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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 marlof@bcgsc.ca (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 mmarra@bcgsc.ca (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)

Identity

Alias_namescapicua (Drosophila) homolog
capicua homolog (Drosophila)
Alias_symbol (synonym)KIAA0306
Other alias
HGNC (Hugo) CIC
LocusID (NCBI) 23152
Atlas_Id 46558
Location 19q13.2  [Link to chromosome band 19q13]
Location_base_pair Starts at 42268537 and ends at 42295796 bp from pter ( according to hg19-Feb_2009)  [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)

DNA/RNA

 
  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.

Protein

 
  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

Note
  
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: http://cancergenome.nih.gov/.
  
  
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: http://cancergenome.nih.gov/. 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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Citation

This paper should be referenced as such :
Firme M, Marra M
CIC (capicua transcriptional repressor);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/CICID46558ch19q13.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 5 ]
  Bone: Angiosarcoma
Breast: carcinoma with t(1;3)(p36;q13) PRDM16/BBX
Soft tissue tumors: an overview
Soft Tissues: Pediatric undifferentiated sarcoma with t(4;19)(q35;q13)
Bone: Vascular Tumors


External links

Nomenclature
HGNC (Hugo)CIC   14214
LRG (Locus Reference Genomic)LRG_999
Cards
AtlasCICID46558ch19q13
Entrez_Gene (NCBI)CIC  23152  capicua transcriptional repressor
Aliases
GeneCards (Weizmann)CIC
Ensembl hg19 (Hinxton)ENSG00000079432 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000079432 [Gene_View]  chr19:42268537-42295796 [Contig_View]  CIC [Vega]
ICGC DataPortalENSG00000079432
TCGA cBioPortalCIC
AceView (NCBI)CIC
Genatlas (Paris)CIC
WikiGenes23152
SOURCE (Princeton)CIC
Genetics Home Reference (NIH)CIC
Genomic and cartography
GoldenPath hg38 (UCSC)CIC  -     chr19:42268537-42295796 +  19q13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CIC  -     19q13.2   [Description]    (hg19-Feb_2009)
EnsemblCIC - 19q13.2 [CytoView hg19]  CIC - 19q13.2 [CytoView hg38]
Mapping of homologs : NCBICIC [Mapview hg19]  CIC [Mapview hg38]
OMIM612082   
Gene and transcription
Genbank (Entrez)AB002304 AF363689 AK025939 BC140443 BF848448
RefSeq transcript (Entrez)NM_001304815 NM_015125
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CIC
Cluster EST : UnigeneHs.388236 [ NCBI ]
CGAP (NCI)Hs.388236
Alternative Splicing GalleryENSG00000079432
Gene ExpressionCIC [ NCBI-GEO ]   CIC [ EBI - ARRAY_EXPRESS ]   CIC [ SEEK ]   CIC [ MEM ]
Gene Expression Viewer (FireBrowse)CIC [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression 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
Splice isoforms : SwissVarQ96RK0
PhosPhoSitePlusQ96RK0
Domaine pattern : Prosite (Expaxy)HMG_BOX_2 (PS50118)   
Domains : Interpro (EBI)HMG_box_dom   
Domain families : Pfam (Sanger)HMG_box (PF00505)   
Domain families : Pfam (NCBI)pfam00505   
Domain families : Smart (EMBL)HMG (SM00398)  
Conserved Domain (NCBI)CIC
DMDM Disease mutations23152
Blocks (Seattle)CIC
PDB (SRS)2M41    4J2J    4J2L   
PDB (PDBSum)2M41    4J2J    4J2L   
PDB (IMB)2M41    4J2J    4J2L   
PDB (RSDB)2M41    4J2J    4J2L   
Structural Biology KnowledgeBase2M41    4J2J    4J2L   
SCOP (Structural Classification of Proteins)2M41    4J2J    4J2L   
CATH (Classification of proteins structures)2M41    4J2J    4J2L   
SuperfamilyQ96RK0
Human Protein Atlas [tissue]ENSG00000079432-CIC [tissue]
Peptide AtlasQ96RK0
HPRD10831
IPIIPI00045360   IPI00920993   
Protein Interaction databases
DIP (DOE-UCLA)Q96RK0
IntAct (EBI)Q96RK0
FunCoupENSG00000079432
BioGRIDCIC
STRING (EMBL)CIC
ZODIACCIC
Ontologies - Pathways
QuickGOQ96RK0
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  DNA binding  protein binding  nucleus  nucleoplasm  transcription, DNA-templated  intracellular membrane-bounded organelle  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  DNA binding  protein binding  nucleus  nucleoplasm  transcription, DNA-templated  intracellular membrane-bounded organelle  
NDEx NetworkCIC
Atlas of Cancer Signalling NetworkCIC
Wikipedia pathwaysCIC
Orthology - Evolution
OrthoDB23152
GeneTree (enSembl)ENSG00000079432
Phylogenetic Trees/Animal Genes : TreeFamCIC
HOVERGENQ96RK0
HOGENOMQ96RK0
Homologs : HomoloGeneCIC
Homology/Alignments : Family Browser (UCSC)CIC
Gene fusions - Rearrangements
Fusion : MitelmanCIC/DUX4 [19q13.2/-]  
Fusion : MitelmanCIC/DUX4L10 [19q13.2/-]  [t(10;19)(q26;q13)]  
Fusion : MitelmanCIC/FOXO4 [19q13.2/Xq13.1]  [t(X;19)(q13;q13)]  
Fusion : MitelmanCIC/KLK11 [19q13.2/19q13.41]  [t(19;19)(q13;q13)]  
Fusion : MitelmanCIC/LMNA [19q13.2/1q22]  [t(1;19)(q22;q13)]  
Fusion : MitelmanCIC/ZFP57 [19q13.2/6p22.1]  [t(6;19)(p22;q13)]  
Fusion : COSMICCIC [19q13.2]  -  DUX4 [4q35.2]  [fusion_1370]  [fusion_1371]  [fusion_1372]  [fusion_1373]  [fusion_1374]  [fusion_1375]  
Fusion : COSMICCIC [19q13.2]  -  FOXO4 [Xq13.1]  [fusion_1708]  [fusion_1709]  [fusion_1710]  [fusion_1711]  
Fusion: TCGA_MDACCCIC 19q13.2 KLK11 19q13.41 LUAD
Fusion: TCGA_MDACCCIC 19q13.2 LMNA 1q22 BRCA
Fusion: TCGA_MDACCCIC 19q13.2 ZFP57 6p22.1 BRCA
Tumor Fusion PortalCIC
Fusion : TICdbCIC [19q13.2]  -  DUX4 [10q26.3]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCIC [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CIC
dbVarCIC
ClinVarCIC
1000_GenomesCIC 
Exome Variant ServerCIC
ExAC (Exome Aggregation Consortium)ENSG00000079432
GNOMAD BrowserENSG00000079432
Genetic variants : HAPMAP23152
Genomic Variants (DGV)CIC [DGVbeta]
DECIPHERCIC [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCIC 
Mutations
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]  
Mutations and Diseases : HGMDCIC
intOGen PortalCIC
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CIC
DgiDB (Drug Gene Interaction Database)CIC
DoCM (Curated mutations)CIC (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CIC (select a term)
intoGenCIC
NCG5 (London)CIC
Cancer3DCIC(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM612082   
Orphanet
DisGeNETCIC
MedgenCIC
Genetic Testing Registry CIC
NextProtQ96RK0 [Medical]
TSGene23152
GENETestsCIC
Target ValidationCIC
Huge Navigator CIC [HugePedia]
snp3D : Map Gene to Disease23152
BioCentury BCIQCIC
ClinGenCIC
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD23152
Chemical/Pharm GKB GenePA26513
Clinical trialCIC
Miscellaneous
canSAR (ICR)CIC (select the gene name)
Probes
Litterature
PubMed41 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCIC
EVEXCIC
GoPubMedCIC
iHOPCIC
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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