Affinage

CIC

Protein capicua homolog · UniProt Q96RK0

Length
2517 aa
Mass
258.0 kDa
Annotated
2026-06-09
100 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2006 High

    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

    PMID:16717057

    Open questions at the time
    • Did not define the wild-type repressive function of native CIC
    • No genome-wide binding map
    • Cofactor requirements of the fusion activator unresolved
  2. 2011 High

    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

    PMID:22014525

    Open questions at the time
    • Biochemical mechanism of ATXN1L-mediated CIC stabilization not resolved
    • Did not address signaling regulation of CIC
  3. 2014 Medium

    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

    PMID:25277207

    Open questions at the time
    • Metabolic link to ACLY is correlative
    • Single lab, no independent replication
    • Functional role of mitochondrial proximity unclear
  4. 2015 Medium

    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

    PMID:26017892

    Open questions at the time
    • Mechanism of mutation-driven nuclear mislocalization not biochemically defined
    • Single lab
  5. 2015 Medium

    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

    PMID:26124181

    Open questions at the time
    • Single lab
    • In vivo relevance of the miRNA axis untested
  6. 2017 High

    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

    PMID:28178529

    Open questions at the time
    • Did not resolve which ETS factor is rate-limiting in vivo
    • Combinatorial therapeutic strategy untested
  7. 2017 High

    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

    PMID:28288114

    Open questions at the time
    • Target genes driving neuronal phenotypes not fully defined
    • Circuit-level mechanism unclear
  8. 2017 High

    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

    PMID:28939681

    Open questions at the time
    • Direct target genes mediating EGF bypass not enumerated
    • Cell-of-origin specificity unresolved
  9. 2017 High

    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

    PMID:28404587

    Open questions at the time
    • Direct vs indirect target distinction limited
    • Mechanism of activation conversion not defined here
  10. 2018 High

    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

    PMID:29844126

    Open questions at the time
    • Stoichiometry and recruitment determinants of SIN3 not resolved
    • Genome-wide site selection rules incomplete
  11. 2018 High

    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

    PMID:30737375

    Open questions at the time
    • Ubiquitination site mapping not detailed
    • Crosstalk with phospho-export pathway unresolved
  12. 2018 Medium

    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

    PMID:30115695

    Open questions at the time
    • Mechanism of pERK-independent pathway activation undefined
    • Single lab
  13. 2018 Medium

    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

    PMID:30093628

    Open questions at the time
    • Biochemical basis of the interaction not fully resolved
    • Single lab
  14. 2019 High

    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

    PMID:31329165

    Open questions at the time
    • Relative contribution of ETV4 vs CCNE1 to metastasis vs survival incompletely partitioned
  15. 2020 High

    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

    PMID:32229723

    Open questions at the time
    • How CIC selects between SIN3 and mSWI/SNF at loci unclear
    • Direct vs assisted recruitment of BRG1 undefined
  16. 2020 High

    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

    PMID:32029440

    Open questions at the time
    • Interplay between Y1455 and S173/S301 phospho-events not resolved
    • Structural basis of export unclear
  17. 2020 High

    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

    PMID:33103082

    Open questions at the time
    • Relative weighting of degradation vs export under physiological signaling unresolved
  18. 2020 Medium

    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

    PMID:32820034

    Open questions at the time
    • Single lab
    • Mechanism of variant-induced FOLR1 downregulation not fully defined
  19. 2020 Medium

    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

    PMID:32015466

    Open questions at the time
    • Single lab
    • Causal contribution to disease phenotype indirect
  20. 2021 High

    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

    PMID:34642317

    Open questions at the time
    • Direct CIC-DUX4/P300 physical interaction not biochemically detailed
    • Specificity over native gene programs incomplete
  21. 2022 High

    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

    PMID:35315355

    Open questions at the time
    • Combination with CDK2 inhibition not benchmarked
    • Resistance mechanisms unexplored
  22. 2023 Medium

    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

    PMID:36647117

    Open questions at the time
    • Single lab
    • Direct vs indirect regulation of SLC7A11 not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3
Partners
14-3-3ATXN1ATXN1LC-SRC (SRC)ERKP300/CBPPJA1SIN3
Complex memberships
ATXN1/ATXN1L-CIC repressor complexBRG1-containing mSWI/SNF complexSIN3-HDAC complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Gene expression analysis, promoter binding assay (direct binding to ERM promoter), NIH 3T3 transformation assay, RT-PCR/sequencing of fusion transcript Human molecular genetics High 16717057
2011 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. Genetic knockout mice (Atxn1L-/-, Atxn1-/-;Atxn1L-/- double KO, Cic conditional KO), gene expression analysis, immunostaining, functional lung phenotype readout Developmental cell High 22014525
2017 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. Genome-scale CRISPR-Cas9 loss-of-function screen, ectopic expression of ETV1/4/5, pharmacologic trametinib treatment across multiple cancer cell lines Cell reports High 28178529
2017 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. Conditional mouse knockouts (forebrain-specific Cic deletion, Atxn1-CIC interaction mutants), behavioral assays, cortical neuron phenotyping, human genetic identification of de novo truncating mutations Nature genetics High 28288114
2018 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. Co-immunoprecipitation, mutagenesis (ERK binding site deletion, S173 phosphorylation), PJA1 knockdown, in vivo GBM xenograft survival experiments, proteasome inhibition assays Nature communications High 30737375
2018 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. 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 Cancer research High 29844126
2020 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. ChIP-seq, mass spectrometry of CIC-interacting proteins, Co-IP, Cic brain-specific conditional knockout mice, neuronal differentiation assays JCI insight High 32229723
2020 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. Co-immunoprecipitation, site-directed mutagenesis (Y1455F), subcellular fractionation/localization, dasatinib pharmacologic treatment, cell viability assays in GBM cells and glioma stem cells Molecular cancer research High 32029440
2020 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. ChIP, promoter binding assays (CRE identification), phosphorylation assays (p90RSK), 14-3-3 interaction assay, subcellular localization studies, mutagenesis (S173, S301) iScience High 33103082
2019 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. 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 The Journal of clinical investigation High 31329165
2017 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. Retroviral transduction of embryonic mesenchymal cells with CIC-DUX4 cDNA, mouse transplantation model, gene expression profiling, siRNA knockdown, CDK4/6 inhibitor treatment Cancer research High 28404587
2015 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. 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 Oncotarget Medium 26124181
2015 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. Lentiviral transfection of glioma cells with mutant and WT CIC, transcriptomic profiling, CIC protein expression analysis, subcellular localization studies Annals of neurology Medium 26017892
2017 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. Cic conditional knockout mice, in vitro neural stem cell culture (EGF-independent growth assay), oligodendrocyte differentiation assay, orthotopic glioma mouse model Cancer research High 28939681
2018 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. CIC knockout in neuroblastoma cell lines, in vivo xenograft tumor growth assays, transcriptomic RAS-MAPK pathway signature analysis Cancer research Medium 30115695
2014 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. 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 Oncotarget Medium 25277207
2020 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. 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 of medical genetics Medium 32820034
2021 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. 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 Oncogenesis High 34642317
2022 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. Transcriptional profiling and kinase activity screen on patient-derived specimens, WEE1 genetic knockdown, WEE1 inhibitor pharmacologic treatment, DNA damage assays, in vivo xenograft experiments JCI insight High 35315355
2020 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. RNA sequencing of schizophrenia discordant twin samples, AC006129.1 overexpression mouse model, promoter binding assay, DNA methylation analysis (bisulfite), DNMT co-immunoprecipitation Molecular psychiatry Medium 32015466
2023 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. CIC knockdown and overexpression in patient-derived glioma lines, RNA-sequencing, non-phosphorylatable CIC-S173A mutant expression, extracellular glutamate measurement, neuronal toxicity assay Acta neuropathologica communications Medium 36647117
2018 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. Isogenic ATXN1LKO and CICKO human cell lines, transcriptome analysis, functional in vitro studies Oncogene Medium 30093628

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 463 22869205
2011 Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science (New York, N.Y.) 422 21817013
1992 Regions involved in the opening of CIC-2 chloride channel by voltage and cell volume. Nature 380 1334533
2006 Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Human molecular genetics 372 16717057
2011 High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes, chromosomes & cancer 273 22072439
2011 Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. The Journal of pathology 229 22072542
2014 Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes, chromosomes & cancer 195 24723486
2016 Recurrent CIC Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases With Concurrent Investigation of PLCG1, KDR, MYC, and FLT4 Gene Alterations. The American journal of surgical pathology 165 26735859
2016 CIC-rearranged Sarcomas: A Study of 20 Cases and Comparisons With Ewing Sarcomas. The American journal of surgical pathology 162 26685084
2014 A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. The American journal of surgical pathology 149 25007147
2012 The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget 147 23100451
2016 Evaluation of ETV4 and WT1 expression in CIC-rearranged sarcomas and histologic mimics. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 139 27443513
2011 The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. Human pathology 135 21813156
2019 Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas. The American journal of surgical pathology 131 30407212
1995 CIC-2: a developmentally dependent chloride channel expressed in the fetal lung and downregulated after birth. American journal of respiratory cell and molecular biology 119 7766424
2012 CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta neuropathologica 115 22588899
2017 Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nature genetics 110 28288114
2013 Undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly aggressive soft tissue tumor with distinctive histopathology. The American journal of surgical pathology 109 23887164
2017 ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition. Cell reports 98 28178529
2017 CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma. Cancer research 93 28404587
2011 ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization. Developmental cell 90 22014525
2017 Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes. Virchows Archiv : an international journal of pathology 83 28197724
2016 CIC-DUX4 fusion-positive round-cell sarcomas of soft tissue and bone: a single-institution morphological and molecular analysis of seven cases. Histopathology 82 27079694
2009 Detailed cytogenetic and array analysis of pediatric primitive sarcomas reveals a recurrent CIC-DUX4 fusion gene event. Cancer genetics and cytogenetics 81 19837261
2015 miR-93/miR-106b/miR-375-CIC-CRABP1: a novel regulatory axis in prostate cancer progression. Oncotarget 78 26124181
2014 CIC-DUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 78 24947144
1995 Stable and functional expression of the CIC-3 chloride channel in somatic cell lines. Neuron 74 7605637
2017 DUX4 Immunohistochemistry Is a Highly Sensitive and Specific Marker for CIC-DUX4 Fusion-positive Round Cell Tumor. The American journal of surgical pathology 72 27879517
2015 CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas. Annals of neurology 72 26017892
2017 CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study. Histopathology 70 28493604
2017 NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. Human pathology 65 28188754
2019 CIC protein instability contributes to tumorigenesis in glioblastoma. Nature communications 63 30737375
2018 The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation. Cancer research 62 29844126
2018 CIC-NUTM1 fusion: A case which expands the spectrum of NUT-rearranged epithelioid malignancies. Genes, chromosomes & cancer 61 29700887
2017 ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements. Genes, chromosomes & cancer 60 28233365
2019 CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs. The Journal of clinical investigation 57 31329165
2017 Generation of novel patient-derived CIC- DUX4 sarcoma xenografts and cell lines. Scientific reports 54 28680140
2015 High-grade undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: emerging entities of soft tissue tumors with unique histopathologic features--a case report and literature review. The American journal of case reports 50 25683183
2018 RAS-MAPK Pathway-Driven Tumor Progression Is Associated with Loss of CIC and Other Genomic Aberrations in Neuroblastoma. Cancer research 48 30115695
2013 Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 48 24030748
2015 Molecular background of oligodendroglioma: 1p/19q, IDH, TERT, CIC and FUBP1. CNS oncology 47 26545048
2022 Systemic treatments and outcomes in CIC-rearranged Sarcoma: A national multi-centre clinicopathological series and literature review. Cancer medicine 46 35178869
2020 Establishment and characterization of NCC-CDS2-C1: a novel patient-derived cell line of CIC-DUX4 sarcoma. Human cell 46 31898195
2020 LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia. Molecular psychiatry 45 32015466
2019 CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF-MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement. The oncologist 45 32043788
2016 Ewing sarcoma and the new emerging Ewing-like sarcomas: (CIC and BCOR-rearranged-sarcomas). A systematic review. Histology and histopathology 45 27306060
2010 A critical role for chloride channel-3 (CIC-3) in smooth muscle cell activation and neointima formation. Arteriosclerosis, thrombosis, and vascular biology 42 21071705
2017 Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation. Cancer research 40 28939681
2016 Round cell sarcoma with CIC-DUX4 gene fusion: Discussion of the distinctive cytomorphologic, immunohistochemical, and molecular features in the differential diagnosis of round cell tumors. Cancer cytopathology 40 26800124
2023 Expanding the Molecular Diversity of CIC-Rearranged Sarcomas With Novel and Very Rare Partners. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 38 36788092
2021 Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma. Oncogenesis 38 34642317
2023 A global collaboRAtive study of CIC-rearranged, BCOR::CCNB3-rearranged and other ultra-rare unclassified undifferentiated small round cell sarcomas (GRACefUl). European journal of cancer (Oxford, England : 1990) 36 36791667
2017 Comparative transcriptome analysis of isogenic cell line models and primary cancers links capicua (CIC) loss to activation of the MAPK signalling cascade. The Journal of pathology 36 28295365
2005 CIC, a gene involved in cerebellar development and ErbB signaling, is significantly expressed in medulloblastomas. Journal of neuro-oncology 36 15981098
2015 ETV/Pea3 family transcription factor-encoding genes are overexpressed in CIC-mutant oligodendrogliomas. Genes, chromosomes & cancer 34 26357005
2020 Superficial sarcomas with CIC rearrangement are aggressive neoplasms: A series of eight cases. Journal of cutaneous pathology 33 32026485
2020 CIC is a critical regulator of neuronal differentiation. JCI insight 33 32229723
2019 Undifferentiated round cell sarcomas with CIC-DUX4 gene fusion: expanding the clinical spectrum. Pathology 33 31870501
1999 Modulation of the gating of CIC-1 by S-(-) 2-(4-chlorophenoxy) propionic acid. British journal of pharmacology 32 10217531
2016 The utility of ETV1, ETV4 and ETV5 RNA in-situ hybridization in the diagnosis of CIC-DUX sarcomas. Histopathology 31 27790742
2014 Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity. Oncotarget 31 25277207
2018 Transcriptomic analysis of CIC and ATXN1L reveal a functional relationship exploited by cancer. Oncogene 30 30093628
2020 CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop. iScience 28 33103082
2022 Integrated Molecular Characterization of Patient-Derived Models Reveals Therapeutic Strategies for Treating CIC-DUX4 Sarcoma. Cancer research 26 34903601
2020 DNA Methylation Profiling for Diagnosing Undifferentiated Sarcoma with Capicua Transcriptional Receptor (CIC) Alterations. International journal of molecular sciences 26 32155762
2020 Radiomics Features Predict CIC Mutation Status in Lower Grade Glioma. Frontiers in oncology 26 32676453
2020 Imaging features and clinical course of undifferentiated round cell sarcomas with CIC-DUX4 and BCOR-CCNB3 translocations. Skeletal radiology 25 32840647
2022 Co-expression of ERG and CD31 in a subset of CIC-rearranged sarcoma: a potential diagnostic pitfall. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 24 35440765
2022 CIC-Rearranged Sarcomas: An Intriguing Entity That May Lead the Way to the Comprehension of More Common Cancers. Cancers 24 36358827
2019 Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs. Scientific reports 24 31676869
2017 Primary Spinal Epidural CIC-DUX4 Undifferentiated Sarcoma in a Child. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 24 28474974
2022 Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1. Neuron 23 36577402
2020 Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor. The Journal of pathology 23 32073140
2020 CIC de novo loss of function variants contribute to cerebral folate deficiency by downregulating FOLR1 expression. Journal of medical genetics 23 32820034
2020 Case Report: A Unique Case of Pediatric Central Nervous System Embryonal Tumor Harboring the CIC-LEUTX Fusion, Germline NBN Variant and Somatic TSC2 Mutation: Expanding the Spectrum of CIC-Rearranged Neoplasia. Frontiers in oncology 23 33344249
2019 MiR-1307 influences the chemotherapeutic sensitivity in ovarian cancer cells through the regulation of the CIC transcriptional repressor. Pathology, research and practice 23 31500928
2023 Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature. NPJ precision oncology 21 36964296
2023 CIC reduces xCT/SLC7A11 expression and glutamate release in glioma. Acta neuropathologica communications 20 36647117
2022 Central nervous system sarcoma with ATXN1::DUX4 fusion expands the concept of CIC-rearranged sarcoma. Genes, chromosomes & cancer 20 35715887
2022 A case of CIC-rearranged sarcoma with CIC-LEUTX gene fusion in spinal cord. Neuropathology : official journal of the Japanese Society of Neuropathology 20 35859319
2020 Advances into Understanding the Vital Role of the Mitochondrial Citrate Carrier (CIC) in Metabolic Diseases. Pharmacological research 20 32814170
2016 A case report of CIC-rearranged undifferentiated small round cell sarcoma in the cerebrum. Diagnostic cytopathology 20 27324529
2023 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. Cancer medicine 19 37212486
2023 Capicua (CIC) mutations in gliomas in association with MAPK activation for exposing a potential therapeutic target. Medical oncology (Northwood, London, England) 19 37291277
2022 Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology. Brain : a journal of neurology 19 35203088
2022 Patterns of care and outcome of CIC-rearranged sarcoma patients: A nationwide study of the French sarcoma group. Cancer medicine 19 36537582
2021 The CAM Model for CIC-DUX4 Sarcoma and Its Potential Use for Precision Medicine. Cells 18 34685592
2018 CIC-DUX4 sarcoma diagnosed by fine-needle aspiration cytology: A case report. Diagnostic cytopathology 18 30353686
1987 Erythrocyte complement receptor type 1 (CR1) expression and circulating immune complex (CIC) levels in hydralazine-induced SLE. Clinical and experimental immunology 18 2958187
2024 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. Histopathology 17 39381843
2022 WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma. JCI insight 17 35315355
2016 Targeted next-generation sequencing of CIC-DUX4 soft tissue sarcomas demonstrates low mutational burden and recurrent chromosome 1p loss. Human pathology 17 27664537
2013 Novel CIC point mutations and an exon-spanning, homozygous deletion identified in oligodendroglial tumors by a comprehensive genomic approach including transcriptome sequencing. PloS one 17 24086756
2023 CIC-Rearranged Sarcoma. Surgical pathology clinics 16 38278603
2022 CIC rearranged sarcomas: A single institution experience of the potential pitfalls in interpreting CIC FISH results. Pathology, research and practice 16 35093696
2020 c-Src Phosphorylates and Inhibits the Function of the CIC Tumor Suppressor Protein. Molecular cancer research : MCR 16 32029440
2017 Head and Neck Round Cell Sarcomas: A Comparative Clinicopathologic Analysis of 2 Molecular Subsets: Ewing and CIC-Rearranged Sarcomas. Head and neck pathology 16 28337592
2017 Primary undifferentiated small round cell sarcoma of the deep abdominal wall with a novel variant of t(10;19) CIC-DUX4 gene fusion. Pathology, research and practice 15 28645808
2007 Identification of ClC-2 and CIC-K2 chloride channels in cultured rat type IV spiral ligament fibrocytes. Journal of the Association for Research in Otolaryngology : JARO 14 17334850
2004 Expression of novel isoforms of the CIC-1 chloride channel in astrocytic glial cells in vitro. Glia 14 15139012

Missed literature

Know a paper Affinage missed for CIC? Flag it for the maintainers and the community.

No submissions yet.