{"gene":"CIC","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2006,"finding":"CIC (capicua homolog) is a high mobility group box transcription factor that directly binds a novel target sequence in the ERM/ETV5 promoter to repress its transcription; fusion with DUX4 C-terminal fragment confers enhanced transcriptional activator activity, leading to upregulation of PEA3 family ETS genes (ERM/ETV5, ETV1) as downstream targets.","method":"Gene expression analysis, promoter binding assay (direct CIC-DUX4 binding to ERM promoter), NIH 3T3 transformation assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — direct promoter binding demonstrated, functional transforming activity shown, downstream targets identified by multiple methods in a single study","pmids":["16717057"],"is_preprint":false},{"year":2011,"finding":"ATXN1L stabilizes CIC protein; loss of ATXN1L destabilizes CIC, leading to derepression of Etv4, an activator of Mmp genes (including MMP9), causing extracellular matrix remodeling defects and lung alveolarization failure. CIC deficiency alone recapitulates the lung alveolarization defect.","method":"Atxn1L-/- and Atxn1-/-;Atxn1L-/- mouse models, gene expression analysis, loss-of-function with defined phenotypic readout","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo with multiple mutant backgrounds and orthogonal molecular readouts, replicated across compound knockouts","pmids":["22014525"],"is_preprint":false},{"year":2017,"finding":"CIC functions as a transcriptional repressor of ETV1, ETV4, and ETV5; loss of CIC (or loss of ATXN1L, which reduces CIC protein levels) promotes survival under MEK inhibitor treatment, identifying the ATXN1L-CIC-ETS transcription factor axis as a mediator of resistance to MAPK pathway inhibition.","method":"Genome-scale CRISPR-Cas9 loss-of-function screen in KRAS-mutant pancreatic cancer cells treated with trametinib; ectopic ETV expression rescue experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genome-scale functional screen with epistasis validation and ETV rescue; mechanistic pathway placement confirmed","pmids":["28178529"],"is_preprint":false},{"year":2017,"finding":"Disruption of the ATXN1-CIC transcriptional repressor complex in the developing mouse forebrain causes hyperactivity, impaired learning/memory, abnormal upper-layer cortical neuron maturation, and social interaction defects dependent on CIC activity in hypothalamus and medial amygdala. De novo heterozygous truncating CIC mutations in humans produce intellectual disability, ADHD, and autism spectrum disorder.","method":"Conditional mouse knockouts with behavioral phenotyping; human patient exome sequencing with matched clinical features","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined cellular and behavioral phenotypes, validated by human clinical genetics","pmids":["28288114"],"is_preprint":false},{"year":2018,"finding":"CIC represses transcription of MAPK pathway effector genes (including cell-cycle and proliferation genes) by interacting with the SIN3 histone deacetylase complex; CIC binding to target gene promoters is abolished by high MAPK activity, leading to increased histone acetylation and transcriptional activation. Oligodendroglioma-associated CIC missense mutations prevent DNA binding.","method":"Genome-wide ChIP-seq in multiple cell types, co-immunoprecipitation of CIC with SIN3 complex, histone acetylation assays, CIC mutant functional analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq, Co-IP, histone modification assays, and mutagenesis combined in one study","pmids":["29844126"],"is_preprint":false},{"year":2019,"finding":"CIC protein is continuously degraded in glioblastoma via proteasome-mediated degradation. The E3 ubiquitin ligase PJA1 mediates CIC degradation, which is triggered by phosphorylation of CIC at residue S173 and requires CIC binding to its DNA target. Deletion of the ERK binding site in CIC stabilizes it and increases therapeutic efficacy of ERK inhibition.","method":"PJA1 knockdown in vivo GBM models (survival assay), phosphorylation site mutagenesis, co-immunoprecipitation, proteasome inhibitor experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — E3 ligase identified by knockdown + in vivo rescue, phosphosite mutagenesis, multiple orthogonal methods","pmids":["30737375"],"is_preprint":false},{"year":2019,"finding":"CIC-DUX4 directly and neomorphically upregulates ETV4 (driving tumor metastasis) and CCNE1/cyclin E1 (driving tumor cell survival) as distinct transcriptional targets; CIC-DUX4-expressing tumors show molecular dependence on the CCNE1-CDK2 cell cycle complex.","method":"ChIP-seq for direct target binding, genetic knockdown of individual targets, CDK2 inhibitor sensitivity assays in CIC-DUX4 cell lines and xenografts","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — direct ChIP-seq binding evidence combined with functional rescue and pharmacological inhibition in vivo","pmids":["31329165"],"is_preprint":false},{"year":2020,"finding":"CIC functions as a transcriptional repressor of DUSP6 by directly binding three cis-regulatory elements in the DUSP6 promoter. p90RSK (downstream of ERK1/2) phosphorylates CIC at S173 and S301, creating a 14-3-3 recognition motif that mediates nuclear export of CIC, thereby derepressing DUSP6 and completing an ERK1/2/p90RSK/CIC/DUSP6 negative feedback circuit.","method":"Promoter-binding assays (ChIP and reporter), site-directed mutagenesis of CIC phosphorylation sites, co-immunoprecipitation with 14-3-3, cellular fractionation/localization","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1-2 — direct promoter binding, phosphorylation site mutagenesis, 14-3-3 interaction, subcellular localization all demonstrated in one study","pmids":["33103082"],"is_preprint":false},{"year":2020,"finding":"CIC represses VGF expression by tethering the SIN3-HDAC corepressor complex to the VGF promoter. Brain-specific deletion of Cic impairs neuroblast-to-immature neuron transition in mouse hippocampus. Mass spectrometry identified BRG1-containing mSWI/SNF complex as an additional CIC-interacting protein required for CIC-dependent transcriptional repression.","method":"Brain-specific Cic conditional KO mice (neuronal differentiation phenotype), ChIP-seq, Co-IP, mass spectrometry of CIC interactors","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq, mass spectrometry interactome, Co-IP, and conditional KO phenotype in one study","pmids":["32229723"],"is_preprint":false},{"year":2017,"finding":"Cic-deficient mouse neural stem cells bypass an EGF requirement for proliferation and display defects in oligodendrocyte differentiation potential. In vivo, Cic loss potentiates glioma formation and reduces tumor latency in an orthotopic mouse model. CIC also activates expression of EGFR-independent genes beyond its known repressor function.","method":"Conditional Cic knockout mice, in vitro neural stem cell proliferation/differentiation assays, orthotopic mouse glioma model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — in vivo and in vitro loss-of-function with defined cellular phenotypes and transcriptional profiling","pmids":["28939681"],"is_preprint":false},{"year":2017,"finding":"CIC-DUX4 mouse model generated by transducing embryonic mesenchymal cells with human CIC-DUX4 cDNA produces undifferentiated sarcomas with upregulation of PEA3 family genes, Ccnd2, Crh, and Zic1. CCND2 and MUC5AC identified as reliable biomarkers. Gene silencing of CIC-DUX4 and its downstream targets (Ccnd2, Ret, Bcl2) inhibits tumor growth.","method":"Ex vivo mouse model, gene expression profiling, gene silencing (shRNA), pharmacological inhibition (palbociclib, trabectedin) in vitro","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — functional mouse model with gene silencing rescue and downstream target identification","pmids":["28404587"],"is_preprint":false},{"year":2014,"finding":"CIC-DUX4 sarcomas display a distinct gene expression signature with upregulation of ETS transcription factors ETV4, ETV1, and ETV5, and WT1 compared to Ewing sarcoma and normal tissue, validated by q-PCR.","method":"Expression profiling with q-PCR validation, immunohistochemistry","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 3 — gene expression with q-PCR validation, no direct mechanistic binding/functional assay","pmids":["24723486"],"is_preprint":false},{"year":2015,"finding":"CIC loss in prostate cancer derepresses ETV5 and CRABP1 expression, promoting cell proliferation and invasion. miR-93, miR-106b, and miR-375 cooperatively downregulate CIC protein levels to promote cancer progression (miR-93/miR-106b/miR-375-CIC-CRABP1 axis).","method":"CIC overexpression and RNAi in prostate cancer cell lines, luciferase reporter for miRNA-CIC interaction, proliferation/invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional gain/loss-of-function with pathway placement, but single lab","pmids":["26124181"],"is_preprint":false},{"year":2014,"finding":"CIC-L (long isoform) localizes predominantly to the nucleus and CIC-S (short isoform) localizes predominantly to the cytoplasm in close proximity to mitochondria. Mutant CIC-R1515H increases cellular 2-hydroxyglutarate levels in IDH1-R132H background. Mutant CIC-S reduces phospho-ACLY levels, suggesting a cytosolic citrate metabolism-related mechanism.","method":"Stable cell line co-expression, subcellular fractionation/localization, 2-HG metabolite measurement, Western blotting for phospho-ACLY","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 — localization and metabolite measurements in overexpression system, single lab","pmids":["25277207"],"is_preprint":false},{"year":2018,"finding":"Loss of CIC in neuroblastoma activates the RAS-MAPK pathway (independently of phosphorylated ERK) and causes significant increase in tumor growth in vivo, establishing CIC as a tumor suppressor functioning downstream of the RAS-MAPK pathway in neuroblastoma.","method":"CIC knockout in neuroblastoma cell lines, in vivo xenograft tumor growth assay, pathway activation analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined in vivo phenotype and pathway analysis, multiple cell line models","pmids":["30115695"],"is_preprint":false},{"year":2021,"finding":"CIC-DUX4 oncoprotein requires P300/CBP acetyltransferase activity to induce histone H3 acetylation, activate its transcriptional targets, and drive oncogenesis. P300/CBP inhibition (iP300w) suppresses CIC-DUX4 transcriptional activity, reverses CIC-DUX4-induced acetylation, and arrests growth of CIC-DUX4 sarcoma xenografts in vivo.","method":"P300/CBP inhibitor (iP300w) treatment, histone acetylation assays, CDS xenograft tumor growth inhibition in vivo","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 — mechanistic link of CIC-DUX4 to P300/CBP established with histone modification readout and in vivo validation","pmids":["34642317"],"is_preprint":false},{"year":2017,"finding":"CIC loss of function is associated with MAPK signaling cascade activation and upregulation of cell-cell adhesion and developmental genes across multiple cancer types (oligodendroglioma and stomach adenocarcinoma); 39 candidate CIC transcriptional targets identified, 7 confirmed as direct targets.","method":"Isogenic CIC knockout cell lines, transcriptome analysis, direct target validation","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — isogenic KO with transcriptome and direct target validation, single lab","pmids":["28295365"],"is_preprint":false},{"year":2018,"finding":"CIC and ATXN1L exhibit a reciprocal functional relationship: CIC and ATXN1L co-regulate cell cycle and division gene sets. Transcriptomic analysis in ATXN1L KO and CIC KO human cell lines shows convergent regulation of mitotic cell cycle pathways.","method":"ATXN1L KO and CIC KO human cell lines, transcriptomic analysis, TCGA cohort analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — isogenic KO cell lines with transcriptomic readout, single lab","pmids":["30093628"],"is_preprint":false},{"year":2020,"finding":"CIC directly binds to octameric sequences in the promoter regions of folate transport genes FOLR1, PCFT, and RFC1. A CIC nonsense variant (p.R353X) downregulates FOLR1 expression in HeLa cells and in iPSCs, and decreases cellular binding of folic acid.","method":"Promoter binding assay, CIC variant functional analysis in HeLa and patient iPSC-derived cells, folate binding assay","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding and functional rescue in patient-derived iPSCs, but single lab","pmids":["32820034"],"is_preprint":false},{"year":2023,"finding":"CIC directly represses xCT/SLC7A11 expression; CIC loss leads to increased extracellular glutamate. CIC repressor function is inhibited by 14-3-3 binding (dependent on Ser173 phosphorylation), as shown by a non-phosphorylatable CIC variant retaining transcriptional repression and reduced xCT/SLC7A11 expression and glutamate release.","method":"CIC gain- and loss-of-function in patient-derived glioma lines, RNA-seq, glutamate release assays, non-phosphorylatable CIC variant (S173A)","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional gain/loss-of-function with mechanistic mutagenesis and metabolic readout, single lab","pmids":["36647117"],"is_preprint":false},{"year":2022,"finding":"CIC-DUX4 sarcomas depend on WEE1 kinase activity as an adaptive survival mechanism to limit DNA damage from CIC-DUX4-mediated CCNE1 upregulation and compromised G1/S checkpoint; WEE1 inhibition causes DNA damage-associated apoptosis in patient-derived CIC-DUX4 sarcoma models in vitro and in vivo.","method":"Kinase activity screen on patient-derived specimens, genetic and pharmacologic WEE1 inhibition, in vivo xenograft assay","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — integrated kinase screen + genetic/pharmacologic KO with in vivo validation; mechanistic pathway placement via CCNE1-WEE1 axis","pmids":["35315355"],"is_preprint":false},{"year":2020,"finding":"Brain-specific deletion of Cic in mice compromises developmental transition of neuroblasts to immature neurons in the hippocampus; VGF identified as an important CIC-repressed target involved in neuronal lineage regulation through ChIP-seq and gene expression analysis. Aberrant VGF expression promotes neural progenitor proliferation by suppressing differentiation.","method":"Brain-specific Cic conditional KO, ChIP-seq, gene expression profiling, VGF overexpression experiments","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq direct target identification, conditional KO with neuronal phenotype, functional rescue via VGF manipulation","pmids":["32229723"],"is_preprint":false}],"current_model":"CIC (capicua transcriptional repressor) is an HMG-box transcription factor that acts downstream of RTK/RAS/MAPK signaling: it directly binds octameric DNA sequences to repress target genes (including ETV1/4/5, DUSP6, VGF, SLC7A11/xCT, and FOLR1) via recruitment of SIN3-HDAC and mSWI/SNF complexes; ERK-activated p90RSK phosphorylates CIC at S173/S301, creating a 14-3-3 binding motif that drives nuclear export and target derepression, while the E3 ligase PJA1 mediates proteasomal degradation of DNA-bound phospho-CIC; CIC is stabilized by ATXN1/ATXN1L interaction, and its loss promotes aberrant proliferation of neural progenitors, MAPK pathway activation, and resistance to MEK/RAF inhibitors, whereas oncogenic CIC-DUX4 fusion acquires neomorphic transcriptional activator activity (dependent on P300/CBP) that directly upregulates ETV4 and CCNE1 to drive sarcoma metastasis and survival."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing CIC as a sequence-specific transcriptional repressor whose fusion with DUX4 converts it into an activator of PEA3-family ETS genes resolved the functional consequence of the t(4;19) translocation in round-cell sarcoma.","evidence":"Promoter binding assays and NIH 3T3 transformation with CIC-DUX4 cDNA","pmids":["16717057"],"confidence":"High","gaps":["No genome-wide target map for wild-type CIC","Mechanism of transcriptional switching from repressor to activator unknown","Cofactors for CIC repression unidentified"]},{"year":2011,"claim":"Demonstrating that ATXN1L stabilizes CIC protein and that CIC loss alone recapitulates developmental lung defects established the ATXN1/ATXN1L–CIC axis as a functional unit controlling ETS target gene repression in vivo.","evidence":"Atxn1L-/- and compound Atxn1/Atxn1L knockout mice with lung phenotyping and Etv4/MMP9 expression analysis","pmids":["22014525"],"confidence":"High","gaps":["Mechanism by which ATXN1L stabilizes CIC protein not defined","Whether ATXN1L modulates CIC DNA binding or chromatin recruitment unknown"]},{"year":2014,"claim":"Expression profiling of CIC-DUX4 sarcomas confirmed upregulation of ETV1/4/5 and WT1 as a molecular signature distinguishing CIC-DUX4 tumors from Ewing sarcoma, providing diagnostic markers and reinforcing PEA3 derepression as the central oncogenic output.","evidence":"Gene expression profiling with qPCR validation in human tumor specimens","pmids":["24723486"],"confidence":"Medium","gaps":["No direct binding or functional assays for WT1 regulation by CIC-DUX4","Contribution of individual ETS targets to tumorigenesis not dissected"]},{"year":2017,"claim":"A genome-scale CRISPR screen identified CIC and ATXN1L loss as drivers of MEK inhibitor resistance through ETV derepression, positioning the CIC repressor axis as a clinically relevant determinant of MAPK pathway drug sensitivity.","evidence":"CRISPR-Cas9 screen in KRAS-mutant pancreatic cancer cells under trametinib, with ETV overexpression rescue","pmids":["28178529"],"confidence":"High","gaps":["Whether CIC loss confers resistance to other MAPK pathway inhibitors beyond MEK not tested","Patient tumor validation of CIC-mediated resistance pending"]},{"year":2017,"claim":"Conditional CIC deletion in mouse forebrain, combined with human exome sequencing, established CIC as a neurodevelopmental gene whose haploinsufficiency causes intellectual disability, ADHD, and autism spectrum disorder, linking its repressor function to cortical neuron maturation.","evidence":"Conditional Cic knockout mice with behavioral phenotyping; de novo CIC truncating variants in human patients","pmids":["28288114"],"confidence":"High","gaps":["Specific CIC target genes mediating neurobehavioral phenotypes not fully defined","Cell-type-specific CIC targets in forebrain circuits unknown"]},{"year":2017,"claim":"CIC loss in neural stem cells bypassed EGF dependence for proliferation and accelerated glioma formation in vivo, establishing CIC as a bona fide tumor suppressor in the brain and revealing that CIC can also activate a subset of genes.","evidence":"Conditional Cic knockout mouse neural stem cells, orthotopic glioma model","pmids":["28939681"],"confidence":"High","gaps":["Mechanism of CIC-mediated transcriptional activation versus repression not resolved","Direct activator targets not validated by ChIP"]},{"year":2018,"claim":"ChIP-seq and co-immunoprecipitation identified the SIN3-HDAC complex as the corepressor recruited by CIC to target promoters, showing that high MAPK activity displaces CIC from DNA and increases histone acetylation—providing the first chromatin-level mechanism for CIC-mediated repression.","evidence":"Genome-wide ChIP-seq, Co-IP with SIN3 complex, histone acetylation assays, CIC mutant analysis in multiple cell types","pmids":["29844126"],"confidence":"High","gaps":["Whether SIN3A or SIN3B is preferentially recruited not distinguished","Structural basis of CIC–SIN3 interaction unknown"]},{"year":2019,"claim":"Identification of PJA1 as the E3 ubiquitin ligase that targets phospho-CIC for proteasomal degradation while CIC is DNA-bound revealed a feed-forward mechanism by which MAPK signaling not only displaces but actively destroys CIC at its target loci.","evidence":"PJA1 knockdown with in vivo GBM survival assay, S173 phosphosite mutagenesis, proteasome inhibitor experiments","pmids":["30737375"],"confidence":"High","gaps":["Full ubiquitination site(s) on CIC not mapped","Whether PJA1 acts on CIC in non-glioma contexts not tested"]},{"year":2019,"claim":"ChIP-seq in CIC-DUX4 sarcoma identified ETV4 and CCNE1 as distinct direct neomorphic targets—ETV4 driving metastasis and CCNE1/CDK2 driving cell survival—deconvolving the oncogenic output into separable effector arms.","evidence":"ChIP-seq for CIC-DUX4 binding, genetic knockdown of individual targets, CDK2 inhibitor sensitivity in xenografts","pmids":["31329165"],"confidence":"High","gaps":["Full repertoire of CIC-DUX4 neomorphic versus retained targets not catalogued","Mechanism by which DUX4 domain converts CIC repressor to activator not structurally resolved"]},{"year":2020,"claim":"Mapping the ERK–p90RSK–CIC–DUSP6 feedback loop showed that p90RSK phosphorylates CIC at S173/S301, creating a 14-3-3 binding site for nuclear export, which completed the mechanistic circuit linking RTK signaling to CIC inactivation and DUSP6 derepression.","evidence":"ChIP, reporter assays, phosphosite mutagenesis, 14-3-3 co-IP, subcellular fractionation","pmids":["33103082"],"confidence":"High","gaps":["Whether additional kinases phosphorylate CIC at other sites not excluded","Kinetics of CIC nuclear re-import after signal attenuation unknown"]},{"year":2020,"claim":"Identification of VGF as a direct CIC-repressed target and BRG1-containing mSWI/SNF as an additional CIC-interacting complex expanded the corepressor machinery and linked CIC to neuroblast-to-neuron transitions in hippocampus.","evidence":"Brain-specific Cic conditional KO, ChIP-seq, mass spectrometry interactome, VGF functional experiments","pmids":["32229723"],"confidence":"High","gaps":["Whether SIN3-HDAC and mSWI/SNF are recruited simultaneously or to distinct loci not resolved","Structural basis of CIC–mSWI/SNF interaction unknown"]},{"year":2021,"claim":"Demonstrating that CIC-DUX4 requires P300/CBP acetyltransferase activity to drive histone H3 acetylation and oncogenesis identified the cofactor that explains CIC-DUX4's neomorphic activator function and revealed a druggable dependency.","evidence":"P300/CBP inhibitor treatment, histone acetylation assays, CDS xenograft growth inhibition in vivo","pmids":["34642317"],"confidence":"High","gaps":["Direct physical interaction between CIC-DUX4 and P300/CBP not demonstrated by Co-IP","Whether P300/CBP is recruited via the DUX4 moiety specifically not determined"]},{"year":2022,"claim":"CIC-DUX4 sarcomas develop an adaptive dependency on WEE1 kinase to manage replication stress from CCNE1 overexpression, establishing a synthetic-lethal relationship exploitable therapeutically.","evidence":"Kinase activity screen on patient-derived specimens, WEE1 genetic/pharmacologic inhibition, in vivo xenograft","pmids":["35315355"],"confidence":"High","gaps":["Whether WEE1 dependency is unique to CIC-DUX4 or shared with other CCNE1-high tumors not assessed","Combination of WEE1 and CDK2 inhibition not tested"]},{"year":2023,"claim":"Identification of SLC7A11/xCT as a direct CIC-repressed target linked CIC loss to glutamate excitotoxicity in glioma and confirmed that S173 phosphorylation-dependent 14-3-3 binding is the general inactivation switch for CIC repressor function.","evidence":"CIC gain/loss-of-function in patient-derived glioma lines, RNA-seq, glutamate assays, S173A non-phosphorylatable variant","pmids":["36647117"],"confidence":"Medium","gaps":["In vivo significance of CIC-mediated glutamate control for tumor microenvironment not tested","Whether xCT derepression contributes to ferroptosis sensitivity not assessed"]},{"year":null,"claim":"The structural basis by which the DUX4 C-terminal domain converts CIC from a repressor to a P300/CBP-dependent activator, the complete genome-wide inventory of direct CIC activator versus repressor targets, and the cell-type-specific functions of CIC-S versus CIC-L isoforms remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of CIC or CIC-DUX4 on DNA","CIC activator targets identified only descriptively, not validated by ChIP","Isoform-specific functions of CIC-S (cytoplasmic) versus CIC-L (nuclear) not mechanistically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,7,8,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,7,8,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,7,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,8,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,3,21]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,17,20]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,15]}],"complexes":["SIN3-HDAC","mSWI/SNF (BRG1-containing)"],"partners":["ATXN1","ATXN1L","PJA1","SIN3A","BRG1","YWHAB","P300"],"other_free_text":[]},"mechanistic_narrative":"CIC is an HMG-box transcriptional repressor that operates as a critical effector downstream of RTK/RAS/MAPK signaling, binding octameric DNA sequences in the promoters of target genes—including ETV1/ETV4/ETV5, DUSP6, VGF, SLC7A11, and FOLR1—to silence their expression through recruitment of the SIN3-HDAC corepressor and BRG1-containing mSWI/SNF complexes [PMID:29844126, PMID:32229723, PMID:33103082, PMID:36647117]. ERK-activated p90RSK phosphorylates CIC at S173 and S301, generating a 14-3-3 binding motif that drives CIC nuclear export and target gene derepression, while the E3 ubiquitin ligase PJA1 mediates proteasomal degradation of DNA-bound phospho-CIC, completing a negative feedback circuit [PMID:33103082, PMID:30737375]. CIC protein is stabilized by interaction with ATXN1/ATXN1L; loss of either partner destabilizes CIC, derepresses PEA3-family ETS genes, and promotes aberrant neural progenitor proliferation, glioma formation, and resistance to MEK/RAF inhibitors [PMID:22014525, PMID:28178529, PMID:28939681]. De novo heterozygous CIC truncating mutations cause intellectual disability, ADHD, and autism spectrum disorder in humans, while the oncogenic CIC-DUX4 fusion acquires P300/CBP-dependent neomorphic transcriptional activator activity that upregulates ETV4 and CCNE1 to drive undifferentiated round-cell sarcoma [PMID:28288114, PMID:31329165, PMID:34642317]."},"prefetch_data":{"uniprot":{"accession":"Q96RK0","full_name":"Protein capicua homolog","aliases":[],"length_aa":2517,"mass_kda":258.0,"function":"Transcriptional repressor which plays a role in development of the central nervous system (CNS). In concert with ATXN1 and ATXN1L, involved in brain development","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96RK0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIC","classification":"Not Classified","n_dependent_lines":32,"n_total_lines":1208,"dependency_fraction":0.026490066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CIC","total_profiled":1310},"omim":[{"mim_id":"621127","title":"BBX HIGH MOBILITY GROUP BOX DOMAIN-CONTAINING PROTEIN; BBX","url":"https://www.omim.org/entry/621127"},{"mim_id":"617600","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 45; MRD45","url":"https://www.omim.org/entry/617600"},{"mim_id":"614301","title":"ATAXIN 1-LIKE; ATXN1L","url":"https://www.omim.org/entry/614301"},{"mim_id":"612082","title":"CAPICUA TRANSCRIPTIONAL REPRESSOR; CIC","url":"https://www.omim.org/entry/612082"},{"mim_id":"606009","title":"DOUBLE HOMEOBOX PROTEIN 4; DUX4","url":"https://www.omim.org/entry/606009"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26794043","citation_count":20,"is_preprint":false},{"pmid":"36647117","id":"PMC_36647117","title":"CIC reduces xCT/SLC7A11 expression and glutamate release in glioma.","date":"2023","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/36647117","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":"27324529","id":"PMC_27324529","title":"A case report of CIC-rearranged undifferentiated small round cell sarcoma in the cerebrum.","date":"2016","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/27324529","citation_count":19,"is_preprint":false},{"pmid":"31871418","id":"PMC_31871418","title":"Analysis of the level of selected parameters of inflammation, circulating immune complexes, and related indicators (neutrophil/lymphocyte, platelet/lymphocyte, CRP/CIC) in patients with obstructive diseases.","date":"2019","source":"Central-European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31871418","citation_count":19,"is_preprint":false},{"pmid":"35203088","id":"PMC_35203088","title":"Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology.","date":"2022","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35203088","citation_count":18,"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":"37212486","id":"PMC_37212486","title":"Clinical characteristics and outcomes for children, adolescents and young adults with \"CIC-fused\" or \"BCOR-rearranged\" soft tissue sarcomas: A multi-institutional European retrospective analysis.","date":"2023","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37212486","citation_count":18,"is_preprint":false},{"pmid":"35715887","id":"PMC_35715887","title":"Central nervous system sarcoma with ATXN1::DUX4 fusion expands the concept of CIC-rearranged sarcoma.","date":"2022","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35715887","citation_count":18,"is_preprint":false},{"pmid":"32048619","id":"PMC_32048619","title":"Clinicopathologic features of undifferentiated round cell sarcomas of bone & soft tissues: An attempt to unravel the BCOR-CCNB3- & CIC-DUX4-positive sarcomas.","date":"2019","source":"The Indian journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/32048619","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 insight","url":"https://pubmed.ncbi.nlm.nih.gov/35315355","citation_count":17,"is_preprint":false},{"pmid":"27664537","id":"PMC_27664537","title":"Targeted next-generation sequencing of CIC-DUX4 soft tissue sarcomas demonstrates low mutational burden and recurrent chromosome 1p loss.","date":"2016","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27664537","citation_count":17,"is_preprint":false},{"pmid":"28137728","id":"PMC_28137728","title":"Novel exon-exon breakpoint in CIC-DUX4 fusion sarcoma identified by anchored multiplex PCR (Archer FusionPlex Sarcoma Panel).","date":"2017","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28137728","citation_count":17,"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":16,"is_preprint":false},{"pmid":"35093696","id":"PMC_35093696","title":"CIC rearranged sarcomas: A single institution experience of the potential pitfalls in interpreting CIC FISH results.","date":"2022","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/35093696","citation_count":16,"is_preprint":false},{"pmid":"24086756","id":"PMC_24086756","title":"Novel CIC point mutations and an exon-spanning, homozygous deletion identified in oligodendroglial tumors by a comprehensive genomic approach including transcriptome sequencing.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24086756","citation_count":16,"is_preprint":false},{"pmid":"39381843","id":"PMC_39381843","title":"Nuclear DUX4 immunohistochemistry is a highly sensitive and specific marker for the presence of CIC::DUX4 fusion in CIC-rearranged sarcomas: a study of 48 molecularly confirmed cases.","date":"2024","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/39381843","citation_count":16,"is_preprint":false},{"pmid":"38278603","id":"PMC_38278603","title":"CIC-Rearranged Sarcoma.","date":"2023","source":"Surgical pathology clinics","url":"https://pubmed.ncbi.nlm.nih.gov/38278603","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52362,"output_tokens":5364,"usd":0.118773},"stage2":{"model":"claude-opus-4-6","input_tokens":8885,"output_tokens":3773,"usd":0.208125},"total_usd":0.326898,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"CIC (capicua homolog) is a high mobility group box transcription factor that directly binds a novel target sequence in the ERM/ETV5 promoter to repress its transcription; fusion with DUX4 C-terminal fragment confers enhanced transcriptional activator activity, leading to upregulation of PEA3 family ETS genes (ERM/ETV5, ETV1) as downstream targets.\",\n      \"method\": \"Gene expression analysis, promoter binding assay (direct CIC-DUX4 binding to ERM promoter), NIH 3T3 transformation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct promoter binding demonstrated, functional transforming activity shown, downstream targets identified by multiple methods in a single study\",\n      \"pmids\": [\"16717057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATXN1L stabilizes CIC protein; loss of ATXN1L destabilizes CIC, leading to derepression of Etv4, an activator of Mmp genes (including MMP9), causing extracellular matrix remodeling defects and lung alveolarization failure. CIC deficiency alone recapitulates the lung alveolarization defect.\",\n      \"method\": \"Atxn1L-/- and Atxn1-/-;Atxn1L-/- mouse models, gene expression analysis, loss-of-function with defined phenotypic readout\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with multiple mutant backgrounds and orthogonal molecular readouts, replicated across compound knockouts\",\n      \"pmids\": [\"22014525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CIC functions as a transcriptional repressor of ETV1, ETV4, and ETV5; loss of CIC (or loss of ATXN1L, which reduces CIC protein levels) promotes survival under MEK inhibitor treatment, identifying the ATXN1L-CIC-ETS transcription factor axis as a mediator of resistance to MAPK pathway inhibition.\",\n      \"method\": \"Genome-scale CRISPR-Cas9 loss-of-function screen in KRAS-mutant pancreatic cancer cells treated with trametinib; ectopic ETV expression rescue experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-scale functional screen with epistasis validation and ETV rescue; mechanistic pathway placement confirmed\",\n      \"pmids\": [\"28178529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Disruption of the ATXN1-CIC transcriptional repressor complex in the developing mouse forebrain causes hyperactivity, impaired learning/memory, abnormal upper-layer cortical neuron maturation, and social interaction defects dependent on CIC activity in hypothalamus and medial amygdala. De novo heterozygous truncating CIC mutations in humans produce intellectual disability, ADHD, and autism spectrum disorder.\",\n      \"method\": \"Conditional mouse knockouts with behavioral phenotyping; human patient exome sequencing with matched clinical features\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined cellular and behavioral phenotypes, validated by human clinical genetics\",\n      \"pmids\": [\"28288114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIC represses transcription of MAPK pathway effector genes (including cell-cycle and proliferation genes) by interacting with the SIN3 histone deacetylase complex; CIC binding to target gene promoters is abolished by high MAPK activity, leading to increased histone acetylation and transcriptional activation. Oligodendroglioma-associated CIC missense mutations prevent DNA binding.\",\n      \"method\": \"Genome-wide ChIP-seq in multiple cell types, co-immunoprecipitation of CIC with SIN3 complex, histone acetylation assays, CIC mutant functional analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq, Co-IP, histone modification assays, and mutagenesis combined in one study\",\n      \"pmids\": [\"29844126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CIC protein is continuously degraded in glioblastoma via proteasome-mediated degradation. The E3 ubiquitin ligase PJA1 mediates CIC degradation, which is triggered by phosphorylation of CIC at residue S173 and requires CIC binding to its DNA target. Deletion of the ERK binding site in CIC stabilizes it and increases therapeutic efficacy of ERK inhibition.\",\n      \"method\": \"PJA1 knockdown in vivo GBM models (survival assay), phosphorylation site mutagenesis, co-immunoprecipitation, proteasome inhibitor experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — E3 ligase identified by knockdown + in vivo rescue, phosphosite mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"30737375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CIC-DUX4 directly and neomorphically upregulates ETV4 (driving tumor metastasis) and CCNE1/cyclin E1 (driving tumor cell survival) as distinct transcriptional targets; CIC-DUX4-expressing tumors show molecular dependence on the CCNE1-CDK2 cell cycle complex.\",\n      \"method\": \"ChIP-seq for direct target binding, genetic knockdown of individual targets, CDK2 inhibitor sensitivity assays in CIC-DUX4 cell lines and xenografts\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct ChIP-seq binding evidence combined with functional rescue and pharmacological inhibition in vivo\",\n      \"pmids\": [\"31329165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIC functions as a transcriptional repressor of DUSP6 by directly binding three cis-regulatory elements in the DUSP6 promoter. p90RSK (downstream of ERK1/2) phosphorylates CIC at S173 and S301, creating a 14-3-3 recognition motif that mediates nuclear export of CIC, thereby derepressing DUSP6 and completing an ERK1/2/p90RSK/CIC/DUSP6 negative feedback circuit.\",\n      \"method\": \"Promoter-binding assays (ChIP and reporter), site-directed mutagenesis of CIC phosphorylation sites, co-immunoprecipitation with 14-3-3, cellular fractionation/localization\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct promoter binding, phosphorylation site mutagenesis, 14-3-3 interaction, subcellular localization all demonstrated in one study\",\n      \"pmids\": [\"33103082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIC represses VGF expression by tethering the SIN3-HDAC corepressor complex to the VGF promoter. Brain-specific deletion of Cic impairs neuroblast-to-immature neuron transition in mouse hippocampus. Mass spectrometry identified BRG1-containing mSWI/SNF complex as an additional CIC-interacting protein required for CIC-dependent transcriptional repression.\",\n      \"method\": \"Brain-specific Cic conditional KO mice (neuronal differentiation phenotype), ChIP-seq, Co-IP, mass spectrometry of CIC interactors\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq, mass spectrometry interactome, Co-IP, and conditional KO phenotype in one study\",\n      \"pmids\": [\"32229723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cic-deficient mouse neural stem cells bypass an EGF requirement for proliferation and display defects in oligodendrocyte differentiation potential. In vivo, Cic loss potentiates glioma formation and reduces tumor latency in an orthotopic mouse model. CIC also activates expression of EGFR-independent genes beyond its known repressor function.\",\n      \"method\": \"Conditional Cic knockout mice, in vitro neural stem cell proliferation/differentiation assays, orthotopic mouse glioma model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro loss-of-function with defined cellular phenotypes and transcriptional profiling\",\n      \"pmids\": [\"28939681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CIC-DUX4 mouse model generated by transducing embryonic mesenchymal cells with human CIC-DUX4 cDNA produces undifferentiated sarcomas with upregulation of PEA3 family genes, Ccnd2, Crh, and Zic1. CCND2 and MUC5AC identified as reliable biomarkers. Gene silencing of CIC-DUX4 and its downstream targets (Ccnd2, Ret, Bcl2) inhibits tumor growth.\",\n      \"method\": \"Ex vivo mouse model, gene expression profiling, gene silencing (shRNA), pharmacological inhibition (palbociclib, trabectedin) in vitro\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional mouse model with gene silencing rescue and downstream target identification\",\n      \"pmids\": [\"28404587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CIC-DUX4 sarcomas display a distinct gene expression signature with upregulation of ETS transcription factors ETV4, ETV1, and ETV5, and WT1 compared to Ewing sarcoma and normal tissue, validated by q-PCR.\",\n      \"method\": \"Expression profiling with q-PCR validation, immunohistochemistry\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — gene expression with q-PCR validation, no direct mechanistic binding/functional assay\",\n      \"pmids\": [\"24723486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CIC loss in prostate cancer derepresses ETV5 and CRABP1 expression, promoting cell proliferation and invasion. miR-93, miR-106b, and miR-375 cooperatively downregulate CIC protein levels to promote cancer progression (miR-93/miR-106b/miR-375-CIC-CRABP1 axis).\",\n      \"method\": \"CIC overexpression and RNAi in prostate cancer cell lines, luciferase reporter for miRNA-CIC interaction, proliferation/invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional gain/loss-of-function with pathway placement, but single lab\",\n      \"pmids\": [\"26124181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CIC-L (long isoform) localizes predominantly to the nucleus and CIC-S (short isoform) localizes predominantly to the cytoplasm in close proximity to mitochondria. Mutant CIC-R1515H increases cellular 2-hydroxyglutarate levels in IDH1-R132H background. Mutant CIC-S reduces phospho-ACLY levels, suggesting a cytosolic citrate metabolism-related mechanism.\",\n      \"method\": \"Stable cell line co-expression, subcellular fractionation/localization, 2-HG metabolite measurement, Western blotting for phospho-ACLY\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization and metabolite measurements in overexpression system, single lab\",\n      \"pmids\": [\"25277207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of CIC in neuroblastoma activates the RAS-MAPK pathway (independently of phosphorylated ERK) and causes significant increase in tumor growth in vivo, establishing CIC as a tumor suppressor functioning downstream of the RAS-MAPK pathway in neuroblastoma.\",\n      \"method\": \"CIC knockout in neuroblastoma cell lines, in vivo xenograft tumor growth assay, pathway activation analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined in vivo phenotype and pathway analysis, multiple cell line models\",\n      \"pmids\": [\"30115695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIC-DUX4 oncoprotein requires P300/CBP acetyltransferase activity to induce histone H3 acetylation, activate its transcriptional targets, and drive oncogenesis. P300/CBP inhibition (iP300w) suppresses CIC-DUX4 transcriptional activity, reverses CIC-DUX4-induced acetylation, and arrests growth of CIC-DUX4 sarcoma xenografts in vivo.\",\n      \"method\": \"P300/CBP inhibitor (iP300w) treatment, histone acetylation assays, CDS xenograft tumor growth inhibition in vivo\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic link of CIC-DUX4 to P300/CBP established with histone modification readout and in vivo validation\",\n      \"pmids\": [\"34642317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CIC loss of function is associated with MAPK signaling cascade activation and upregulation of cell-cell adhesion and developmental genes across multiple cancer types (oligodendroglioma and stomach adenocarcinoma); 39 candidate CIC transcriptional targets identified, 7 confirmed as direct targets.\",\n      \"method\": \"Isogenic CIC knockout cell lines, transcriptome analysis, direct target validation\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isogenic KO with transcriptome and direct target validation, single lab\",\n      \"pmids\": [\"28295365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIC and ATXN1L exhibit a reciprocal functional relationship: CIC and ATXN1L co-regulate cell cycle and division gene sets. Transcriptomic analysis in ATXN1L KO and CIC KO human cell lines shows convergent regulation of mitotic cell cycle pathways.\",\n      \"method\": \"ATXN1L KO and CIC KO human cell lines, transcriptomic analysis, TCGA cohort analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isogenic KO cell lines with transcriptomic readout, single lab\",\n      \"pmids\": [\"30093628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIC directly binds to octameric sequences in the promoter regions of folate transport genes FOLR1, PCFT, and RFC1. A CIC nonsense variant (p.R353X) downregulates FOLR1 expression in HeLa cells and in iPSCs, and decreases cellular binding of folic acid.\",\n      \"method\": \"Promoter binding assay, CIC variant functional analysis in HeLa and patient iPSC-derived cells, folate binding assay\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding and functional rescue in patient-derived iPSCs, but single lab\",\n      \"pmids\": [\"32820034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CIC directly represses xCT/SLC7A11 expression; CIC loss leads to increased extracellular glutamate. CIC repressor function is inhibited by 14-3-3 binding (dependent on Ser173 phosphorylation), as shown by a non-phosphorylatable CIC variant retaining transcriptional repression and reduced xCT/SLC7A11 expression and glutamate release.\",\n      \"method\": \"CIC gain- and loss-of-function in patient-derived glioma lines, RNA-seq, glutamate release assays, non-phosphorylatable CIC variant (S173A)\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional gain/loss-of-function with mechanistic mutagenesis and metabolic readout, single lab\",\n      \"pmids\": [\"36647117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CIC-DUX4 sarcomas depend on WEE1 kinase activity as an adaptive survival mechanism to limit DNA damage from CIC-DUX4-mediated CCNE1 upregulation and compromised G1/S checkpoint; WEE1 inhibition causes DNA damage-associated apoptosis in patient-derived CIC-DUX4 sarcoma models in vitro and in vivo.\",\n      \"method\": \"Kinase activity screen on patient-derived specimens, genetic and pharmacologic WEE1 inhibition, in vivo xenograft assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — integrated kinase screen + genetic/pharmacologic KO with in vivo validation; mechanistic pathway placement via CCNE1-WEE1 axis\",\n      \"pmids\": [\"35315355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Brain-specific deletion of Cic in mice compromises developmental transition of neuroblasts to immature neurons in the hippocampus; VGF identified as an important CIC-repressed target involved in neuronal lineage regulation through ChIP-seq and gene expression analysis. Aberrant VGF expression promotes neural progenitor proliferation by suppressing differentiation.\",\n      \"method\": \"Brain-specific Cic conditional KO, ChIP-seq, gene expression profiling, VGF overexpression experiments\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq direct target identification, conditional KO with neuronal phenotype, functional rescue via VGF manipulation\",\n      \"pmids\": [\"32229723\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CIC (capicua transcriptional repressor) is an HMG-box transcription factor that acts downstream of RTK/RAS/MAPK signaling: it directly binds octameric DNA sequences to repress target genes (including ETV1/4/5, DUSP6, VGF, SLC7A11/xCT, and FOLR1) via recruitment of SIN3-HDAC and mSWI/SNF complexes; ERK-activated p90RSK phosphorylates CIC at S173/S301, creating a 14-3-3 binding motif that drives nuclear export and target derepression, while the E3 ligase PJA1 mediates proteasomal degradation of DNA-bound phospho-CIC; CIC is stabilized by ATXN1/ATXN1L interaction, and its loss promotes aberrant proliferation of neural progenitors, MAPK pathway activation, and resistance to MEK/RAF inhibitors, whereas oncogenic CIC-DUX4 fusion acquires neomorphic transcriptional activator activity (dependent on P300/CBP) that directly upregulates ETV4 and CCNE1 to drive sarcoma metastasis and survival.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CIC is an HMG-box transcriptional repressor that operates as a critical effector downstream of RTK/RAS/MAPK signaling, binding octameric DNA sequences in the promoters of target genes—including ETV1/ETV4/ETV5, DUSP6, VGF, SLC7A11, and FOLR1—to silence their expression through recruitment of the SIN3-HDAC corepressor and BRG1-containing mSWI/SNF complexes [PMID:29844126, PMID:32229723, PMID:33103082, PMID:36647117]. ERK-activated p90RSK phosphorylates CIC at S173 and S301, generating a 14-3-3 binding motif that drives CIC nuclear export and target gene derepression, while the E3 ubiquitin ligase PJA1 mediates proteasomal degradation of DNA-bound phospho-CIC, completing a negative feedback circuit [PMID:33103082, PMID:30737375]. CIC protein is stabilized by interaction with ATXN1/ATXN1L; loss of either partner destabilizes CIC, derepresses PEA3-family ETS genes, and promotes aberrant neural progenitor proliferation, glioma formation, and resistance to MEK/RAF inhibitors [PMID:22014525, PMID:28178529, PMID:28939681]. De novo heterozygous CIC truncating mutations cause intellectual disability, ADHD, and autism spectrum disorder in humans, while the oncogenic CIC-DUX4 fusion acquires P300/CBP-dependent neomorphic transcriptional activator activity that upregulates ETV4 and CCNE1 to drive undifferentiated round-cell sarcoma [PMID:28288114, PMID:31329165, PMID:34642317].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing CIC as a sequence-specific transcriptional repressor whose fusion with DUX4 converts it into an activator of PEA3-family ETS genes resolved the functional consequence of the t(4;19) translocation in round-cell sarcoma.\",\n      \"evidence\": \"Promoter binding assays and NIH 3T3 transformation with CIC-DUX4 cDNA\",\n      \"pmids\": [\"16717057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No genome-wide target map for wild-type CIC\", \"Mechanism of transcriptional switching from repressor to activator unknown\", \"Cofactors for CIC repression unidentified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that ATXN1L stabilizes CIC protein and that CIC loss alone recapitulates developmental lung defects established the ATXN1/ATXN1L–CIC axis as a functional unit controlling ETS target gene repression in vivo.\",\n      \"evidence\": \"Atxn1L-/- and compound Atxn1/Atxn1L knockout mice with lung phenotyping and Etv4/MMP9 expression analysis\",\n      \"pmids\": [\"22014525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ATXN1L stabilizes CIC protein not defined\", \"Whether ATXN1L modulates CIC DNA binding or chromatin recruitment unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expression profiling of CIC-DUX4 sarcomas confirmed upregulation of ETV1/4/5 and WT1 as a molecular signature distinguishing CIC-DUX4 tumors from Ewing sarcoma, providing diagnostic markers and reinforcing PEA3 derepression as the central oncogenic output.\",\n      \"evidence\": \"Gene expression profiling with qPCR validation in human tumor specimens\",\n      \"pmids\": [\"24723486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding or functional assays for WT1 regulation by CIC-DUX4\", \"Contribution of individual ETS targets to tumorigenesis not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A genome-scale CRISPR screen identified CIC and ATXN1L loss as drivers of MEK inhibitor resistance through ETV derepression, positioning the CIC repressor axis as a clinically relevant determinant of MAPK pathway drug sensitivity.\",\n      \"evidence\": \"CRISPR-Cas9 screen in KRAS-mutant pancreatic cancer cells under trametinib, with ETV overexpression rescue\",\n      \"pmids\": [\"28178529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CIC loss confers resistance to other MAPK pathway inhibitors beyond MEK not tested\", \"Patient tumor validation of CIC-mediated resistance pending\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional CIC deletion in mouse forebrain, combined with human exome sequencing, established CIC as a neurodevelopmental gene whose haploinsufficiency causes intellectual disability, ADHD, and autism spectrum disorder, linking its repressor function to cortical neuron maturation.\",\n      \"evidence\": \"Conditional Cic knockout mice with behavioral phenotyping; de novo CIC truncating variants in human patients\",\n      \"pmids\": [\"28288114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific CIC target genes mediating neurobehavioral phenotypes not fully defined\", \"Cell-type-specific CIC targets in forebrain circuits unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CIC loss in neural stem cells bypassed EGF dependence for proliferation and accelerated glioma formation in vivo, establishing CIC as a bona fide tumor suppressor in the brain and revealing that CIC can also activate a subset of genes.\",\n      \"evidence\": \"Conditional Cic knockout mouse neural stem cells, orthotopic glioma model\",\n      \"pmids\": [\"28939681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CIC-mediated transcriptional activation versus repression not resolved\", \"Direct activator targets not validated by ChIP\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ChIP-seq and co-immunoprecipitation identified the SIN3-HDAC complex as the corepressor recruited by CIC to target promoters, showing that high MAPK activity displaces CIC from DNA and increases histone acetylation—providing the first chromatin-level mechanism for CIC-mediated repression.\",\n      \"evidence\": \"Genome-wide ChIP-seq, Co-IP with SIN3 complex, histone acetylation assays, CIC mutant analysis in multiple cell types\",\n      \"pmids\": [\"29844126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SIN3A or SIN3B is preferentially recruited not distinguished\", \"Structural basis of CIC–SIN3 interaction unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of PJA1 as the E3 ubiquitin ligase that targets phospho-CIC for proteasomal degradation while CIC is DNA-bound revealed a feed-forward mechanism by which MAPK signaling not only displaces but actively destroys CIC at its target loci.\",\n      \"evidence\": \"PJA1 knockdown with in vivo GBM survival assay, S173 phosphosite mutagenesis, proteasome inhibitor experiments\",\n      \"pmids\": [\"30737375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full ubiquitination site(s) on CIC not mapped\", \"Whether PJA1 acts on CIC in non-glioma contexts not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ChIP-seq in CIC-DUX4 sarcoma identified ETV4 and CCNE1 as distinct direct neomorphic targets—ETV4 driving metastasis and CCNE1/CDK2 driving cell survival—deconvolving the oncogenic output into separable effector arms.\",\n      \"evidence\": \"ChIP-seq for CIC-DUX4 binding, genetic knockdown of individual targets, CDK2 inhibitor sensitivity in xenografts\",\n      \"pmids\": [\"31329165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of CIC-DUX4 neomorphic versus retained targets not catalogued\", \"Mechanism by which DUX4 domain converts CIC repressor to activator not structurally resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping the ERK–p90RSK–CIC–DUSP6 feedback loop showed that p90RSK phosphorylates CIC at S173/S301, creating a 14-3-3 binding site for nuclear export, which completed the mechanistic circuit linking RTK signaling to CIC inactivation and DUSP6 derepression.\",\n      \"evidence\": \"ChIP, reporter assays, phosphosite mutagenesis, 14-3-3 co-IP, subcellular fractionation\",\n      \"pmids\": [\"33103082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional kinases phosphorylate CIC at other sites not excluded\", \"Kinetics of CIC nuclear re-import after signal attenuation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of VGF as a direct CIC-repressed target and BRG1-containing mSWI/SNF as an additional CIC-interacting complex expanded the corepressor machinery and linked CIC to neuroblast-to-neuron transitions in hippocampus.\",\n      \"evidence\": \"Brain-specific Cic conditional KO, ChIP-seq, mass spectrometry interactome, VGF functional experiments\",\n      \"pmids\": [\"32229723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SIN3-HDAC and mSWI/SNF are recruited simultaneously or to distinct loci not resolved\", \"Structural basis of CIC–mSWI/SNF interaction unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that CIC-DUX4 requires P300/CBP acetyltransferase activity to drive histone H3 acetylation and oncogenesis identified the cofactor that explains CIC-DUX4's neomorphic activator function and revealed a druggable dependency.\",\n      \"evidence\": \"P300/CBP inhibitor treatment, histone acetylation assays, CDS xenograft growth inhibition in vivo\",\n      \"pmids\": [\"34642317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between CIC-DUX4 and P300/CBP not demonstrated by Co-IP\", \"Whether P300/CBP is recruited via the DUX4 moiety specifically not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CIC-DUX4 sarcomas develop an adaptive dependency on WEE1 kinase to manage replication stress from CCNE1 overexpression, establishing a synthetic-lethal relationship exploitable therapeutically.\",\n      \"evidence\": \"Kinase activity screen on patient-derived specimens, WEE1 genetic/pharmacologic inhibition, in vivo xenograft\",\n      \"pmids\": [\"35315355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WEE1 dependency is unique to CIC-DUX4 or shared with other CCNE1-high tumors not assessed\", \"Combination of WEE1 and CDK2 inhibition not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of SLC7A11/xCT as a direct CIC-repressed target linked CIC loss to glutamate excitotoxicity in glioma and confirmed that S173 phosphorylation-dependent 14-3-3 binding is the general inactivation switch for CIC repressor function.\",\n      \"evidence\": \"CIC gain/loss-of-function in patient-derived glioma lines, RNA-seq, glutamate assays, S173A non-phosphorylatable variant\",\n      \"pmids\": [\"36647117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo significance of CIC-mediated glutamate control for tumor microenvironment not tested\", \"Whether xCT derepression contributes to ferroptosis sensitivity not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis by which the DUX4 C-terminal domain converts CIC from a repressor to a P300/CBP-dependent activator, the complete genome-wide inventory of direct CIC activator versus repressor targets, and the cell-type-specific functions of CIC-S versus CIC-L isoforms remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of CIC or CIC-DUX4 on DNA\", \"CIC activator targets identified only descriptively, not validated by ChIP\", \"Isoform-specific functions of CIC-S (cytoplasmic) versus CIC-L (nuclear) not mechanistically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 7, 8, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 7, 8, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 7, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 8, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 3, 21]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 17, 20]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 15]}\n    ],\n    \"complexes\": [\n      \"SIN3-HDAC\",\n      \"mSWI/SNF (BRG1-containing)\"\n    ],\n    \"partners\": [\n      \"ATXN1\",\n      \"ATXN1L\",\n      \"PJA1\",\n      \"SIN3A\",\n      \"BRG1\",\n      \"YWHAB\",\n      \"P300\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}