{"gene":"CIC","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2006,"finding":"CIC (human homolog of Drosophila capicua) encodes a high mobility group box transcription factor that, when fused to DUX4 via t(4;19)(q35;q13), acquires enhanced transcriptional activity and directly binds the ERM/ETV5 promoter via a novel target sequence to upregulate ERM/ETV5 and ETV1 expression. CIC-DUX4 transforms NIH 3T3 fibroblasts.","method":"Gene expression analysis, promoter binding assay (direct binding to ERM promoter), NIH 3T3 transformation assay, RT-PCR/sequencing of fusion transcript","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct promoter binding demonstrated, transformation assay, multiple orthogonal methods in a single focused study establishing mechanism","pmids":["16717057"],"is_preprint":false},{"year":2011,"finding":"Loss of ATXN1L destabilizes the transcriptional repressor CIC in mouse lungs, leading to derepression of Etv4 (a PEA3-family ETS activator), which in turn upregulates MMP9 expression and causes lung alveolarization defects. CIC deficiency alone recapitulates the lung phenotype, establishing CIC as a downstream effector of the ATXN1/ATXN1L complex in extracellular matrix remodeling.","method":"Genetic knockout mice (Atxn1L-/-, Atxn1-/-;Atxn1L-/- double KO, Cic conditional KO), gene expression analysis, immunostaining, functional lung phenotype readout","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models with orthogonal phenotypic and molecular readouts, replicated across compound mutants","pmids":["22014525"],"is_preprint":false},{"year":2017,"finding":"Loss of CIC, a transcriptional repressor of ETV1, ETV4, and ETV5, promotes survival under MEK1/2 inhibitor (trametinib) treatment in KRAS-mutant cancer cells. ATXN1L deletion (which reduces CIC protein levels) or ectopic ETV1/4/5 expression phenocopies CIC loss in conferring MAPKi resistance, defining the ATXN1L-CIC-ETS axis as a mediator of resistance to MAPK pathway inhibition.","method":"Genome-scale CRISPR-Cas9 loss-of-function screen, ectopic expression of ETV1/4/5, pharmacologic trametinib treatment across multiple cancer cell lines","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale CRISPR screen validated by orthogonal rescue experiments (ETV overexpression, ATXN1L deletion) across multiple cell lines","pmids":["28178529"],"is_preprint":false},{"year":2017,"finding":"Disruption of the ATXN1-CIC transcriptional repressor complex in mice causes hyperactivity, impaired learning and memory, abnormal maturation of upper-layer cortical neurons, and altered social interactions via CIC activity in hypothalamus and medial amygdala. De novo heterozygous truncating CIC mutations in humans produce intellectual disability, ADHD, and autism spectrum disorder, linking ATXN1-CIC complex loss-of-function to neurobehavioral phenotypes.","method":"Conditional mouse knockouts (forebrain-specific Cic deletion, Atxn1-CIC interaction mutants), behavioral assays, cortical neuron phenotyping, human genetic identification of de novo truncating mutations","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse genetic models with defined cellular and behavioral readouts, corroborated by human genetics","pmids":["28288114"],"is_preprint":false},{"year":2018,"finding":"CIC binds its DNA target sequences and is phosphorylated at S173 by ERK, which triggers binding to the E3 ubiquitin ligase PJA1 and subsequent proteasome-mediated degradation of CIC in glioblastoma. Deletion of the ERK binding site stabilizes CIC. PJA1 knockdown increases CIC stability and extends survival in in vivo GBM models.","method":"Co-immunoprecipitation, mutagenesis (ERK binding site deletion, S173 phosphorylation), PJA1 knockdown, in vivo GBM xenograft survival experiments, proteasome inhibition assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-specific mutagenesis combined with Co-IP, in vivo validation, and functional rescue in a single rigorous study","pmids":["30737375"],"is_preprint":false},{"year":2018,"finding":"CIC interacts with the SIN3 histone deacetylase complex to repress transcription of MAPK pathway effector genes (including cell-cycle and proliferation genes). Genome-wide CIC binding is abolished by high MAPK activity, leading to transcriptional activation of targets. Single amino acid substitutions found in oligodendrogliomas prevent CIC from binding its target genes, resulting in increased histone acetylation and mitogen-independent tumor growth.","method":"ChIP-seq (genome-wide CIC binding), Co-immunoprecipitation with SIN3 complex, site-directed mutagenesis of CIC residues mutated in oligodendroglioma, histone acetylation assays, gene expression profiling","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP-seq, Co-IP with deacetylase complex, mutagenesis, and functional histone acetylation readout in one study","pmids":["29844126"],"is_preprint":false},{"year":2020,"finding":"CIC represses VGF transcription by recruiting the SIN3-HDAC corepressor complex to VGF target loci. CIC also associates with the BRG1-containing mSWI/SNF complex, which is required for CIC-dependent transcriptional repression. Brain-specific deletion of Cic in mice compromises neuroblast-to-immature neuron transition in the hippocampus.","method":"ChIP-seq, mass spectrometry of CIC-interacting proteins, Co-IP, Cic brain-specific conditional knockout mice, neuronal differentiation assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP-seq, unbiased mass spectrometry interactome, Co-IP, and in vivo KO with defined cellular phenotype in one study","pmids":["32229723"],"is_preprint":false},{"year":2020,"finding":"c-Src binds CIC and tyrosine-phosphorylates it at residue Y1455 downstream of EGFR/RTK activation, promoting nuclear export of CIC. A CIC-Y1455F mutant that cannot be phosphorylated by c-Src remains nuclear and retains repressor activity against ETV1 and ETV5. Dasatinib (Src family kinase inhibitor) prevents EGF-mediated tyrosine phosphorylation of CIC and reduces GBM cell viability in a CIC-dependent manner.","method":"Co-immunoprecipitation, site-directed mutagenesis (Y1455F), subcellular fractionation/localization, dasatinib pharmacologic treatment, cell viability assays in GBM cells and glioma stem cells","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP, mutagenesis, localization, and pharmacologic rescue experiment with mutant rescue controls in one study","pmids":["32029440"],"is_preprint":false},{"year":2020,"finding":"p90RSK (a downstream target of ERK1/2) phosphorylates CIC at S173 and S301, creating a 14-3-3 recognition motif that leads to 14-3-3-mediated nuclear export of CIC, thereby derepressing DUSP6 transcription. CIC directly represses DUSP6 by binding three cis-regulatory elements in the DUSP6 promoter. The oncogenic CIC-DUX4 fusion protein acts as a transcriptional activator of DUSP6, and its nuclear/cytoplasmic distribution remains regulated by ERK1/2 signaling.","method":"ChIP, promoter binding assays (CRE identification), phosphorylation assays (p90RSK), 14-3-3 interaction assay, subcellular localization studies, mutagenesis (S173, S301)","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct promoter binding with CRE mapping, kinase-substrate assay, 14-3-3 interaction, localization with mutagenesis in one study","pmids":["33103082"],"is_preprint":false},{"year":2019,"finding":"The CIC-DUX4 fusion oncoprotein directly upregulates ETV4 (via neomorphic transcriptional activation) and CCNE1 (cyclin E1), which drive tumor metastasis and cell survival, respectively. CIC-DUX4-expressing tumors exhibit molecular dependence on the CCNE1-CDK2 cell cycle complex, rendering them sensitive to CDK2 inhibition.","method":"ChIP-seq (direct binding of CIC-DUX4 to ETV4 and CCNE1 loci), gene expression profiling, CIC-DUX4 KD, CDK2 inhibitor sensitivity assays in patient-derived and mouse CDS models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP-seq demonstrating direct binding, KD experiments, pharmacologic CDK2 inhibition with multiple model systems","pmids":["31329165"],"is_preprint":false},{"year":2017,"finding":"CIC-DUX4 expression in mouse embryonic mesenchymal cells induces rapid formation of undifferentiated sarcomas in vivo. Downstream CIC-DUX4 targets including PEA3 family genes (ETS), Ccnd2, Crh, and Zic1 are upregulated. Gene silencing of CIC-DUX4, Ccnd2, Ret, or Bcl2 inhibits CDS tumor cell growth in vitro.","method":"Retroviral transduction of embryonic mesenchymal cells with CIC-DUX4 cDNA, mouse transplantation model, gene expression profiling, siRNA knockdown, CDK4/6 inhibitor treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model of CIC-DUX4 oncogenesis, gene expression profiling of downstream targets, orthogonal KD validation","pmids":["28404587"],"is_preprint":false},{"year":2015,"finding":"CIC suppresses prostate cancer cell proliferation, invasion, and migration. Knockdown of CIC derepresses ETV5 and CRABP1 in LNCaP and PC-3 cells, respectively, promoting proliferation and invasion. miR-93, miR-106b, and miR-375 cooperatively downregulate CIC protein levels, identifying miR-93/miR-106b/miR-375-CIC-CRABP1 as a regulatory axis in prostate cancer.","method":"CIC overexpression and RNAi knockdown in prostate cancer cell lines, invasion/migration/proliferation assays, dual luciferase reporter assay (miRNA-3'UTR binding), gene expression assays for ETV5 and CRABP1","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional KD/OE with defined phenotypes and direct target gene derepression, miRNA validated by luciferase assay; single lab","pmids":["26124181"],"is_preprint":false},{"year":2015,"finding":"CIC mutations in 1p/19q-codeleted gliomas result in loss of CIC nuclear targeting and protein inactivation, with upregulation of normally CIC-repressed genes ETV1, ETV4, ETV5, and CCND1, as well as DUSP4 and SPRED1. A truncating CIC mutation causes defective nuclear localization of CIC protein in human glioma cells expressing IDH1-R132H.","method":"Lentiviral transfection of glioma cells with mutant and WT CIC, transcriptomic profiling, CIC protein expression analysis, subcellular localization studies","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — isogenic lentiviral cell model with transcriptomic profiling and subcellular localization; single lab, no independent replication stated","pmids":["26017892"],"is_preprint":false},{"year":2017,"finding":"CIC loss in mouse neural stem cells bypasses the EGF requirement for proliferation and causes a defect in oligodendrocyte differentiation potential. Cic-deficient mice produce an aberrant proliferative neural population. In an orthotopic mouse glioma model, Cic loss potentiates tumor formation and reduces latency.","method":"Cic conditional knockout mice, in vitro neural stem cell culture (EGF-independent growth assay), oligodendrocyte differentiation assay, orthotopic glioma mouse model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo and in vitro experiments with defined cellular and tumor phenotypes in a single study","pmids":["28939681"],"is_preprint":false},{"year":2018,"finding":"CIC loss in neuroblastoma activates the RAS-MAPK pathway (independently of phosphorylated ERK) and significantly increases tumor growth in vivo. CIC deletion in neuroblastoma cell lines induces RAS-MAPK pathway activation, establishing CIC as a tumor suppressor functioning downstream of this pathway.","method":"CIC knockout in neuroblastoma cell lines, in vivo xenograft tumor growth assays, transcriptomic RAS-MAPK pathway signature analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KO cell lines with in vivo tumor growth and pathway signature readout; single lab study","pmids":["30115695"],"is_preprint":false},{"year":2014,"finding":"Endogenous long (CIC-L) and short (CIC-S) CIC isoforms are predominantly localized to the nucleus or cytoplasm, respectively, with cytoplasmic CIC-S found in close proximity to mitochondria. Co-expression of mutant CIC-S (R201W or R1515H) with mutant IDH1-R132H reduces cell clonogenicity in an additive manner and increases 2-hydroxyglutarate levels compared to WT CIC. Mutant CIC-S reduces phosphorylated ACLY levels, suggesting a cytosolic citrate metabolism-related mechanism.","method":"Stable transfection of HEK293 and HOG cells with WT/mutant CIC and IDH1 constructs, subcellular fractionation/localization, clonogenic assays, 2-HG metabolite measurement, western blot for phospho-ACLY","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — isogenic cell lines, subcellular localization, metabolite measurement, and functional clonogenicity assay; single lab","pmids":["25277207"],"is_preprint":false},{"year":2020,"finding":"CIC binds to an octameric sequence in the promoter regions of folate transport genes FOLR1, PCFT, and RFC1 (SLC19A1). A CIC nonsense variant (p.R353X) downregulates FOLR1 expression and decreases cellular folic acid binding in HeLa cells and iPSCs derived from a CFD proband.","method":"Promoter binding assay (CIC binding to FOLR1/PCFT/RFC1 promoters), HeLa cell transfection with CIC p.R353X variant, FOLR1 expression assay, folate binding assay in cells, iPSC model","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated with functional validation in two cell models (HeLa and patient iPSC); single lab","pmids":["32820034"],"is_preprint":false},{"year":2021,"finding":"CIC-DUX4 fusion oncoprotein requires P300/CBP acetyltransferase activity to induce histone H3 acetylation at target loci, activate downstream target genes, and drive oncogenesis. The selective P300/CBP inhibitor iP300w suppresses CIC-DUX4 transcriptional activity, reverses CIC-DUX4-induced histone acetylation, induces cell cycle arrest, and prevents CDS xenograft tumor growth in vivo.","method":"P300/CBP inhibitor treatment (iP300w, A-485), histone acetylation assays, CIC-DUX4 transcriptional activity assays, in vivo CDS xenograft tumor growth experiments, cell cycle analysis","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic histone acetylation assay linked to transcriptional output, confirmed in vivo with pharmacologic and functional readouts","pmids":["34642317"],"is_preprint":false},{"year":2022,"finding":"CIC-DUX4 sarcomas depend on the G2/M checkpoint kinase WEE1 as an adaptive survival mechanism. CIC-DUX4-mediated CCNE1 upregulation compromises the G1/S transition, creating dependence on WEE1 to limit DNA damage and prevent unscheduled mitotic entry. Genetic or pharmacologic WEE1 inhibition induces DNA damage-associated apoptosis in patient-derived CIC-DUX4 sarcoma cells in vitro and in vivo.","method":"Transcriptional profiling and kinase activity screen on patient-derived specimens, WEE1 genetic knockdown, WEE1 inhibitor pharmacologic treatment, DNA damage assays, in vivo xenograft experiments","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — integrative kinase screen validated by genetic KD and pharmacologic inhibition in vitro and in vivo with mechanistic DNA damage readout","pmids":["35315355"],"is_preprint":false},{"year":2020,"finding":"AC006129.1 lncRNA binds to the CIC promoter, facilitates interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation. This relieves CIC-mediated repression of SOCS3 and CASP1, derepressing SOCS3 to enhance anti-inflammatory JAK/STAT signaling inhibition.","method":"RNA sequencing of schizophrenia discordant twin samples, AC006129.1 overexpression mouse model, promoter binding assay, DNA methylation analysis (bisulfite), DNMT co-immunoprecipitation","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter binding and DNMT interaction demonstrated with functional gene expression readout; single lab with in vivo validation","pmids":["32015466"],"is_preprint":false},{"year":2023,"finding":"CIC loss in glioma leads to upregulation of xCT/SLC7A11 expression and increased extracellular glutamate release. Non-phosphorylatable CIC (Ser173 mutant unable to interact with 14-3-3) shows enhanced transcriptional repressor function, demonstrating that 14-3-3 interaction inhibits CIC repressor activity in glioma. CIC restoration in oligodendroglioma reduces extracellular glutamate, neuronal toxicity, and xCT/SLC7A11 levels.","method":"CIC knockdown and overexpression in patient-derived glioma lines, RNA-sequencing, non-phosphorylatable CIC-S173A mutant expression, extracellular glutamate measurement, neuronal toxicity assay","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional KD/OE with defined molecular readouts including mutagenesis; single lab","pmids":["36647117"],"is_preprint":false},{"year":2018,"finding":"ATXN1L functionally interacts with CIC to repress CIC target genes. In isogenic ATXN1L knockout and CIC knockout human cell lines, CIC and ATXN1L show reciprocal functional relationship in transcriptomic profiles. Loss of either CIC or ATXN1L converges on dysregulation of mitotic cell cycle and division gene sets.","method":"Isogenic ATXN1LKO and CICKO human cell lines, transcriptome analysis, functional in vitro studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — isogenic KO models with transcriptomic readout; functional relationship established but mechanism of interaction not fully biochemically resolved","pmids":["30093628"],"is_preprint":false}],"current_model":"CIC (Capicua) is an evolutionarily conserved HMG-box transcriptional repressor that acts downstream of RTK/RAS/MAPK signaling: in the basal state CIC directly binds octameric target sequences to repress genes including ETV1/4/5, CCND1, DUSP6, and FOLR1 via recruitment of the SIN3-HDAC deacetylase complex and the BRG1-containing mSWI/SNF complex; upon pathway activation, ERK and p90RSK phosphorylate CIC (at S173/S301), creating 14-3-3 docking sites that mediate nuclear export, while c-Src phosphorylates CIC at Y1455 to promote cytoplasmic sequestration, and the E3 ligase PJA1 drives proteasome-mediated CIC degradation; the ATXN1/ATXN1L proteins stabilize and are required for full CIC repressor activity; CIC loss derepresses oncogenic ETS transcription factors and MAPK effectors, driving proliferation and resistance to MAPKi; in the CIC-DUX4 fusion oncoprotein, the C-terminal DUX4 domain converts CIC into a transcriptional activator requiring P300/CBP that directly upregulates ETV4 and CCNE1, conferring CDK2 and WEE1 dependence."},"narrative":{"mechanistic_narrative":"CIC (Capicua) is an HMG-box transcriptional repressor that functions as the principal nuclear effector restraining RTK/RAS/MAPK output, directly binding octameric target sequences in the promoters of PEA3-family ETS genes (ETV1/4/5), CCND1, DUSP6, and the folate transporters FOLR1/PCFT/RFC1 to keep them silent in the basal state [PMID:29844126, PMID:33103082, PMID:26017892, PMID:32820034]. Repression is enforced through recruitment of the SIN3-HDAC deacetylase complex and association with the BRG1-containing mSWI/SNF complex, and oligodendroglioma point mutations that abolish DNA binding raise histone acetylation at targets and confer mitogen-independent growth [PMID:29844126, PMID:32229723]. CIC activity is gated by multiple post-translational inputs downstream of pathway activation: ERK and p90RSK phosphorylate CIC at S173/S301 to create 14-3-3 docking sites that drive nuclear export and target derepression, ERK-dependent S173 phosphorylation additionally recruits the E3 ligase PJA1 for proteasomal degradation, and c-Src tyrosine-phosphorylates CIC at Y1455 to promote cytoplasmic sequestration [PMID:30737375, PMID:32029440, PMID:33103082, PMID:36647117]. CIC repressor function further depends on ATXN1/ATXN1L, which stabilize the protein and are required for full target repression [PMID:22014525, PMID:28178529, PMID:30093628]. Loss of CIC—by mutation, ATXN1L loss, or miRNA-mediated downregulation—derepresses ETS and MAPK effector genes to drive proliferation, invasion, MAPK-inhibitor resistance, and tumor formation across glioma, neuroblastoma, and prostate cancer, and CIC truncating mutations cause a neurobehavioral syndrome of intellectual disability, ADHD, and autism [PMID:28178529, PMID:28288114, PMID:26124181, PMID:28939681, PMID:30115695]. In the oncogenic CIC-DUX4 fusion, a C-terminal DUX4 domain converts CIC into a P300/CBP-dependent transcriptional activator that directly upregulates ETV4 and CCNE1, transforming mesenchymal cells and conferring dependence on the CCNE1-CDK2 axis and on WEE1 [PMID:16717057, PMID:31329165, PMID:28404587, PMID:34642317, PMID:35315355].","teleology":[{"year":2006,"claim":"Established that the human CIC gene encodes an HMG-box transcription factor and that its fusion to DUX4 creates a neomorphic activator, reframing a repressor as the basis of an oncogenic driver.","evidence":"Promoter binding assay to the ERM/ETV5 promoter and NIH 3T3 transformation with the CIC-DUX4 fusion","pmids":["16717057"],"confidence":"High","gaps":["Did not define the wild-type repressive function of native CIC","No genome-wide binding map","Cofactor requirements of the fusion activator unresolved"]},{"year":2011,"claim":"Placed CIC downstream of the ATXN1/ATXN1L complex, showing CIC is a stability-dependent repressor whose loss derepresses Etv4 and disrupts tissue remodeling.","evidence":"Atxn1L and Cic knockout mouse models with lung phenotyping and Etv4/MMP9 expression analysis","pmids":["22014525"],"confidence":"High","gaps":["Biochemical mechanism of ATXN1L-mediated CIC stabilization not resolved","Did not address signaling regulation of CIC"]},{"year":2014,"claim":"Distinguished nuclear (CIC-L) from cytoplasmic (CIC-S) isoforms and linked mutant CIC-S to altered cytosolic citrate metabolism in an IDH1-mutant context.","evidence":"Isogenic HEK293/HOG transfections, subcellular fractionation, 2-HG measurement, phospho-ACLY western blot","pmids":["25277207"],"confidence":"Medium","gaps":["Metabolic link to ACLY is correlative","Single lab, no independent replication","Functional role of mitochondrial proximity unclear"]},{"year":2015,"claim":"Connected CIC inactivating mutations in 1p/19q-codeleted glioma to loss of nuclear targeting and derepression of ETS and cell-cycle genes, defining a tumor-suppressor mode.","evidence":"Lentiviral WT/mutant CIC expression in IDH1-R132H glioma cells, transcriptomics, localization studies","pmids":["26017892"],"confidence":"Medium","gaps":["Mechanism of mutation-driven nuclear mislocalization not biochemically defined","Single lab"]},{"year":2015,"claim":"Identified a miRNA-CIC regulatory axis in prostate cancer, showing CIC loss promotes proliferation and invasion via ETV5 and CRABP1 derepression.","evidence":"CIC overexpression/RNAi in prostate cell lines, invasion/migration assays, miRNA-3'UTR luciferase assays","pmids":["26124181"],"confidence":"Medium","gaps":["Single lab","In vivo relevance of the miRNA axis untested"]},{"year":2017,"claim":"Defined the ATXN1L-CIC-ETS axis as a mediator of MAPK-inhibitor resistance, explaining how CIC loss sustains proliferation under MEK blockade.","evidence":"Genome-scale CRISPR screen under trametinib with ETV1/4/5 rescue and ATXN1L deletion phenocopy across cell lines","pmids":["28178529"],"confidence":"High","gaps":["Did not resolve which ETS factor is rate-limiting in vivo","Combinatorial therapeutic strategy untested"]},{"year":2017,"claim":"Linked ATXN1-CIC complex loss to neurodevelopmental and behavioral phenotypes in mice and to a human neurobehavioral syndrome, extending CIC function beyond cancer.","evidence":"Forebrain-specific Cic and Atxn1-CIC interaction-mutant mice with behavioral/cortical phenotyping plus human de novo truncating mutations","pmids":["28288114"],"confidence":"High","gaps":["Target genes driving neuronal phenotypes not fully defined","Circuit-level mechanism unclear"]},{"year":2017,"claim":"Showed CIC loss bypasses EGF dependence in neural stem cells and potentiates gliomagenesis, demonstrating CIC restrains mitogen-driven proliferation.","evidence":"Cic conditional KO mice, EGF-independent growth and oligodendrocyte differentiation assays, orthotopic glioma model","pmids":["28939681"],"confidence":"High","gaps":["Direct target genes mediating EGF bypass not enumerated","Cell-of-origin specificity unresolved"]},{"year":2017,"claim":"Demonstrated CIC-DUX4 is sufficient to generate undifferentiated sarcomas in vivo and identified actionable downstream dependencies.","evidence":"Retroviral CIC-DUX4 transduction of mesenchymal cells, transplantation, expression profiling, siRNA and CDK4/6 inhibitor assays","pmids":["28404587"],"confidence":"High","gaps":["Direct vs indirect target distinction limited","Mechanism of activation conversion not defined here"]},{"year":2018,"claim":"Identified the corepressor machinery (SIN3-HDAC) and showed DNA-binding mutations convert CIC loss into mitogen-independent growth via increased histone acetylation.","evidence":"ChIP-seq, SIN3 Co-IP, oligodendroglioma mutation mutagenesis, histone acetylation and expression readouts","pmids":["29844126"],"confidence":"High","gaps":["Stoichiometry and recruitment determinants of SIN3 not resolved","Genome-wide site selection rules incomplete"]},{"year":2018,"claim":"Established ERK-dependent S173 phosphorylation as the trigger for PJA1-mediated CIC degradation, defining a signal-coupled turnover mechanism.","evidence":"Co-IP, ERK-site and S173 mutagenesis, PJA1 knockdown, proteasome inhibition, in vivo GBM survival","pmids":["30737375"],"confidence":"High","gaps":["Ubiquitination site mapping not detailed","Crosstalk with phospho-export pathway unresolved"]},{"year":2018,"claim":"Showed CIC loss activates RAS-MAPK output and drives neuroblastoma growth, generalizing CIC's tumor-suppressor role across lineages.","evidence":"CIC knockout neuroblastoma lines, xenograft growth, RAS-MAPK signature analysis","pmids":["30115695"],"confidence":"Medium","gaps":["Mechanism of pERK-independent pathway activation undefined","Single lab"]},{"year":2018,"claim":"Demonstrated reciprocal CIC-ATXN1L functional interaction converging on mitotic cell-cycle gene control.","evidence":"Isogenic ATXN1L-KO and CIC-KO human cell lines with transcriptomic comparison","pmids":["30093628"],"confidence":"Medium","gaps":["Biochemical basis of the interaction not fully resolved","Single lab"]},{"year":2019,"claim":"Mapped the direct neomorphic targets of CIC-DUX4 (ETV4 and CCNE1) and revealed a CCNE1-CDK2 dependency exploitable therapeutically.","evidence":"ChIP-seq, knockdown, CDK2 inhibitor sensitivity in patient-derived and mouse CDS models","pmids":["31329165"],"confidence":"High","gaps":["Relative contribution of ETV4 vs CCNE1 to metastasis vs survival incompletely partitioned"]},{"year":2020,"claim":"Resolved the SIN3-HDAC plus BRG1/mSWI/SNF requirement for CIC repression and demonstrated a neuronal differentiation role in vivo.","evidence":"ChIP-seq, mass-spec interactome, Co-IP, brain-specific Cic KO with neuroblast transition assays","pmids":["32229723"],"confidence":"High","gaps":["How CIC selects between SIN3 and mSWI/SNF at loci unclear","Direct vs assisted recruitment of BRG1 undefined"]},{"year":2020,"claim":"Defined c-Src/Y1455 tyrosine phosphorylation as a parallel cytoplasmic-export mechanism inactivating CIC downstream of EGFR.","evidence":"Co-IP, Y1455F mutagenesis, localization, dasatinib treatment and CIC-dependent viability assays","pmids":["32029440"],"confidence":"High","gaps":["Interplay between Y1455 and S173/S301 phospho-events not resolved","Structural basis of export unclear"]},{"year":2020,"claim":"Established the p90RSK-S173/S301-14-3-3 nuclear export module that derepresses DUSP6, completing the signal-to-localization logic.","evidence":"ChIP with DUSP6 CRE mapping, p90RSK kinase assay, 14-3-3 interaction, localization mutagenesis","pmids":["33103082"],"confidence":"High","gaps":["Relative weighting of degradation vs export under physiological signaling unresolved"]},{"year":2020,"claim":"Extended CIC's direct targets to folate transporter genes and linked a CIC nonsense variant to cerebral folate deficiency.","evidence":"Promoter binding to FOLR1/PCFT/RFC1, CIC p.R353X expression, folate binding assays in HeLa and patient iPSCs","pmids":["32820034"],"confidence":"Medium","gaps":["Single lab","Mechanism of variant-induced FOLR1 downregulation not fully defined"]},{"year":2020,"claim":"Identified an lncRNA-driven epigenetic route to CIC silencing relevant to schizophrenia, derepressing SOCS3/CASP1.","evidence":"RNA-seq from discordant twins, AC006129.1 overexpression mouse, promoter binding, bisulfite methylation, DNMT Co-IP","pmids":["32015466"],"confidence":"Medium","gaps":["Single lab","Causal contribution to disease phenotype indirect"]},{"year":2021,"claim":"Showed CIC-DUX4 requires P300/CBP acetyltransferase activity for its activator function, providing an epigenetic therapeutic vulnerability.","evidence":"iP300w/A-485 treatment, histone acetylation and transcriptional activity assays, CDS xenografts","pmids":["34642317"],"confidence":"High","gaps":["Direct CIC-DUX4/P300 physical interaction not biochemically detailed","Specificity over native gene programs incomplete"]},{"year":2022,"claim":"Defined a WEE1 dependency in CIC-DUX4 sarcoma arising from CCNE1-driven replication stress, expanding the synthetic-lethal landscape.","evidence":"Kinase activity screen on patient specimens, WEE1 knockdown and inhibitor, DNA damage assays, xenografts","pmids":["35315355"],"confidence":"High","gaps":["Combination with CDK2 inhibition not benchmarked","Resistance mechanisms unexplored"]},{"year":2023,"claim":"Linked CIC loss to xCT/SLC7A11-driven glutamate excitotoxicity in glioma and confirmed that 14-3-3 binding inhibits CIC repressor activity.","evidence":"Patient-derived glioma KD/OE, RNA-seq, non-phosphorylatable CIC-S173A mutant, extracellular glutamate and neurotoxicity assays","pmids":["36647117"],"confidence":"Medium","gaps":["Single lab","Direct vs indirect regulation of SLC7A11 not fully mapped"]},{"year":null,"claim":"How the multiple inactivating inputs (S173/S301 phospho-export, Y1455 cytoplasmic sequestration, PJA1 degradation, ATXN1L-dependent stabilization) are integrated quantitatively to set CIC repressor output in a given cell context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model weighting export vs degradation under physiological signaling","Structural basis of DNA target selection incompletely defined","Determinants of SIN3-HDAC vs mSWI/SNF cofactor choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,8,9,12,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,8,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5,7,12,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,8,15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal 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CIC-Rearranged Neoplasia.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33344249","citation_count":23,"is_preprint":false},{"pmid":"31500928","id":"PMC_31500928","title":"MiR-1307 influences the chemotherapeutic sensitivity in ovarian cancer cells through the regulation of the CIC transcriptional repressor.","date":"2019","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/31500928","citation_count":23,"is_preprint":false},{"pmid":"36964296","id":"PMC_36964296","title":"Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature.","date":"2023","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36964296","citation_count":21,"is_preprint":false},{"pmid":"36647117","id":"PMC_36647117","title":"CIC reduces xCT/SLC7A11 expression and glutamate release in glioma.","date":"2023","source":"Acta neuropathologica 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neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35203088","citation_count":19,"is_preprint":false},{"pmid":"36537582","id":"PMC_36537582","title":"Patterns of care and outcome of CIC-rearranged sarcoma patients: A nationwide study of the French sarcoma group.","date":"2022","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36537582","citation_count":19,"is_preprint":false},{"pmid":"37291277","id":"PMC_37291277","title":"Capicua (CIC) mutations in gliomas in association with MAPK activation for exposing a potential therapeutic target.","date":"2023","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/37291277","citation_count":19,"is_preprint":false},{"pmid":"34685592","id":"PMC_34685592","title":"The CAM Model for CIC-DUX4 Sarcoma and Its Potential Use for Precision Medicine.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34685592","citation_count":18,"is_preprint":false},{"pmid":"2958187","id":"PMC_2958187","title":"Erythrocyte complement receptor type 1 (CR1) expression and circulating immune complex (CIC) levels in hydralazine-induced SLE.","date":"1987","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2958187","citation_count":18,"is_preprint":false},{"pmid":"30353686","id":"PMC_30353686","title":"CIC-DUX4 sarcoma diagnosed by fine-needle aspiration cytology: A case report.","date":"2018","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/30353686","citation_count":18,"is_preprint":false},{"pmid":"35315355","id":"PMC_35315355","title":"WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma.","date":"2022","source":"JCI 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and Neck Round Cell Sarcomas: A Comparative Clinicopathologic Analysis of 2 Molecular Subsets: Ewing and CIC-Rearranged Sarcomas.","date":"2017","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28337592","citation_count":16,"is_preprint":false},{"pmid":"28645808","id":"PMC_28645808","title":"Primary undifferentiated small round cell sarcoma of the deep abdominal wall with a novel variant of t(10;19) CIC-DUX4 gene fusion.","date":"2017","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/28645808","citation_count":15,"is_preprint":false},{"pmid":"15139012","id":"PMC_15139012","title":"Expression of novel isoforms of the CIC-1 chloride channel in astrocytic glial cells in vitro.","date":"2004","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/15139012","citation_count":14,"is_preprint":false},{"pmid":"17334850","id":"PMC_17334850","title":"Identification of ClC-2 and CIC-K2 chloride channels in cultured rat type IV spiral ligament fibrocytes.","date":"2007","source":"Journal of the Association for Research in Otolaryngology : JARO","url":"https://pubmed.ncbi.nlm.nih.gov/17334850","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53607,"output_tokens":6387,"usd":0.128313,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15194,"output_tokens":6179,"usd":0.115223,"stage2_stop_reason":"end_turn"},"total_usd":0.243536,"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\": 2006,\n      \"finding\": \"CIC (human homolog of Drosophila capicua) encodes a high mobility group box transcription factor that, when fused to DUX4 via t(4;19)(q35;q13), acquires enhanced transcriptional activity and directly binds the ERM/ETV5 promoter via a novel target sequence to upregulate ERM/ETV5 and ETV1 expression. CIC-DUX4 transforms NIH 3T3 fibroblasts.\",\n      \"method\": \"Gene expression analysis, promoter binding assay (direct binding to ERM promoter), NIH 3T3 transformation assay, RT-PCR/sequencing of fusion transcript\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct promoter binding demonstrated, transformation assay, multiple orthogonal methods in a single focused study establishing mechanism\",\n      \"pmids\": [\"16717057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of ATXN1L destabilizes the transcriptional repressor CIC in mouse lungs, leading to derepression of Etv4 (a PEA3-family ETS activator), which in turn upregulates MMP9 expression and causes lung alveolarization defects. CIC deficiency alone recapitulates the lung phenotype, establishing CIC as a downstream effector of the ATXN1/ATXN1L complex in extracellular matrix remodeling.\",\n      \"method\": \"Genetic knockout mice (Atxn1L-/-, Atxn1-/-;Atxn1L-/- double KO, Cic conditional KO), gene expression analysis, immunostaining, functional lung phenotype readout\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models with orthogonal phenotypic and molecular readouts, replicated across compound mutants\",\n      \"pmids\": [\"22014525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of CIC, a transcriptional repressor of ETV1, ETV4, and ETV5, promotes survival under MEK1/2 inhibitor (trametinib) treatment in KRAS-mutant cancer cells. ATXN1L deletion (which reduces CIC protein levels) or ectopic ETV1/4/5 expression phenocopies CIC loss in conferring MAPKi resistance, defining the ATXN1L-CIC-ETS axis as a mediator of resistance to MAPK pathway inhibition.\",\n      \"method\": \"Genome-scale CRISPR-Cas9 loss-of-function screen, ectopic expression of ETV1/4/5, pharmacologic trametinib treatment across multiple cancer cell lines\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale CRISPR screen validated by orthogonal rescue experiments (ETV overexpression, ATXN1L deletion) across multiple cell lines\",\n      \"pmids\": [\"28178529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Disruption of the ATXN1-CIC transcriptional repressor complex in mice causes hyperactivity, impaired learning and memory, abnormal maturation of upper-layer cortical neurons, and altered social interactions via CIC activity in hypothalamus and medial amygdala. De novo heterozygous truncating CIC mutations in humans produce intellectual disability, ADHD, and autism spectrum disorder, linking ATXN1-CIC complex loss-of-function to neurobehavioral phenotypes.\",\n      \"method\": \"Conditional mouse knockouts (forebrain-specific Cic deletion, Atxn1-CIC interaction mutants), behavioral assays, cortical neuron phenotyping, human genetic identification of de novo truncating mutations\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse genetic models with defined cellular and behavioral readouts, corroborated by human genetics\",\n      \"pmids\": [\"28288114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIC binds its DNA target sequences and is phosphorylated at S173 by ERK, which triggers binding to the E3 ubiquitin ligase PJA1 and subsequent proteasome-mediated degradation of CIC in glioblastoma. Deletion of the ERK binding site stabilizes CIC. PJA1 knockdown increases CIC stability and extends survival in in vivo GBM models.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis (ERK binding site deletion, S173 phosphorylation), PJA1 knockdown, in vivo GBM xenograft survival experiments, proteasome inhibition assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-specific mutagenesis combined with Co-IP, in vivo validation, and functional rescue in a single rigorous study\",\n      \"pmids\": [\"30737375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIC interacts with the SIN3 histone deacetylase complex to repress transcription of MAPK pathway effector genes (including cell-cycle and proliferation genes). Genome-wide CIC binding is abolished by high MAPK activity, leading to transcriptional activation of targets. Single amino acid substitutions found in oligodendrogliomas prevent CIC from binding its target genes, resulting in increased histone acetylation and mitogen-independent tumor growth.\",\n      \"method\": \"ChIP-seq (genome-wide CIC binding), Co-immunoprecipitation with SIN3 complex, site-directed mutagenesis of CIC residues mutated in oligodendroglioma, histone acetylation assays, gene expression profiling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP-seq, Co-IP with deacetylase complex, mutagenesis, and functional histone acetylation readout in one study\",\n      \"pmids\": [\"29844126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIC represses VGF transcription by recruiting the SIN3-HDAC corepressor complex to VGF target loci. CIC also associates with the BRG1-containing mSWI/SNF complex, which is required for CIC-dependent transcriptional repression. Brain-specific deletion of Cic in mice compromises neuroblast-to-immature neuron transition in the hippocampus.\",\n      \"method\": \"ChIP-seq, mass spectrometry of CIC-interacting proteins, Co-IP, Cic brain-specific conditional knockout mice, neuronal differentiation assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP-seq, unbiased mass spectrometry interactome, Co-IP, and in vivo KO with defined cellular phenotype in one study\",\n      \"pmids\": [\"32229723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Src binds CIC and tyrosine-phosphorylates it at residue Y1455 downstream of EGFR/RTK activation, promoting nuclear export of CIC. A CIC-Y1455F mutant that cannot be phosphorylated by c-Src remains nuclear and retains repressor activity against ETV1 and ETV5. Dasatinib (Src family kinase inhibitor) prevents EGF-mediated tyrosine phosphorylation of CIC and reduces GBM cell viability in a CIC-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (Y1455F), subcellular fractionation/localization, dasatinib pharmacologic treatment, cell viability assays in GBM cells and glioma stem cells\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP, mutagenesis, localization, and pharmacologic rescue experiment with mutant rescue controls in one study\",\n      \"pmids\": [\"32029440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p90RSK (a downstream target of ERK1/2) phosphorylates CIC at S173 and S301, creating a 14-3-3 recognition motif that leads to 14-3-3-mediated nuclear export of CIC, thereby derepressing DUSP6 transcription. CIC directly represses DUSP6 by binding three cis-regulatory elements in the DUSP6 promoter. The oncogenic CIC-DUX4 fusion protein acts as a transcriptional activator of DUSP6, and its nuclear/cytoplasmic distribution remains regulated by ERK1/2 signaling.\",\n      \"method\": \"ChIP, promoter binding assays (CRE identification), phosphorylation assays (p90RSK), 14-3-3 interaction assay, subcellular localization studies, mutagenesis (S173, S301)\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct promoter binding with CRE mapping, kinase-substrate assay, 14-3-3 interaction, localization with mutagenesis in one study\",\n      \"pmids\": [\"33103082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The CIC-DUX4 fusion oncoprotein directly upregulates ETV4 (via neomorphic transcriptional activation) and CCNE1 (cyclin E1), which drive tumor metastasis and cell survival, respectively. CIC-DUX4-expressing tumors exhibit molecular dependence on the CCNE1-CDK2 cell cycle complex, rendering them sensitive to CDK2 inhibition.\",\n      \"method\": \"ChIP-seq (direct binding of CIC-DUX4 to ETV4 and CCNE1 loci), gene expression profiling, CIC-DUX4 KD, CDK2 inhibitor sensitivity assays in patient-derived and mouse CDS models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP-seq demonstrating direct binding, KD experiments, pharmacologic CDK2 inhibition with multiple model systems\",\n      \"pmids\": [\"31329165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CIC-DUX4 expression in mouse embryonic mesenchymal cells induces rapid formation of undifferentiated sarcomas in vivo. Downstream CIC-DUX4 targets including PEA3 family genes (ETS), Ccnd2, Crh, and Zic1 are upregulated. Gene silencing of CIC-DUX4, Ccnd2, Ret, or Bcl2 inhibits CDS tumor cell growth in vitro.\",\n      \"method\": \"Retroviral transduction of embryonic mesenchymal cells with CIC-DUX4 cDNA, mouse transplantation model, gene expression profiling, siRNA knockdown, CDK4/6 inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model of CIC-DUX4 oncogenesis, gene expression profiling of downstream targets, orthogonal KD validation\",\n      \"pmids\": [\"28404587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CIC suppresses prostate cancer cell proliferation, invasion, and migration. Knockdown of CIC derepresses ETV5 and CRABP1 in LNCaP and PC-3 cells, respectively, promoting proliferation and invasion. miR-93, miR-106b, and miR-375 cooperatively downregulate CIC protein levels, identifying miR-93/miR-106b/miR-375-CIC-CRABP1 as a regulatory axis in prostate cancer.\",\n      \"method\": \"CIC overexpression and RNAi knockdown in prostate cancer cell lines, invasion/migration/proliferation assays, dual luciferase reporter assay (miRNA-3'UTR binding), gene expression assays for ETV5 and CRABP1\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional KD/OE with defined phenotypes and direct target gene derepression, miRNA validated by luciferase assay; single lab\",\n      \"pmids\": [\"26124181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CIC mutations in 1p/19q-codeleted gliomas result in loss of CIC nuclear targeting and protein inactivation, with upregulation of normally CIC-repressed genes ETV1, ETV4, ETV5, and CCND1, as well as DUSP4 and SPRED1. A truncating CIC mutation causes defective nuclear localization of CIC protein in human glioma cells expressing IDH1-R132H.\",\n      \"method\": \"Lentiviral transfection of glioma cells with mutant and WT CIC, transcriptomic profiling, CIC protein expression analysis, subcellular localization studies\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — isogenic lentiviral cell model with transcriptomic profiling and subcellular localization; single lab, no independent replication stated\",\n      \"pmids\": [\"26017892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CIC loss in mouse neural stem cells bypasses the EGF requirement for proliferation and causes a defect in oligodendrocyte differentiation potential. Cic-deficient mice produce an aberrant proliferative neural population. In an orthotopic mouse glioma model, Cic loss potentiates tumor formation and reduces latency.\",\n      \"method\": \"Cic conditional knockout mice, in vitro neural stem cell culture (EGF-independent growth assay), oligodendrocyte differentiation assay, orthotopic glioma mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo and in vitro experiments with defined cellular and tumor phenotypes in a single study\",\n      \"pmids\": [\"28939681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIC loss in neuroblastoma activates the RAS-MAPK pathway (independently of phosphorylated ERK) and significantly increases tumor growth in vivo. CIC deletion in neuroblastoma cell lines induces RAS-MAPK pathway activation, establishing CIC as a tumor suppressor functioning downstream of this pathway.\",\n      \"method\": \"CIC knockout in neuroblastoma cell lines, in vivo xenograft tumor growth assays, transcriptomic RAS-MAPK pathway signature analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KO cell lines with in vivo tumor growth and pathway signature readout; single lab study\",\n      \"pmids\": [\"30115695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Endogenous long (CIC-L) and short (CIC-S) CIC isoforms are predominantly localized to the nucleus or cytoplasm, respectively, with cytoplasmic CIC-S found in close proximity to mitochondria. Co-expression of mutant CIC-S (R201W or R1515H) with mutant IDH1-R132H reduces cell clonogenicity in an additive manner and increases 2-hydroxyglutarate levels compared to WT CIC. Mutant CIC-S reduces phosphorylated ACLY levels, suggesting a cytosolic citrate metabolism-related mechanism.\",\n      \"method\": \"Stable transfection of HEK293 and HOG cells with WT/mutant CIC and IDH1 constructs, subcellular fractionation/localization, clonogenic assays, 2-HG metabolite measurement, western blot for phospho-ACLY\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — isogenic cell lines, subcellular localization, metabolite measurement, and functional clonogenicity assay; single lab\",\n      \"pmids\": [\"25277207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIC binds to an octameric sequence in the promoter regions of folate transport genes FOLR1, PCFT, and RFC1 (SLC19A1). A CIC nonsense variant (p.R353X) downregulates FOLR1 expression and decreases cellular folic acid binding in HeLa cells and iPSCs derived from a CFD proband.\",\n      \"method\": \"Promoter binding assay (CIC binding to FOLR1/PCFT/RFC1 promoters), HeLa cell transfection with CIC p.R353X variant, FOLR1 expression assay, folate binding assay in cells, iPSC model\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated with functional validation in two cell models (HeLa and patient iPSC); single lab\",\n      \"pmids\": [\"32820034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIC-DUX4 fusion oncoprotein requires P300/CBP acetyltransferase activity to induce histone H3 acetylation at target loci, activate downstream target genes, and drive oncogenesis. The selective P300/CBP inhibitor iP300w suppresses CIC-DUX4 transcriptional activity, reverses CIC-DUX4-induced histone acetylation, induces cell cycle arrest, and prevents CDS xenograft tumor growth in vivo.\",\n      \"method\": \"P300/CBP inhibitor treatment (iP300w, A-485), histone acetylation assays, CIC-DUX4 transcriptional activity assays, in vivo CDS xenograft tumor growth experiments, cell cycle analysis\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic histone acetylation assay linked to transcriptional output, confirmed in vivo with pharmacologic and functional readouts\",\n      \"pmids\": [\"34642317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CIC-DUX4 sarcomas depend on the G2/M checkpoint kinase WEE1 as an adaptive survival mechanism. CIC-DUX4-mediated CCNE1 upregulation compromises the G1/S transition, creating dependence on WEE1 to limit DNA damage and prevent unscheduled mitotic entry. Genetic or pharmacologic WEE1 inhibition induces DNA damage-associated apoptosis in patient-derived CIC-DUX4 sarcoma cells in vitro and in vivo.\",\n      \"method\": \"Transcriptional profiling and kinase activity screen on patient-derived specimens, WEE1 genetic knockdown, WEE1 inhibitor pharmacologic treatment, DNA damage assays, in vivo xenograft experiments\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — integrative kinase screen validated by genetic KD and pharmacologic inhibition in vitro and in vivo with mechanistic DNA damage readout\",\n      \"pmids\": [\"35315355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AC006129.1 lncRNA binds to the CIC promoter, facilitates interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation. This relieves CIC-mediated repression of SOCS3 and CASP1, derepressing SOCS3 to enhance anti-inflammatory JAK/STAT signaling inhibition.\",\n      \"method\": \"RNA sequencing of schizophrenia discordant twin samples, AC006129.1 overexpression mouse model, promoter binding assay, DNA methylation analysis (bisulfite), DNMT co-immunoprecipitation\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter binding and DNMT interaction demonstrated with functional gene expression readout; single lab with in vivo validation\",\n      \"pmids\": [\"32015466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CIC loss in glioma leads to upregulation of xCT/SLC7A11 expression and increased extracellular glutamate release. Non-phosphorylatable CIC (Ser173 mutant unable to interact with 14-3-3) shows enhanced transcriptional repressor function, demonstrating that 14-3-3 interaction inhibits CIC repressor activity in glioma. CIC restoration in oligodendroglioma reduces extracellular glutamate, neuronal toxicity, and xCT/SLC7A11 levels.\",\n      \"method\": \"CIC knockdown and overexpression in patient-derived glioma lines, RNA-sequencing, non-phosphorylatable CIC-S173A mutant expression, extracellular glutamate measurement, neuronal toxicity assay\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional KD/OE with defined molecular readouts including mutagenesis; single lab\",\n      \"pmids\": [\"36647117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATXN1L functionally interacts with CIC to repress CIC target genes. In isogenic ATXN1L knockout and CIC knockout human cell lines, CIC and ATXN1L show reciprocal functional relationship in transcriptomic profiles. Loss of either CIC or ATXN1L converges on dysregulation of mitotic cell cycle and division gene sets.\",\n      \"method\": \"Isogenic ATXN1LKO and CICKO human cell lines, transcriptome analysis, functional in vitro studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — isogenic KO models with transcriptomic readout; functional relationship established but mechanism of interaction not fully biochemically resolved\",\n      \"pmids\": [\"30093628\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CIC (Capicua) is an evolutionarily conserved HMG-box transcriptional repressor that acts downstream of RTK/RAS/MAPK signaling: in the basal state CIC directly binds octameric target sequences to repress genes including ETV1/4/5, CCND1, DUSP6, and FOLR1 via recruitment of the SIN3-HDAC deacetylase complex and the BRG1-containing mSWI/SNF complex; upon pathway activation, ERK and p90RSK phosphorylate CIC (at S173/S301), creating 14-3-3 docking sites that mediate nuclear export, while c-Src phosphorylates CIC at Y1455 to promote cytoplasmic sequestration, and the E3 ligase PJA1 drives proteasome-mediated CIC degradation; the ATXN1/ATXN1L proteins stabilize and are required for full CIC repressor activity; CIC loss derepresses oncogenic ETS transcription factors and MAPK effectors, driving proliferation and resistance to MAPKi; in the CIC-DUX4 fusion oncoprotein, the C-terminal DUX4 domain converts CIC into a transcriptional activator requiring P300/CBP that directly upregulates ETV4 and CCNE1, conferring CDK2 and WEE1 dependence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIC (Capicua) is an HMG-box transcriptional repressor that functions as the principal nuclear effector restraining RTK/RAS/MAPK output, directly binding octameric target sequences in the promoters of PEA3-family ETS genes (ETV1/4/5), CCND1, DUSP6, and the folate transporters FOLR1/PCFT/RFC1 to keep them silent in the basal state [#5, #8, #12, #16]. Repression is enforced through recruitment of the SIN3-HDAC deacetylase complex and association with the BRG1-containing mSWI/SNF complex, and oligodendroglioma point mutations that abolish DNA binding raise histone acetylation at targets and confer mitogen-independent growth [#5, #6]. CIC activity is gated by multiple post-translational inputs downstream of pathway activation: ERK and p90RSK phosphorylate CIC at S173/S301 to create 14-3-3 docking sites that drive nuclear export and target derepression, ERK-dependent S173 phosphorylation additionally recruits the E3 ligase PJA1 for proteasomal degradation, and c-Src tyrosine-phosphorylates CIC at Y1455 to promote cytoplasmic sequestration [#4, #7, #8, #20]. CIC repressor function further depends on ATXN1/ATXN1L, which stabilize the protein and are required for full target repression [#1, #2, #21]. Loss of CIC—by mutation, ATXN1L loss, or miRNA-mediated downregulation—derepresses ETS and MAPK effector genes to drive proliferation, invasion, MAPK-inhibitor resistance, and tumor formation across glioma, neuroblastoma, and prostate cancer, and CIC truncating mutations cause a neurobehavioral syndrome of intellectual disability, ADHD, and autism [#2, #3, #11, #13, #14]. In the oncogenic CIC-DUX4 fusion, a C-terminal DUX4 domain converts CIC into a P300/CBP-dependent transcriptional activator that directly upregulates ETV4 and CCNE1, transforming mesenchymal cells and conferring dependence on the CCNE1-CDK2 axis and on WEE1 [#0, #9, #10, #17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that the human CIC gene encodes an HMG-box transcription factor and that its fusion to DUX4 creates a neomorphic activator, reframing a repressor as the basis of an oncogenic driver.\",\n      \"evidence\": \"Promoter binding assay to the ERM/ETV5 promoter and NIH 3T3 transformation with the CIC-DUX4 fusion\",\n      \"pmids\": [\"16717057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the wild-type repressive function of native CIC\", \"No genome-wide binding map\", \"Cofactor requirements of the fusion activator unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed CIC downstream of the ATXN1/ATXN1L complex, showing CIC is a stability-dependent repressor whose loss derepresses Etv4 and disrupts tissue remodeling.\",\n      \"evidence\": \"Atxn1L and Cic knockout mouse models with lung phenotyping and Etv4/MMP9 expression analysis\",\n      \"pmids\": [\"22014525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of ATXN1L-mediated CIC stabilization not resolved\", \"Did not address signaling regulation of CIC\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Distinguished nuclear (CIC-L) from cytoplasmic (CIC-S) isoforms and linked mutant CIC-S to altered cytosolic citrate metabolism in an IDH1-mutant context.\",\n      \"evidence\": \"Isogenic HEK293/HOG transfections, subcellular fractionation, 2-HG measurement, phospho-ACLY western blot\",\n      \"pmids\": [\"25277207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Metabolic link to ACLY is correlative\", \"Single lab, no independent replication\", \"Functional role of mitochondrial proximity unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected CIC inactivating mutations in 1p/19q-codeleted glioma to loss of nuclear targeting and derepression of ETS and cell-cycle genes, defining a tumor-suppressor mode.\",\n      \"evidence\": \"Lentiviral WT/mutant CIC expression in IDH1-R132H glioma cells, transcriptomics, localization studies\",\n      \"pmids\": [\"26017892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mutation-driven nuclear mislocalization not biochemically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a miRNA-CIC regulatory axis in prostate cancer, showing CIC loss promotes proliferation and invasion via ETV5 and CRABP1 derepression.\",\n      \"evidence\": \"CIC overexpression/RNAi in prostate cell lines, invasion/migration assays, miRNA-3'UTR luciferase assays\",\n      \"pmids\": [\"26124181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo relevance of the miRNA axis untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the ATXN1L-CIC-ETS axis as a mediator of MAPK-inhibitor resistance, explaining how CIC loss sustains proliferation under MEK blockade.\",\n      \"evidence\": \"Genome-scale CRISPR screen under trametinib with ETV1/4/5 rescue and ATXN1L deletion phenocopy across cell lines\",\n      \"pmids\": [\"28178529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which ETS factor is rate-limiting in vivo\", \"Combinatorial therapeutic strategy untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked ATXN1-CIC complex loss to neurodevelopmental and behavioral phenotypes in mice and to a human neurobehavioral syndrome, extending CIC function beyond cancer.\",\n      \"evidence\": \"Forebrain-specific Cic and Atxn1-CIC interaction-mutant mice with behavioral/cortical phenotyping plus human de novo truncating mutations\",\n      \"pmids\": [\"28288114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes driving neuronal phenotypes not fully defined\", \"Circuit-level mechanism unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed CIC loss bypasses EGF dependence in neural stem cells and potentiates gliomagenesis, demonstrating CIC restrains mitogen-driven proliferation.\",\n      \"evidence\": \"Cic conditional KO mice, EGF-independent growth and oligodendrocyte differentiation assays, orthotopic glioma model\",\n      \"pmids\": [\"28939681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes mediating EGF bypass not enumerated\", \"Cell-of-origin specificity unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated CIC-DUX4 is sufficient to generate undifferentiated sarcomas in vivo and identified actionable downstream dependencies.\",\n      \"evidence\": \"Retroviral CIC-DUX4 transduction of mesenchymal cells, transplantation, expression profiling, siRNA and CDK4/6 inhibitor assays\",\n      \"pmids\": [\"28404587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect target distinction limited\", \"Mechanism of activation conversion not defined here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the corepressor machinery (SIN3-HDAC) and showed DNA-binding mutations convert CIC loss into mitogen-independent growth via increased histone acetylation.\",\n      \"evidence\": \"ChIP-seq, SIN3 Co-IP, oligodendroglioma mutation mutagenesis, histone acetylation and expression readouts\",\n      \"pmids\": [\"29844126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and recruitment determinants of SIN3 not resolved\", \"Genome-wide site selection rules incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established ERK-dependent S173 phosphorylation as the trigger for PJA1-mediated CIC degradation, defining a signal-coupled turnover mechanism.\",\n      \"evidence\": \"Co-IP, ERK-site and S173 mutagenesis, PJA1 knockdown, proteasome inhibition, in vivo GBM survival\",\n      \"pmids\": [\"30737375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination site mapping not detailed\", \"Crosstalk with phospho-export pathway unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CIC loss activates RAS-MAPK output and drives neuroblastoma growth, generalizing CIC's tumor-suppressor role across lineages.\",\n      \"evidence\": \"CIC knockout neuroblastoma lines, xenograft growth, RAS-MAPK signature analysis\",\n      \"pmids\": [\"30115695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of pERK-independent pathway activation undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated reciprocal CIC-ATXN1L functional interaction converging on mitotic cell-cycle gene control.\",\n      \"evidence\": \"Isogenic ATXN1L-KO and CIC-KO human cell lines with transcriptomic comparison\",\n      \"pmids\": [\"30093628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical basis of the interaction not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped the direct neomorphic targets of CIC-DUX4 (ETV4 and CCNE1) and revealed a CCNE1-CDK2 dependency exploitable therapeutically.\",\n      \"evidence\": \"ChIP-seq, knockdown, CDK2 inhibitor sensitivity in patient-derived and mouse CDS models\",\n      \"pmids\": [\"31329165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of ETV4 vs CCNE1 to metastasis vs survival incompletely partitioned\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the SIN3-HDAC plus BRG1/mSWI/SNF requirement for CIC repression and demonstrated a neuronal differentiation role in vivo.\",\n      \"evidence\": \"ChIP-seq, mass-spec interactome, Co-IP, brain-specific Cic KO with neuroblast transition assays\",\n      \"pmids\": [\"32229723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CIC selects between SIN3 and mSWI/SNF at loci unclear\", \"Direct vs assisted recruitment of BRG1 undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined c-Src/Y1455 tyrosine phosphorylation as a parallel cytoplasmic-export mechanism inactivating CIC downstream of EGFR.\",\n      \"evidence\": \"Co-IP, Y1455F mutagenesis, localization, dasatinib treatment and CIC-dependent viability assays\",\n      \"pmids\": [\"32029440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between Y1455 and S173/S301 phospho-events not resolved\", \"Structural basis of export unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the p90RSK-S173/S301-14-3-3 nuclear export module that derepresses DUSP6, completing the signal-to-localization logic.\",\n      \"evidence\": \"ChIP with DUSP6 CRE mapping, p90RSK kinase assay, 14-3-3 interaction, localization mutagenesis\",\n      \"pmids\": [\"33103082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weighting of degradation vs export under physiological signaling unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended CIC's direct targets to folate transporter genes and linked a CIC nonsense variant to cerebral folate deficiency.\",\n      \"evidence\": \"Promoter binding to FOLR1/PCFT/RFC1, CIC p.R353X expression, folate binding assays in HeLa and patient iPSCs\",\n      \"pmids\": [\"32820034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of variant-induced FOLR1 downregulation not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified an lncRNA-driven epigenetic route to CIC silencing relevant to schizophrenia, derepressing SOCS3/CASP1.\",\n      \"evidence\": \"RNA-seq from discordant twins, AC006129.1 overexpression mouse, promoter binding, bisulfite methylation, DNMT Co-IP\",\n      \"pmids\": [\"32015466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causal contribution to disease phenotype indirect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed CIC-DUX4 requires P300/CBP acetyltransferase activity for its activator function, providing an epigenetic therapeutic vulnerability.\",\n      \"evidence\": \"iP300w/A-485 treatment, histone acetylation and transcriptional activity assays, CDS xenografts\",\n      \"pmids\": [\"34642317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CIC-DUX4/P300 physical interaction not biochemically detailed\", \"Specificity over native gene programs incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a WEE1 dependency in CIC-DUX4 sarcoma arising from CCNE1-driven replication stress, expanding the synthetic-lethal landscape.\",\n      \"evidence\": \"Kinase activity screen on patient specimens, WEE1 knockdown and inhibitor, DNA damage assays, xenografts\",\n      \"pmids\": [\"35315355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combination with CDK2 inhibition not benchmarked\", \"Resistance mechanisms unexplored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked CIC loss to xCT/SLC7A11-driven glutamate excitotoxicity in glioma and confirmed that 14-3-3 binding inhibits CIC repressor activity.\",\n      \"evidence\": \"Patient-derived glioma KD/OE, RNA-seq, non-phosphorylatable CIC-S173A mutant, extracellular glutamate and neurotoxicity assays\",\n      \"pmids\": [\"36647117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs indirect regulation of SLC7A11 not fully mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple inactivating inputs (S173/S301 phospho-export, Y1455 cytoplasmic sequestration, PJA1 degradation, ATXN1L-dependent stabilization) are integrated quantitatively to set CIC repressor output in a given cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model weighting export vs degradation under physiological signaling\", \"Structural basis of DNA target selection incompletely defined\", \"Determinants of SIN3-HDAC vs mSWI/SNF cofactor choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 8, 9, 12, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 8, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5, 7, 12, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 8, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 8, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 8, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 9, 13, 18]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 6, 17]}\n    ],\n    \"complexes\": [\"SIN3-HDAC complex\", \"BRG1-containing mSWI/SNF complex\", \"ATXN1/ATXN1L-CIC repressor complex\"],\n    \"partners\": [\"ATXN1L\", \"ATXN1\", \"SIN3\", \"PJA1\", \"c-Src (SRC)\", \"14-3-3\", \"P300/CBP\", \"ERK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}