Affinage

CIC

Protein capicua homolog · UniProt Q96RK0

Length
2517 aa
Mass
258.0 kDa
Annotated
2026-04-28
100 papers in source corpus 21 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    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

    PMID:16717057

    Open questions at the time
    • No genome-wide target map for wild-type CIC
    • Mechanism of transcriptional switching from repressor to activator unknown
    • Cofactors for CIC repression unidentified
  2. 2011 High

    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

    PMID:22014525

    Open questions at the time
    • Mechanism by which ATXN1L stabilizes CIC protein not defined
    • Whether ATXN1L modulates CIC DNA binding or chromatin recruitment unknown
  3. 2014 Medium

    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

    PMID:24723486

    Open questions at the time
    • No direct binding or functional assays for WT1 regulation by CIC-DUX4
    • Contribution of individual ETS targets to tumorigenesis not dissected
  4. 2017 High

    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

    PMID:28178529

    Open questions at the time
    • Whether CIC loss confers resistance to other MAPK pathway inhibitors beyond MEK not tested
    • Patient tumor validation of CIC-mediated resistance pending
  5. 2017 High

    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

    PMID:28288114

    Open questions at the time
    • Specific CIC target genes mediating neurobehavioral phenotypes not fully defined
    • Cell-type-specific CIC targets in forebrain circuits unknown
  6. 2017 High

    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

    PMID:28939681

    Open questions at the time
    • Mechanism of CIC-mediated transcriptional activation versus repression not resolved
    • Direct activator targets not validated by ChIP
  7. 2018 High

    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

    PMID:29844126

    Open questions at the time
    • Whether SIN3A or SIN3B is preferentially recruited not distinguished
    • Structural basis of CIC–SIN3 interaction unknown
  8. 2019 High

    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

    PMID:30737375

    Open questions at the time
    • Full ubiquitination site(s) on CIC not mapped
    • Whether PJA1 acts on CIC in non-glioma contexts not tested
  9. 2019 High

    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

    PMID:31329165

    Open questions at the time
    • Full repertoire of CIC-DUX4 neomorphic versus retained targets not catalogued
    • Mechanism by which DUX4 domain converts CIC repressor to activator not structurally resolved
  10. 2020 High

    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

    PMID:33103082

    Open questions at the time
    • Whether additional kinases phosphorylate CIC at other sites not excluded
    • Kinetics of CIC nuclear re-import after signal attenuation unknown
  11. 2020 High

    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

    PMID:32229723

    Open questions at the time
    • Whether SIN3-HDAC and mSWI/SNF are recruited simultaneously or to distinct loci not resolved
    • Structural basis of CIC–mSWI/SNF interaction unknown
  12. 2021 High

    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

    PMID:34642317

    Open questions at the time
    • 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
  13. 2022 High

    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

    PMID:35315355

    Open questions at the time
    • 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
  14. 2023 Medium

    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

    PMID:36647117

    Open questions at the time
    • In vivo significance of CIC-mediated glutamate control for tumor microenvironment not tested
    • Whether xCT derepression contributes to ferroptosis sensitivity not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 2
Partners
ATXN1ATXN1LBRG1P300PJA1SIN3AYWHAB
Complex memberships
SIN3-HDACmSWI/SNF (BRG1-containing)

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Gene expression analysis, promoter binding assay (direct CIC-DUX4 binding to ERM promoter), NIH 3T3 transformation assay Human molecular genetics High 16717057
2011 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. Atxn1L-/- and Atxn1-/-;Atxn1L-/- mouse models, gene expression analysis, loss-of-function with defined phenotypic readout Developmental cell High 22014525
2017 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. Genome-scale CRISPR-Cas9 loss-of-function screen in KRAS-mutant pancreatic cancer cells treated with trametinib; ectopic ETV expression rescue experiments Cell reports High 28178529
2017 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. Conditional mouse knockouts with behavioral phenotyping; human patient exome sequencing with matched clinical features Nature genetics High 28288114
2018 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. Genome-wide ChIP-seq in multiple cell types, co-immunoprecipitation of CIC with SIN3 complex, histone acetylation assays, CIC mutant functional analysis Cancer research High 29844126
2019 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. PJA1 knockdown in vivo GBM models (survival assay), phosphorylation site mutagenesis, co-immunoprecipitation, proteasome inhibitor experiments Nature communications High 30737375
2019 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. ChIP-seq for direct target binding, genetic knockdown of individual targets, CDK2 inhibitor sensitivity assays in CIC-DUX4 cell lines and xenografts The Journal of clinical investigation High 31329165
2020 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. Promoter-binding assays (ChIP and reporter), site-directed mutagenesis of CIC phosphorylation sites, co-immunoprecipitation with 14-3-3, cellular fractionation/localization iScience High 33103082
2020 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. Brain-specific Cic conditional KO mice (neuronal differentiation phenotype), ChIP-seq, Co-IP, mass spectrometry of CIC interactors JCI insight High 32229723
2017 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. Conditional Cic knockout mice, in vitro neural stem cell proliferation/differentiation assays, orthotopic mouse glioma model Cancer research High 28939681
2017 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. Ex vivo mouse model, gene expression profiling, gene silencing (shRNA), pharmacological inhibition (palbociclib, trabectedin) in vitro Cancer research High 28404587
2014 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. Expression profiling with q-PCR validation, immunohistochemistry Genes, chromosomes & cancer Medium 24723486
2015 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). CIC overexpression and RNAi in prostate cancer cell lines, luciferase reporter for miRNA-CIC interaction, proliferation/invasion assays Oncotarget Medium 26124181
2014 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. Stable cell line co-expression, subcellular fractionation/localization, 2-HG metabolite measurement, Western blotting for phospho-ACLY Oncotarget Medium 25277207
2018 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. CIC knockout in neuroblastoma cell lines, in vivo xenograft tumor growth assay, pathway activation analysis Cancer research High 30115695
2021 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. P300/CBP inhibitor (iP300w) treatment, histone acetylation assays, CDS xenograft tumor growth inhibition in vivo Oncogenesis High 34642317
2017 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. Isogenic CIC knockout cell lines, transcriptome analysis, direct target validation The Journal of pathology Medium 28295365
2018 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. ATXN1L KO and CIC KO human cell lines, transcriptomic analysis, TCGA cohort analysis Oncogene Medium 30093628
2020 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. Promoter binding assay, CIC variant functional analysis in HeLa and patient iPSC-derived cells, folate binding assay Journal of medical genetics Medium 32820034
2023 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. CIC gain- and loss-of-function in patient-derived glioma lines, RNA-seq, glutamate release assays, non-phosphorylatable CIC variant (S173A) Acta neuropathologica communications Medium 36647117
2022 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. Kinase activity screen on patient-derived specimens, genetic and pharmacologic WEE1 inhibition, in vivo xenograft assay JCI insight High 35315355
2020 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. Brain-specific Cic conditional KO, ChIP-seq, gene expression profiling, VGF overexpression experiments JCI insight High 32229723

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 462 22869205
2011 Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science (New York, N.Y.) 420 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 367 16717057
2017 Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. The American journal of surgical pathology 312 28346326
1995 Gating of the voltage-dependent chloride channel CIC-0 by the permeant anion. Nature 298 7845466
2011 High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes, chromosomes & cancer 270 22072439
2011 Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. The Journal of pathology 228 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 193 24723486
2016 CIC-rearranged Sarcomas: A Study of 20 Cases and Comparisons With Ewing Sarcomas. The American journal of surgical pathology 160 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 146 25007147
2012 The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget 146 23100451
2011 The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. Human pathology 135 21813156
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 134 27443513
2019 Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas. The American journal of surgical pathology 127 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 109 28288114
2016 ETV4 is a useful marker for the diagnosis of CIC-rearranged undifferentiated round-cell sarcomas: a study of 127 cases including mimicking lesions. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 108 27562494
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 108 23887164
2017 ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition. Cell reports 96 28178529
2017 CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma. Cancer research 92 28404587
2011 ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization. Developmental cell 89 22014525
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 Cloning of a putative human voltage-gated chloride channel (CIC-2) cDNA widely expressed in human tissues. Human molecular genetics 78 7795595
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
2017 CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study. Histopathology 67 28493604
1997 Identification of functionally important regions of the muscular chloride channel CIC-1 by analysis of recessive and dominant myotonic mutations. Human molecular genetics 65 9158157
2017 NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. Human pathology 63 28188754
2019 CIC protein instability contributes to tumorigenesis in glioblastoma. Nature communications 61 30737375
2018 The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation. Cancer research 59 29844126
2019 CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs. The Journal of clinical investigation 56 31329165
2017 Generation of novel patient-derived CIC- DUX4 sarcoma xenografts and cell lines. Scientific reports 53 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
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
2018 RAS-MAPK Pathway-Driven Tumor Progression Is Associated with Loss of CIC and Other Genomic Aberrations in Neuroblastoma. Cancer research 47 30115695
2013 Superficial EWSR1-negative undifferentiated small round cell sarcoma with CIC/DUX4 gene fusion: a new variant of Ewing-like tumors with locoregional lymph node metastasis. Virchows Archiv : an international journal of pathology 47 24213312
2022 Systemic treatments and outcomes in CIC-rearranged Sarcoma: A national multi-centre clinicopathological series and literature review. Cancer medicine 45 35178869
2020 Establishment and characterization of NCC-CDS2-C1: a novel patient-derived cell line of CIC-DUX4 sarcoma. Human cell 45 31898195
2015 Molecular background of oligodendroglioma: 1p/19q, IDH, TERT, CIC and FUBP1. CNS oncology 44 26545048
2020 LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia. Molecular psychiatry 42 32015466
2016 Ewing sarcoma and the new emerging Ewing-like sarcomas: (CIC and BCOR-rearranged-sarcomas). A systematic review. Histology and histopathology 42 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 39 28939681
2012 The mitochondrial citrate carrier (CIC) is present and regulates insulin secretion by human male gamete. Endocrinology 39 22355067
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
2005 CIC, a gene involved in cerebellar development and ErbB signaling, is significantly expressed in medulloblastomas. Journal of neuro-oncology 36 15981098
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 35 36788092
2021 Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma. Oncogenesis 35 34642317
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 35 28295365
2020 Molecular identification of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specific signature genes. Acta neuropathologica communications 34 32650833
2015 ETV/Pea3 family transcription factor-encoding genes are overexpressed in CIC-mutant oligodendrogliomas. Genes, chromosomes & cancer 34 26357005
2018 Clinicopathologic Features of a Series of Primary Renal CIC-rearranged Sarcomas With Comprehensive Molecular Analysis. The American journal of surgical pathology 33 29901569
2019 Undifferentiated round cell sarcomas with CIC-DUX4 gene fusion: expanding the clinical spectrum. Pathology 32 31870501
2013 A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with mutations in FUBP1, CIC, and IDH1. PloS one 32 23527265
1999 Modulation of the gating of CIC-1 by S-(-) 2-(4-chlorophenoxy) propionic acid. British journal of pharmacology 32 10217531
2020 Superficial sarcomas with CIC rearrangement are aggressive neoplasms: A series of eight cases. Journal of cutaneous pathology 31 32026485
2020 CIC is a critical regulator of neuronal differentiation. JCI insight 30 32229723
2018 Transcriptomic analysis of CIC and ATXN1L reveal a functional relationship exploited by cancer. Oncogene 30 30093628
2017 An overview of combined D-2- and L-2-hydroxyglutaric aciduria: functional analysis of CIC variants. Journal of inherited metabolic disease 30 29238895
2016 The utility of ETV1, ETV4 and ETV5 RNA in-situ hybridization in the diagnosis of CIC-DUX sarcomas. Histopathology 30 27790742
2014 Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity. Oncotarget 30 25277207
2003 Biogenesis of rat mitochondrial citrate carrier (CIC): the N-terminal presequence facilitates the solubility of the preprotein but does not act as a targeting signal. Journal of molecular biology 29 12488104
2020 CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop. iScience 27 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 25 32676453
1996 A short CIC-2 mRNA transcript is produced by exon skipping. Nucleic acids research 25 8811102
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 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 23 35440765
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
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
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 23 31676869
2022 CIC-Rearranged Sarcomas: An Intriguing Entity That May Lead the Way to the Comprehension of More Common Cancers. Cancers 22 36358827
2019 17β-Estradiol Attenuates Neuropathic Pain Caused by Spared Nerve Injury by Upregulating CIC-3 in the Dorsal Root Ganglion of Ovariectomized Rats. Frontiers in neuroscience 21 31787875
1997 Alternative splicing of ClC-6 (a member of the CIC chloride-channel family) transcripts generates three truncated isoforms one of which, ClC-6c, is kidney-specific. The Biochemical journal 21 9224655
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 Estimation of copy number aberrations: Comparison of exome sequencing data with SNP microarrays identifies homozygous deletions of 19q13.2 and CIC in neuroblastoma. International journal of oncology 20 26794043
2023 CIC reduces xCT/SLC7A11 expression and glutamate release in glioma. Acta neuropathologica communications 19 36647117
2022 Patterns of care and outcome of CIC-rearranged sarcoma patients: A nationwide study of the French sarcoma group. Cancer medicine 19 36537582
2019 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. Central-European journal of immunology 19 31871418
2016 A case report of CIC-rearranged undifferentiated small round cell sarcoma in the cerebrum. Diagnostic cytopathology 19 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 18 37212486
2022 Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology. Brain : a journal of neurology 18 35203088
2022 Central nervous system sarcoma with ATXN1::DUX4 fusion expands the concept of CIC-rearranged sarcoma. Genes, chromosomes & cancer 18 35715887
2021 The CAM Model for CIC-DUX4 Sarcoma and Its Potential Use for Precision Medicine. Cells 18 34685592
2019 Clinicopathologic features of undifferentiated round cell sarcomas of bone & soft tissues: An attempt to unravel the BCOR-CCNB3- & CIC-DUX4-positive sarcomas. The Indian journal of medical research 18 32048619
2022 WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma. JCI insight 17 35315355
2017 Novel exon-exon breakpoint in CIC-DUX4 fusion sarcoma identified by anchored multiplex PCR (Archer FusionPlex Sarcoma Panel). Journal of clinical pathology 17 28137728
2016 Targeted next-generation sequencing of CIC-DUX4 soft tissue sarcomas demonstrates low mutational burden and recurrent chromosome 1p loss. Human pathology 17 27664537
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 16 39381843
2023 Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature. NPJ precision oncology 16 36964296
2022 CIC rearranged sarcomas: A single institution experience of the potential pitfalls in interpreting CIC FISH results. Pathology, research and practice 16 35093696
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 16 24086756
2023 CIC-Rearranged Sarcoma. Surgical pathology clinics 15 38278603