",\n      \"pmids\": [\"33961781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GATA4 promotes RNA polymerase III-directed transcription and tumor cell proliferation by activating Sp1 gene transcription (via GATA4 binding to the Sp1 promoter), which in turn activates BRF1 and GTF3C2 expression; GATA4 depletion reduces GTF3C2 expression and decreases Pol III machinery occupancy at Pol III target gene loci.\",\n      \"method\": \"ChIP, RT-PCR, Western blot, promoter reporter assays, shRNA knockdown, cell proliferation assays in SaOS2 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established with ChIP at endogenous loci, multiple orthogonal methods, pathway ordering defined\",\n      \"pmids\": [\"35038452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TFAP2A (AP-2α) transcription factor activates GTF3C2 expression as part of a program promoting Pol III-directed transcription; TFAP2A was found to positively modulate assembly of the Pol III transcription machinery at Pol III target genes, with GTF3C2 being one of the Pol III transcription-related factors whose expression is induced by TFAP2A.\",\n      \"method\": \"ChIP, RT-PCR, Western blot, shRNA knockdown, cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and functional knockdown, multiple factors examined; GTF3C2 is one of several targets and not the sole focus\",\n      \"pmids\": [\"36707053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GTF3C2 accumulates in the nucleus of pulmonary microvascular endothelial cells (PMVECs) treated with IL-1β and TNF-α (cytokines released by HP-PRRSV-infected macrophages) and regulates transcription of claudin-8 and claudin-4 tight junction proteins, thereby contributing to endothelial barrier disruption in acute lung injury.\",\n      \"method\": \"Nuclear fractionation, transcription factor binding analysis, cytokine treatment, Transwell barrier assay, gene expression analysis in porcine PMVECs\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — nuclear accumulation confirmed by fractionation, functional link to tight junction gene regulation established, but GTF3C2-specific mechanistic details (e.g. direct DNA binding validation) limited\",\n      \"pmids\": [\"38806818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GTF3C2 promotes hepatocellular carcinoma cell proliferation by transcriptionally activating USP21 (ubiquitin-specific peptidase 21), which subsequently stabilizes MEK2 protein and activates the ERK1/2 signaling pathway; GTF3C2 knockdown suppressed proliferation in vitro and tumor growth in vivo, while co-overexpression of USP21 and MEK2 rescued proliferation inhibited by GTF3C2 knockdown.\",\n      \"method\": \"Luciferase reporter assay, RT-qPCR, Western blot, CCK-8/EdU/colony formation assays, shRNA knockdown, overexpression, subcutaneous xenograft mouse model\",\n      \"journal\": \"Journal of clinical and translational hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay establishes direct transcriptional activation, epistasis rescue experiments define pathway order, in vivo validation\",\n      \"pmids\": [\"40385937\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GTF3C2 (TFIIIC110) is the 110 kDa subunit of the TFIIIC2 complex that binds B-box promoter elements and is required for RNA polymerase III transcription of tRNA, 5S rRNA, and other non-coding RNA genes; its expression is transcriptionally controlled by Sp1 (itself activated by GATA4 and TFAP2A) binding to the GTF3C2P2 promoter, it physically interacts with NF1 to support accurate termination and reinitiation of Pol III transcription, it associates with mTOR via a TOR signaling motif in TFIIIC to couple nutrient sensing to Pol III output, it is proteolytically degraded by calpain downstream of Leishmania gp63/PAR1/Ca2+ signaling to suppress ncRNA transcription in macrophages, it accumulates in the nucleus of endothelial cells in response to inflammatory cytokines to regulate claudin tight junction gene transcription, and it drives hepatocellular carcinoma proliferation by transcriptionally activating USP21 to stabilize MEK2 and activate ERK1/2 signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GTF3C2 (TFIIIC110) is a subunit of the TFIIIC2 complex that is essential for RNA polymerase III-directed transcription of tRNA, 5S rRNA, and B-box-containing non-coding RNA genes, and also functions as a nuclear transcriptional activator of protein-coding genes. Within the TFIIIC2 complex, GTF3C2 interacts with NF1 to promote accurate termination and reinitiation of Pol III transcription, is recruited to tRNA and 5S rRNA loci in vivo, and its proteolytic degradation by µ-calpain (via the Leishmania gp63/PAR1/Ca²⁺ pathway) represses Pol III-transcribed ncRNAs including Alu, 7SL, and vault RNAs [PMID:11118217, PMID:16822860, PMID:21149457]. GTF3C2 expression is transcriptionally controlled by Sp1 acting downstream of FLNA/GATA4 and TFAP2A signaling axes, linking its abundance to cell proliferation and Pol III output [PMID:32115405, PMID:35038452, PMID:36707053]. Beyond its canonical Pol III role, GTF3C2 transcriptionally activates USP21 to drive MEK2/ERK1/2 signaling and hepatocellular carcinoma proliferation, and regulates claudin-8/claudin-4 transcription to control endothelial barrier integrity [PMID:40385937, PMID:38806818].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The discovery that NF1 physically interacts with GTF3C2 (TFIIIC110) and TFIIIC220 to promote Pol III termination and reinitiation established GTF3C2 as a functionally important TFIIIC subunit with a defined role beyond simple promoter recognition.\",\n      \"evidence\": \"Purification of TFIIIC2 with peptide sequencing, co-immunoprecipitation, immunodepletion, and in vitro transcription on VA1 template\",\n      \"pmids\": [\"11118217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NF1–GTF3C2 interaction unknown\", \"Whether NF1 interaction is required at all Pol III gene classes not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that overexpressed GTF3C2 localizes to the nucleus, binds other TFIIIC subunits, and is recruited to tRNA/5S rRNA loci—yet fails to upregulate Pol III transcription alone—established that GTF3C2 abundance is not rate-limiting and that additional regulatory inputs are required.\",\n      \"evidence\": \"Inducible overexpression in HeLa/HEK293 cells with ChIP at Pol III loci and imaging\",\n      \"pmids\": [\"16822860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the true rate-limiting step for Pol III transcription not resolved\", \"Endogenous stoichiometry of TFIIIC subunits not measured\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that µ-calpain degrades GTF3C2 downstream of the Leishmania gp63/PAR1/Ca²⁺ axis, leading to repression of B-box-containing Pol III ncRNAs, revealed a pathogen-exploited post-translational mechanism for controlling Pol III output through GTF3C2 proteolysis.\",\n      \"evidence\": \"Leishmania infection of macrophages with calpain/PAR1 inhibitors, gp63-negative mutant controls, Western blot and ncRNA expression assays; extended to M2 macrophages with surface molecule blocking\",\n      \"pmids\": [\"21149457\", \"21165676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calpain cleavage site on GTF3C2 not mapped\", \"Whether this degradation pathway operates in non-macrophage contexts unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying Sp1 as a direct transcriptional activator of GTF3C2 via its promoter, with FLNA acting as an upstream repressor of Sp1, connected GTF3C2 expression to a defined signaling axis controlling Pol III transcription and cancer cell proliferation.\",\n      \"evidence\": \"Luciferase reporter, ChIP for Sp1/TBP/TFIIA/p300 at GTF3C2 promoter, shRNA/overexpression in multiple cell lines\",\n      \"pmids\": [\"32115405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Sp1-mediated GTF3C2 regulation is tissue-specific not addressed\", \"Contribution of GTF3C2P1 versus GTF3C2P2 promoter usage not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending the regulatory cascade to show that GATA4 activates Sp1 transcription, which in turn drives GTF3C2 expression and Pol III machinery assembly, defined a multi-tiered FLNA/GATA4/Sp1/GTF3C2 transcriptional hierarchy controlling cell proliferation.\",\n      \"evidence\": \"siRNA knockdown of GATA4 in SaOS2 cells with ChIP at Pol III loci and Sp1/GTF3C2 promoters, proliferation assays\",\n      \"pmids\": [\"35038452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GATA4 direct binding to Sp1 promoter versus indirect effects not fully distinguished\", \"In vivo relevance of GATA4–GTF3C2 axis in tumors not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that TFAP2A independently activates GTF3C2 expression and Pol III machinery assembly revealed a parallel transcriptional input converging on GTF3C2 to control Pol III output and proliferation.\",\n      \"evidence\": \"siRNA knockdown of TFAP2A with ChIP at Pol III loci, RT-qPCR/Western for GTF3C2, cell proliferation assays\",\n      \"pmids\": [\"36707053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TFAP2A and Sp1 act additively or redundantly on the GTF3C2 promoter not resolved\", \"Direct TFAP2A binding site on GTF3C2 promoter not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing that GTF3C2 accumulates in endothelial nuclei upon inflammatory cytokine signaling and transcriptionally regulates claudin-8 and claudin-4 to control barrier permeability established a non-canonical, Pol III-independent transcriptional function for GTF3C2.\",\n      \"evidence\": \"Nuclear fractionation and immunofluorescence in PMVECs; cytokine stimulation; siRNA knockdown with claudin expression and Transwell permeability readouts\",\n      \"pmids\": [\"38806818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GTF3C2 directly binds claudin gene promoters or acts through intermediaries not determined\", \"Mechanism by which cytokines drive GTF3C2 nuclear accumulation unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that GTF3C2 transcriptionally activates USP21, which stabilizes MEK2 to activate ERK1/2 signaling and drive HCC proliferation in vitro and in xenografts, defined a second Pol II-dependent transcriptional target axis for GTF3C2 with oncogenic significance.\",\n      \"evidence\": \"Luciferase reporter for USP21 promoter; shRNA/overexpression with rescue in multiple HCC lines; xenograft model\",\n      \"pmids\": [\"40385937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of GTF3C2 to USP21 promoter not shown by ChIP\", \"Whether GTF3C2 acts alone or requires cofactors for Pol II gene activation unknown\", \"Generalizability beyond HCC not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GTF3C2 switches between its canonical role as a TFIIIC2 subunit directing Pol III transcription and its non-canonical role as a transcriptional activator of Pol II-transcribed genes (USP21, claudins) remains mechanistically undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of GTF3C2 within TFIIIC2 or in its free form\", \"Whether GTF3C2 possesses intrinsic DNA-binding or transactivation domains for Pol II genes is unknown\", \"Genome-wide identification of GTF3C2-regulated Pol II targets has not been performed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 5, 6, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"TFIIIC2\"],\n    \"partners\": [\"NF1\", \"TFIIIC220\", \"SP1\", \"USP21\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway term_id. \"GO:0074160\" is not a valid Reactome pathway ID. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"GTF3C2 (TFIIIC110) is a subunit of the TFIIIC2 complex that is essential for RNA polymerase III-directed transcription of tRNA, 5S rRNA, and B-box-containing non-coding RNA genes, and also functions as a nuclear transcriptional activator of protein-coding genes. Within the TFIIIC2 complex, GTF3C2 interacts with NF1 to promote accurate termination and reinitiation of Pol III transcription, is recruited to tRNA and 5S rRNA loci in vivo, and its proteolytic degradation by µ-calpain (via the Leishmania gp63/PAR1/Ca²⁺ pathway) represses Pol III-transcribed ncRNAs including Alu, 7SL, and vault RNAs [PMID:11118217, PMID:16822860, PMID:21149457]. GTF3C2 expression is transcriptionally controlled by Sp1 acting downstream of FLNA/GATA4 and TFAP2A signaling axes, linking its abundance to cell proliferation and Pol III output [PMID:32115405, PMID:35038452, PMID:36707053]. Beyond its canonical Pol III role, GTF3C2 transcriptionally activates USP21 to drive MEK2/ERK1/2 signaling and hepatocellular carcinoma proliferation, and regulates claudin-8/claudin-4 transcription to control endothelial barrier integrity [PMID:40385937, PMID:38806818].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The discovery that NF1 physically interacts with GTF3C2 (TFIIIC110) and TFIIIC220 to promote Pol III termination and reinitiation established GTF3C2 as a functionally important TFIIIC subunit with a defined role beyond simple promoter recognition.\",\n      \"evidence\": \"Purification of TFIIIC2 with peptide sequencing, co-immunoprecipitation, immunodepletion, and in vitro transcription on VA1 template\",\n      \"pmids\": [\"11118217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NF1–GTF3C2 interaction unknown\", \"Whether NF1 interaction is required at all Pol III gene classes not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that overexpressed GTF3C2 localizes to the nucleus, binds other TFIIIC subunits, and is recruited to tRNA/5S rRNA loci—yet fails to upregulate Pol III transcription alone—established that GTF3C2 abundance is not rate-limiting and that additional regulatory inputs are required.\",\n      \"evidence\": \"Inducible overexpression in HeLa/HEK293 cells with ChIP at Pol III loci and imaging\",\n      \"pmids\": [\"16822860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the true rate-limiting step for Pol III transcription not resolved\", \"Endogenous stoichiometry of TFIIIC subunits not measured\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that µ-calpain degrades GTF3C2 downstream of the Leishmania gp63/PAR1/Ca²⁺ axis, leading to repression of B-box-containing Pol III ncRNAs, revealed a pathogen-exploited post-translational mechanism for controlling Pol III output through GTF3C2 proteolysis.\",\n      \"evidence\": \"Leishmania infection of macrophages with calpain/PAR1 inhibitors, gp63-negative mutant controls, Western blot and ncRNA expression assays; extended to M2 macrophages with surface molecule blocking\",\n      \"pmids\": [\"21149457\", \"21165676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calpain cleavage site on GTF3C2 not mapped\", \"Whether this degradation pathway operates in non-macrophage contexts unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying Sp1 as a direct transcriptional activator of GTF3C2 via its promoter, with FLNA acting as an upstream repressor of Sp1, connected GTF3C2 expression to a defined signaling axis controlling Pol III transcription and cancer cell proliferation.\",\n      \"evidence\": \"Luciferase reporter, ChIP for Sp1/TBP/TFIIA/p300 at GTF3C2 promoter, shRNA/overexpression in multiple cell lines\",\n      \"pmids\": [\"32115405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Sp1-mediated GTF3C2 regulation is tissue-specific not addressed\", \"Contribution of GTF3C2P1 versus GTF3C2P2 promoter usage not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending the regulatory cascade to show that GATA4 activates Sp1 transcription, which in turn drives GTF3C2 expression and Pol III machinery assembly, defined a multi-tiered FLNA/GATA4/Sp1/GTF3C2 transcriptional hierarchy controlling cell proliferation.\",\n      \"evidence\": \"siRNA knockdown of GATA4 in SaOS2 cells with ChIP at Pol III loci and Sp1/GTF3C2 promoters, proliferation assays\",\n      \"pmids\": [\"35038452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GATA4 direct binding to Sp1 promoter versus indirect effects not fully distinguished\", \"In vivo relevance of GATA4–GTF3C2 axis in tumors not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that TFAP2A independently activates GTF3C2 expression and Pol III machinery assembly revealed a parallel transcriptional input converging on GTF3C2 to control Pol III output and proliferation.\",\n      \"evidence\": \"siRNA knockdown of TFAP2A with ChIP at Pol III loci, RT-qPCR/Western for GTF3C2, cell proliferation assays\",\n      \"pmids\": [\"36707053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TFAP2A and Sp1 act additively or redundantly on the GTF3C2 promoter not resolved\", \"Direct TFAP2A binding site on GTF3C2 promoter not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing that GTF3C2 accumulates in endothelial nuclei upon inflammatory cytokine signaling and transcriptionally regulates claudin-8 and claudin-4 to control barrier permeability established a non-canonical, Pol III-independent transcriptional function for GTF3C2.\",\n      \"evidence\": \"Nuclear fractionation and immunofluorescence in PMVECs; cytokine stimulation; siRNA knockdown with claudin expression and Transwell permeability readouts\",\n      \"pmids\": [\"38806818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GTF3C2 directly binds claudin gene promoters or acts through intermediaries not determined\", \"Mechanism by which cytokines drive GTF3C2 nuclear accumulation unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that GTF3C2 transcriptionally activates USP21, which stabilizes MEK2 to activate ERK1/2 signaling and drive HCC proliferation in vitro and in xenografts, defined a second Pol II-dependent transcriptional target axis for GTF3C2 with oncogenic significance.\",\n      \"evidence\": \"Luciferase reporter for USP21 promoter; shRNA/overexpression with rescue in multiple HCC lines; xenograft model\",\n      \"pmids\": [\"40385937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of GTF3C2 to USP21 promoter not shown by ChIP\", \"Whether GTF3C2 acts alone or requires cofactors for Pol II gene activation unknown\", \"Generalizability beyond HCC not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GTF3C2 switches between its canonical role as a TFIIIC2 subunit directing Pol III transcription and its non-canonical role as a transcriptional activator of Pol II-transcribed genes (USP21, claudins) remains mechanistically undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of GTF3C2 within TFIIIC2 or in its free form\", \"Whether GTF3C2 possesses intrinsic DNA-binding or transactivation domains for Pol II genes is unknown\", \"Genome-wide identification of GTF3C2-regulated Pol II targets has not been performed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 5, 6, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"TFIIIC2\"],\n    \"partners\": [\"NF1\", \"GTF3C1\", \"SP1\", \"USP21\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"GTF3C2 (TFIIIC110) is a core subunit of the human TFIIIC2 complex that recognizes B-box promoter elements and is essential for RNA polymerase III transcription of tRNA, 5S rRNA, and other non-coding RNA genes. GTF3C2 enters the nucleus, assembles with other TFIIIC subunits, and is recruited to Pol III gene loci, yet its overexpression alone is insufficient to activate Pol III transcription, indicating that TFIIIC2 complex integrity and additional regulatory inputs are required [PMID:16822860]; these inputs include physical association of the TFIIIC complex with mTOR, which couples nutrient sensing to Pol III output [PMID:20543138], interaction with NF1 to support accurate termination and reinitiation [PMID:11118217], and transcriptional control of GTF3C2 itself by Sp1 (activated upstream by GATA4 and TFAP2A) [PMID:32115405, PMID:35038452]. GTF3C2 is subject to proteolytic degradation by μ-calpain downstream of Leishmania gp63/PAR1/Ca²⁺ signaling in macrophages, which suppresses B-box-dependent ncRNA transcription and promotes pathogen survival [PMID:21149457]. Beyond canonical Pol III targets, GTF3C2 drives hepatocellular carcinoma proliferation by transcriptionally activating USP21 to stabilize MEK2 and engage ERK1/2 signaling, and it accumulates in the nucleus of cytokine-stimulated endothelial cells where it regulates claudin tight junction gene transcription [PMID:40385937, PMID:38806818].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of GTF3C2 as a novel human gene provided the molecular entry point for studying its function in transcription.\",\n      \"evidence\": \"cDNA cloning from KG-1 myeloid cell line with full-length sequencing\",\n      \"pmids\": [\"7584026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No function assigned at this stage\",\n        \"Relationship to Pol III machinery not yet established\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstration that NF1 physically interacts with TFIIIC110 and TFIIIC220 and that this interaction supports accurate termination and reinitiation of Pol III transcription established GTF3C2 as a functional hub within the TFIIIC2 complex.\",\n      \"evidence\": \"Protein purification, co-immunoprecipitation, immunodepletion, and in vitro transcription on VA1 template with mutational analysis\",\n      \"pmids\": [\"11118217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of NF1–TFIIIC110 interaction undefined\",\n        \"In vivo relevance of NF1–TFIIIC interaction at endogenous Pol III loci not tested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showing that induced GTF3C2 enters the nucleus, binds other TFIIIC subunits, and occupies tRNA and 5S rRNA loci — yet fails to increase Pol III transcript levels — demonstrated that TFIIIC110 abundance alone is not rate-limiting for Pol III transcription.\",\n      \"evidence\": \"Doxycycline-inducible expression, ChIP at endogenous Pol III gene loci, RT-PCR in HeLa and HEK293 cells\",\n      \"pmids\": [\"16822860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the rate-limiting cofactors required alongside GTF3C2 not established\",\n        \"Post-translational regulation of endogenous GTF3C2 not addressed\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that mTOR associates with TFIIIC through a TOR signaling motif and is recruited to Pol III gene loci linked nutrient/growth-factor sensing directly to the TFIIIC complex containing GTF3C2.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, proximity ligation assay, in vitro kinase assay\",\n      \"pmids\": [\"20543138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether mTOR directly phosphorylates GTF3C2 or other TFIIIC subunits at specific sites not resolved\",\n        \"Functional consequence of mTOR–TFIIIC interaction on individual Pol III target gene output not quantified\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Leishmania gp63 activates a PAR1/Ca²⁺/μ-calpain cascade that proteolytically degrades GTF3C2, suppressing B-box ncRNA transcription — the first demonstration that pathogen-induced GTF3C2 destruction modulates Pol III output in innate immune cells.\",\n      \"evidence\": \"Western blot, Ca²⁺ measurements, protease inhibitor experiments, avirulent gp63-negative parasite controls in macrophages; extended to M2-polarized macrophages with LPG/gp63 mutant parasites\",\n      \"pmids\": [\"21149457\", \"21165676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific calpain cleavage site(s) on GTF3C2 not mapped\",\n        \"Whether GTF3C2 degradation is necessary and sufficient for Leishmania intracellular survival not formally tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of Sp1 as a direct transcriptional activator of GTF3C2 via the GTF3C2P2 promoter established a transcription-factor cascade controlling Pol III output through GTF3C2 expression levels.\",\n      \"evidence\": \"ChIP, reporter assay, shRNA knockdown and overexpression in HeLa, 293T, and SaOS2 cells\",\n      \"pmids\": [\"32115405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contributions of alternative GTF3C2 promoters to total expression unknown\",\n        \"Signal transduction events upstream of Sp1 that regulate GTF3C2 not fully mapped\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placing GATA4 upstream of Sp1 and subsequently GTF3C2 extended the regulatory hierarchy controlling Pol III transcription and linked oncogenic GATA4 activity to GTF3C2 expression and tumor cell proliferation.\",\n      \"evidence\": \"ChIP at endogenous loci, reporter assays, shRNA epistasis, cell proliferation assays in SaOS2 cells\",\n      \"pmids\": [\"35038452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether GATA4–Sp1–GTF3C2 axis operates in non-transformed tissues not tested\",\n        \"Direct comparison of GATA4 versus TFAP2A contribution to GTF3C2 levels not performed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Nuclear accumulation of GTF3C2 in cytokine-stimulated endothelial cells and its regulation of claudin-8 and claudin-4 transcription revealed a non-canonical role for GTF3C2 in tight junction gene control and barrier function.\",\n      \"evidence\": \"Nuclear fractionation, transcription factor binding analysis, Transwell barrier assay in porcine PMVECs treated with IL-1β and TNF-α\",\n      \"pmids\": [\"38806818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether GTF3C2 binds claudin promoters directly or acts through Pol III-independent intermediates not resolved\",\n        \"Mechanism of cytokine-induced nuclear accumulation of GTF3C2 unknown\",\n        \"Replication in human endothelial cells needed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"GTF3C2 transcriptionally activates USP21, which stabilizes MEK2 and activates ERK1/2 signaling to drive hepatocellular carcinoma proliferation — the first defined oncogenic mechanism for GTF3C2 beyond general Pol III transcription enhancement.\",\n      \"evidence\": \"Luciferase reporter, shRNA/overexpression epistasis rescue, EdU/colony formation assays, subcutaneous xenograft in mice\",\n      \"pmids\": [\"40385937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether GTF3C2 activates USP21 through canonical Pol III or Pol II promoter elements not established\",\n        \"Mutational mapping of GTF3C2 domains required for USP21 activation absent\",\n        \"Relevance to other cancer types not explored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of GTF3C2 within the TFIIIC2 holocomplex, the identity of its direct DNA-binding domains versus those contributed by other TFIIIC subunits, the complete catalog of post-translational modifications that regulate its activity, and whether its non-canonical gene-regulatory roles (claudin genes, USP21) proceed through Pol III or Pol II mechanisms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of human TFIIIC2 with GTF3C2 resolved\",\n        \"Genome-wide occupancy of GTF3C2 independent of other TFIIIC subunits not mapped\",\n        \"Functional significance of EGF-induced phosphorylation sites on GTF3C2 not determined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 5, 11, 13, 16]},\n      {\"term_id\": \"GO:0140223\", \"supporting_discovery_ids\": [1, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 6, 11, 13, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\n      \"TFIIIC2\"\n    ],\n    \"partners\": [\n      \"GTF3C1\",\n      \"NF1\",\n      \"MTOR\",\n      \"SP1\",\n      \"USP21\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}