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CIC (capicua transcriptional repressor)

Written2015-07Marlo Firme, Marco Marra
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada (MF); Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada (MM)

Abstract CIC is a tissue-specific transcriptional repressor that is highly conserved between metazoan organisms and is required for the normal development of multiple adult structures. CIC functions to transduce receptor tyrosine kinase (RTK) signalling into gene expression changes through a mechanism termed default repression, wherein CIC is bound to target gene promoters or enhancers and inhibits transcription in the absence of signal. This CIC-DNA interaction can be inhibited through activation of the RTK core signalling molecule mitogen-activated protein kinase (MAPK), which then allows for the transcription of CIC targets through this RTK-MAPK signalling axis. Components of RTK signalling are commonly dysregulated in cancers, possibly implying that CIC alterations observed in specific cancer types (e.g. oligodendroglioma and Ewing-like sarcomas) are a form of RTK signalling dysregulation that drives oncogenesis. CIC is also specifically expressed in cells of the developing central nervous system and its dysfunction is associated with the neurodegenerative disorder spinocerebellar ataxia type 1, implicating CIC in neuronal cell development and/or homeostasis. Other possible cellular and physiological roles for CIC include cell cycle control, ATP-citrate lyase phosphorylation, reactive oxygen species homeostasis, and bile acid homeostasis.

Keywords Oligodendroglioma, spinocerebellar ataxia type 1, Ewing-like sarcoma, transcription factor, receptor tyrosine kinase

(Note : for Links provided by Atlas : click)


HGNC Alias symbKIAA0306
HGNC Previous namecapicua (Drosophila) homolog
 capicua homolog (Drosophila)
LocusID (NCBI) 23152
Atlas_Id 46558
Location 19q13.2  [Link to chromosome band 19q13]
Location_base_pair Starts at 42284469 and ends at 42295796 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping CIC.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CIC (19q13.2)::BOLA2 (16p11.2)CIC (19q13.2)::CIC (19q13.2)CIC (19q13.2)::DUX4 (-)
CIC (19q13.2)::DUX4 (4q35.2)CIC (19q13.2)::DUX4L10 (10q26.3)CIC (19q13.2)::FOXO4 (Xq13.1)
CIC (19q13.2)::KLK11 (19q13.41)CIC (19q13.2)::LEUTX (19q13.2)CIC (19q13.2)::LMNA (1q22)
CIC (19q13.2)::ZFP57 (6p22.1)DUX4 (-)::CIC (19q13.2)MICAL2 (11p15.3)::CIC (19q13.2)


  Figure 1. Exon structure of 2 main CIC isoforms in humans: CIC short (CIC-S) and long (CIC-L). The highly conserved DNA-binding high mobility group (HMG) box domain is encoded mostly by exon 5 and partially by exon 6 while the highly conserved C1 motif is encoded within exon 20. Figure was obtained from Chittaranjan et al. 2014 with labels added.
Description CIC is located on the positive strand and spans approximately 27 kilobases. It has 21 exons. According to Entrez-Gene, CIC maps to NC_000019.10 of the assembly GRCh38.p2.
Transcription There are two known isoforms of CIC: short (CIC-S) and long (CIC-L). CIC-S and CIC-L have alternative transcription start sites at exon 1 and exon 0, respectively, and share exons 2-20 (Figure 1).
Pseudogene According to Entrez-Gene, CIC has 28 related pseudogenes.


  Figure 2. Functional domains of CIC short (CIC-S) and long (CIC-L) isoforms in humans. N1: Conserved CIC-L N-terminal domain of unknown function. Ataxin-1 BD: Binding domain that directly interacts with Ataxin-1 (Lam et al. 2006; Kim et al. 2013). 14-3-3 BD: binding domain that directly interacts with 14-3-3 proteins. This domain harbours a serine residue that is phosphorylated by p90RSK to mediate 14-3-3 binding and consequent inhibition of DNA binding upon MAPK activation. An additional 14-3-3 BD flanking the other end of the HMG domain may also be required for 14-3-3 dimer recognition (Dissanayake et al. 2011). HMG: DNA-binding high mobility group box domain (Jimenez et al. 2000; Lee et al. 2002). NLS: Nuclear localisation signal recognized by the nuclear importer KPNA3. Phosphorylation of two nearby serine residues may mask the NLS and potentially interferes with nuclear shuttling upon MAPK activation. Other NLS sequence(s) may be encoded within the HMG domain (Dissanayake et al. 2011). C1: Highly conserved c-terminal motif that may be essential for CIC-mediated transcriptional repression in some contexts (Astigarraga et al. 2007). C2: Motif that mediates direct binding with MAPK (Futran et al. 2015).
Expression In Drosophila and zebrafish, CIC mRNA is maternally provided to the egg (Jimenez et al. 2000; Chen et al. 2014). In zebrafish and mice, CIC mRNA is detected at various developmental stages, especially in the developing central nervous system (Lee et al. 2002; Chen et al. 2014). In adult mice, CIC mRNA is relatively highly expressed in the brain, spleen, testis, and kidney. CIC mRNA may also be expressed in the heart, lung, mammary tissue, thymus, and lymph nodes in adult mice (Lee et al. 2002).
Localisation CIC-S and CIC-L localize to both the cytoplasm and the nucleus in multiple human cell lines. CIC may also accumulate close to the mitochondria (Chittaranjan et al. 2014).
Function CIC has invariably been observed to act as a repressor of transcription through its DNA-binding activity. CIC has a high mobility group (HMG) box domain that confers binding to an octameric DNA motif T(G/C)AATG(A/G)A within the promoters or enhancers of its target genes (Jimenez et al. 2012). In Drosophila, presence of this octameric motif at the regulatory region of a reporter gene was necessary to confer CIC-mediated transcriptional repression, although recruitment of a corepressor protein such as Groucho may be necessary to confer repression (Ajuria et al. 2011). CIC's DNA-binding activity can be inhibited through the activation (phosphorylation) of mitogen-activated protein kinase (MAPK), a core signaling molecule of receptor tyrosine kinase (RTK) pathways (Jimenez et al. 2002; Dissanayake et al. 2011). This provides a mechanism for allowing CIC target gene transcription upon RTK signaling. MAPK potentially regulates CIC's transcriptionally repressive activity in three ways: through direct binding with CIC (Astigarraga et al. 2007, Futran et al. 2015), through the activation of the downstream signaling molecule p90RSK (Figure 2) to inhibit CIC's DNA-binding activity (Dissanayake et al. 2011), or through influencing CIC's nucleocytoplasmic shuttling (Dissanayake et al. 2011, Grimm et al. 2012). CIC levels in turn also positively regulate MAPK phosphorylation in vivo in Drosophila by protecting MAPK from phosphatases (Kim et al. 2011).
CIC functions in multiple developmental contexts in both Drosophila and mammals. For example, in Drosophila, CIC can regulate proper embryonic patterning, cell differentiation to form wing vein cells, and cell proliferation in the developing eye. In all these contexts, CIC functions in cells by restricting the expression of specific target genes when an extracellular growth signaling molecule is absent (Jimenez et al. 2002; Roch et al. 2002; Tseng et al. 2007). CIC has also been reported to function in reactive oxygen species homeostasis (Krivy et al. 2013), ATP-citrate lyase phosphorylation (Chittaranjan et al. 2014), and bile acid homeostasis (Kim et al. 2015).
Homology CIC has homologs in mice, zebrafish, Drosophila, and C. elegans (Jimenez et al. 2000; Lee et al. 2002). Amino acid sequence identity of CIC's N1 domain, HMG box domain, and C1 motif (Figure 2) is highly conserved between species (Jimenez et al 2012). This indicates that at least some of CIC's biochemical functions are evolutionary conserved between animals.

Implicated in

Entity CIC-rearranged Ewing-like sarcomas
Note The overwhelming majority of Ewing sarcoma/primitive neuroectodermal family of tumours (EFTs) harbour rearrangements of the EWSR1 gene with an ETS family member (Delattre et al. 1994; Mariño-Enrèquez & Fletcher 2014). However, up to 2/3 of EWSR1 fusion-negative EFTs may harbour rearrangements of CIC with a copy of DUX4 on either 4q35 or 10q26. CIC-DUX4. EFTs are aggressive and typically share characteristics such as geographical necrosis and greater heterogeneity in nuclear shape and size than classical EFTs (Italiano et al. 2012). CIC-DUX4 proteins have oncogenic transforming potential in vitro and may drive oncogenesis by strongly activating transcription of CIC's oncogenic target genes ETV1, ETV4, and ETV5 instead of normally repressing them (Kawamura-Saito et al. 2006). Consistent with this, EWSR1-ETV1 and EWSR1-ETV4 fusions, which presumably function as aberrant versions of the transcription factors ETV1 and ETV4, respectively, have been observed in EFTs (Jeon et al. 1995; Kaneko et al. 1996). EFTs with CIC-FOXO4 fusions have also been reported (Sugita et al. 2014; Solomon et al. 2014).
Entity Oligodendroglioma
Note CIC mutations are detected in about 70% of "classical" oligodendrogliomas (ODGs, i.e. gliomas harbouring deletions of the chromosomal arms 1p and 19q) (Bettegowda et al. 2011; Yip et al. 2012). Classical ODGs also present with a characteristic set of other somatic mutations, namely in IDH1 or IDH2 (in 100% of cases), in the TERT promoter (about 90% of cases), and in FUBP1 (about 25-40% of cases) (Bettegowda et al. 2011; Sahm et al. 2012; Jiao et al. 2012; Labussire et al. 2014). This indicates potential synergistic interactions between these mutations to promote ODG progression. Different types of detected CIC mutations seem to converge on conferring a CIC loss-of-function phenotype, indicating CIC mutations may inactivate a tumour suppressive activity (Gleize et al. 2015). A CIC mutation in a 1p/19q co-deleted background may also be compatible with the notion of a tumour suppressive role for CIC, since one allele is lost as a consequence of 19q loss while the other allele is mutated. However, there is an enrichment of CIC mutations that affect a single amino acid residue and may preserve CIC's structure (Figure 3). Such "hotspots" are often detected in oncogenes (Liu et al. 2011; Stehr et al. 2011). Multiple distinct CIC mutations can arise within different areas of a single ODG lesion (Suzuki et al. 2015), possibly implicating the importance of CIC mutations in driving clonal expansion but not necessarily tumour initiation.
Figure 3. CIC-S: short isoform of CIC. HMG: high-mobility group. C1 motif: highly conserved c-terminal domain. Recurrently detected mutations are indicated in stacked symbols. Frequencies of different mutation types are given in parentheses. Mutational data were gathered from multiple sources (Bettegowda et al. 2011; Jiao et al. 2012; Sahm et al. 2012; Yip et al. 2012) and the cbioportal database (Gao et al. 2013; Chan et al. 2014). The results shown here are in part based upon data generated by the TCGA Research Network:
Entity Other cancers
Note Recurrent somatic CIC mutations, deletions, and amplifications have been detected in a number of other cancer types (Figure 4). Loss of CIC expression is also implicated in prostate cancer progression (Choi et al. 2015). CIC alterations may therefore promote oncogenesis in various cancers.
Figure 4. Frequency of CIC alterations detected in non-glioma cancers. Figure was obtained and modified from the cbioportal database (Cerami et al. 2012; Gao et al. 2013). The results shown here are in whole or part based upon data generated by the TCGA Research Network: Cancer types with 2 or more detected CIC alterations are shown. CNA: copy number alteration.
Entity Spinocerebellar ataxia type 1
Note Spinocerebellar ataxia type 1 (SCA1) is an inherited neurodegenerative disorder that is caused by the production of a toxic form of the Ataxin-1 protein harbouring an expanded tract of glutamine residues (polyQ Ataxin-1) (Orr et al. 1993). SCA1 pathogenesis is associated with a direct physical interaction of polyQ Ataxin-1 with CIC in a large (about 1.8 MDa) complex, as well as with a decrease in wild type Ataxin-1-CIC complex formation. Modulation of CIC's transcriptionally repressive activity by polyQ Ataxin-1 provides a possible mechanistic basis for SCA1 pathogenesis (Lam et al. 2006; Bowman et al. 2007). SCA1 pathogenesis may also result from the preferential accumulation of another polyQ Ataxin-1 complex that includes the RBM17 protein and excludes CIC (Lim et al. 2008). In a mouse model of SCA1, a modest exercise regimen extends longevity by reducing CIC levels in the brainstem. CIC loss through genetic perturbation also mitigates multiple SCA1 phenotypes in this model (Fryer et al. 2011).


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PMID 23048183
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This paper should be referenced as such :
Marlo Firme, Marco Marra
CIC (capicua transcriptional repressor)
Atlas Genet Cytogenet Oncol Haematol. 2016;20(5):250-255.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(19;19)(q13;q13) PPP1R12C::CIC

External links


HGNC (Hugo)CIC   14214
LRG (Locus Reference Genomic)LRG_999
Atlas Explorer : (Salamanque)CIC
Entrez_Gene (NCBI)CIC    capicua transcriptional repressor
GeneCards (Weizmann)CIC
Ensembl hg19 (Hinxton)ENSG00000079432 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000079432 [Gene_View]  ENSG00000079432 [Sequence]  chr19:42284469-42295796 [Contig_View]  CIC [Vega]
ICGC DataPortalENSG00000079432
TCGA cBioPortalCIC
Genatlas (Paris)CIC
SOURCE (Princeton)CIC
Genetics Home Reference (NIH)CIC
Genomic and cartography
GoldenPath hg38 (UCSC)CIC  -     chr19:42284469-42295796 +  19q13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CIC  -     19q13.2   [Description]    (hg19-Feb_2009)
GoldenPathCIC - 19q13.2 [CytoView hg19]  CIC - 19q13.2 [CytoView hg38]
Genome Data Viewer NCBICIC [Mapview hg19]  
OMIM612082   617600   
Gene and transcription
Genbank (Entrez)AB002304 AF363689 AK025939 BF848448
RefSeq transcript (Entrez)NM_001304815 NM_001379480 NM_001379482 NM_001379484 NM_001379485 NM_001386298 NM_015125
Consensus coding sequences : CCDS (NCBI)CIC
Gene ExpressionCIC [ NCBI-GEO ]   CIC [ EBI - ARRAY_EXPRESS ]   CIC [ SEEK ]   CIC [ MEM ]
Gene Expression Viewer (FireBrowse)CIC [ Firebrowse - Broad ]
GenevisibleExpression of CIC in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)23152
GTEX Portal (Tissue expression)CIC
Human Protein AtlasENSG00000079432-CIC [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96RK0   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ96RK0  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ96RK0
Domaine pattern : Prosite (Expaxy)HMG_BOX_2 (PS50118)   
Domains : Interpro (EBI)HMG_box_dom    HMG_box_dom_sf   
Domain families : Pfam (Sanger)HMG_box (PF00505)   
Domain families : Pfam (NCBI)pfam00505   
Domain families : Smart (EMBL)HMG (SM00398)  
Conserved Domain (NCBI)CIC
PDB (RSDB)2M41    4J2J    4J2L    6JRP    6KZG    6KZH   
PDB Europe2M41    4J2J    4J2L    6JRP    6KZG    6KZH   
PDB (PDBSum)2M41    4J2J    4J2L    6JRP    6KZG    6KZH   
PDB (IMB)2M41    4J2J    4J2L    6JRP    6KZG    6KZH   
Structural Biology KnowledgeBase2M41    4J2J    4J2L    6JRP    6KZG    6KZH   
SCOP (Structural Classification of Proteins)2M41    4J2J    4J2L    6JRP    6KZG    6KZH   
CATH (Classification of proteins structures)2M41    4J2J    4J2L    6JRP    6KZG    6KZH   
AlphaFold pdb e-kbQ96RK0   
Human Protein Atlas [tissue]ENSG00000079432-CIC [tissue]
Protein Interaction databases
IntAct (EBI)Q96RK0
Ontologies - Pathways
Ontology : AmiGOchromatin  RNA polymerase II transcription regulatory region sequence-specific DNA binding  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription factor activity, RNA polymerase II-specific  protein binding  nucleus  nucleoplasm  regulation of transcription by RNA polymerase II  brain development  learning  memory  social behavior  intracellular membrane-bounded organelle  negative regulation of transcription, DNA-templated  
Ontology : EGO-EBIchromatin  RNA polymerase II transcription regulatory region sequence-specific DNA binding  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription factor activity, RNA polymerase II-specific  protein binding  nucleus  nucleoplasm  regulation of transcription by RNA polymerase II  brain development  learning  memory  social behavior  intracellular membrane-bounded organelle  negative regulation of transcription, DNA-templated  
NDEx NetworkCIC
Atlas of Cancer Signalling NetworkCIC
Wikipedia pathwaysCIC
Orthology - Evolution
GeneTree (enSembl)ENSG00000079432
Phylogenetic Trees/Animal Genes : TreeFamCIC
Homologs : HomoloGeneCIC
Homology/Alignments : Family Browser (UCSC)CIC
Gene fusions - Rearrangements
Fusion : MitelmanCIC::DUX4 [19q13.2/-]  
Fusion : MitelmanCIC::DUX4L10 [19q13.2/-]  
Fusion : MitelmanCIC::FOXO4 [19q13.2/Xq13.1]  
Fusion : MitelmanCIC::KLK11 [19q13.2/19q13.41]  
Fusion : MitelmanCIC::LMNA [19q13.2/1q22]  
Fusion : MitelmanCIC::ZFP57 [19q13.2/6p22.1]  
Fusion : COSMICCIC [19q13.2]  -  DUX4 [4q35.2]  [fusion_1370]  [fusion_1372]  [fusion_1373]  [fusion_1374]  
Fusion : COSMICCIC [19q13.2]  -  DUX4L1 [4q35.2]  [fusion_1371]  
Fusion : COSMICCIC [19q13.2]  -  FOXO4 [Xq13.1]  [fusion_1708]  [fusion_1709]  [fusion_1710]  [fusion_1711]  
Fusion : FusionHubAC006486.9--CIC    AKT2--CIC    BCAR1--CIC    CERS4--CIC    CIC--ADCK4    CIC--BOLA2    CIC--CIC    CIC--CITED1    CIC--CNNM4    CIC--DEDD2   
CIC--DLK1    CIC--DUX4    CIC--DUX4L1    CIC--ERF    CIC--FOXO4    CIC--KLK11    CIC--LEUTX    CIC--LIMD1    CIC--LMNA    CIC--NUTM1   
CIC--NUTM2A    CIC--OCIC    CIC--PPIA    CIC--SMTN    CIC--ZFP36L2    CIC--ZFP57    CIC--ZMAT3    COL4A2--CIC    DDX5--CIC    DUX4--CIC   
SKA2--CIC    TNK2--CIC    ZNF331--CIC   
Fusion : QuiverCIC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCIC [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CIC
Exome Variant ServerCIC
GNOMAD BrowserENSG00000079432
Varsome BrowserCIC
ACMGCIC variants
Genomic Variants (DGV)CIC [DGVbeta]
DECIPHERCIC [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCIC 
ICGC Data PortalCIC 
TCGA Data PortalCIC 
Broad Tumor PortalCIC
OASIS PortalCIC [ Somatic mutations - Copy number]
Cancer Gene: CensusCIC 
Somatic Mutations in Cancer : COSMICCIC  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DCIC
Mutations and Diseases : HGMDCIC
intOGen PortalCIC
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)CIC
DoCM (Curated mutations)CIC
CIViC (Clinical Interpretations of Variants in Cancer)CIC
NCG (London)CIC
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM612082    617600   
Genetic Testing Registry CIC
NextProtQ96RK0 [Medical]
Target ValidationCIC
Huge Navigator CIC [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDCIC
Pharm GKB GenePA26513
Clinical trialCIC
DataMed IndexCIC
PubMed94 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Jan 20 14:04:26 CET 2022

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