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.
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.
Proteins
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). CICs 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 CICs 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 CICs DNA-binding activity (Dissanayake et al. 2011), or through influencing CICs 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).
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 CICs 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 CICs biochemical functions are evolutionary conserved between animals.
Implicated in
Entity name
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 CICs 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 name
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 CICs 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 name
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 name
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 CICs 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).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 21270056 | 2011 | Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila. | Ajuria L et al |
| 17255944 | 2007 | A MAPK docking site is critical for downregulation of Capicua by Torso and EGFR RTK signaling. | Astigarraga S et al |
| 21817013 | 2011 | Mutations in CIC and FUBP1 contribute to human oligodendroglioma. | Bettegowda C et al |
| 17322884 | 2007 | Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. | Bowman AB et al |
| 24030748 | 2014 | Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors. | Chan AK et al |
| 25079045 | 2014 | Characterization of Bbx, a member of a novel subfamily of the HMG-box superfamily together with Cic. | Chen T et al |
| 25277207 | 2014 | Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity. | Chittaranjan S et al |
| 26124181 | 2015 | miR-93/miR-106b/miR-375-CIC-CRABP1: a novel regulatory axis in prostate cancer progression. | Choi N et al |
| 15510215 | 2004 | Capicua integrates input from two maternal systems in Drosophila terminal patterning. | Cinnamon E et al |
| 8022439 | 1994 | The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. | Delattre O et al |
| 21087211 | 2011 | ERK/p90(RSK)/14-3-3 signalling has an impact on expression of PEA3 Ets transcription factors via the transcriptional repressor capicúa. | Dissanayake K et al |
| 22053053 | 2011 | Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. | Fryer JD et al |
| 26124095 | 2015 | Mapping the binding interface of ERK and transcriptional repressor Capicua using photocrosslinking. | Futran AS et al |
| 26017892 | 2015 | CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas. | Gleize V et al |
| 23048183 | 2012 | Torso RTK controls Capicua degradation by changing its subcellular localization. | Grimm O et al |
| 22072439 | 2012 | High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. | Italiano A et al |
| 7700648 | 1995 | A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. | Jeon IS et al |
| 22869205 | 2012 | Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. | Jiao Y et al |
| 10652276 | 2000 | Relief of gene repression by torso RTK signaling: role of capicua in Drosophila terminal and dorsoventral patterning. | Jiménez G et al |
| 8834175 | 1996 | Fusion of an ETS-family gene, EIAF, to EWS by t(17;22)(q12;q12) chromosome translocation in an undifferentiated sarcoma of infancy. | Kaneko Y et al |
| 16717057 | 2006 | Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. | Kawamura-Saito M et al |
| 23512657 | 2013 | Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein Ataxin-1 and Capicua. | Kim E et al |
| 25653040 | 2015 | Deficiency of Capicua disrupts bile acid homeostasis. | Kim E et al |
| 21283143 | 2011 | Substrate-dependent control of MAPK phosphorylation in vivo. | Kim Y et al |
| 23429853 | 2013 | Capicua regulates proliferation and survival of RB-deficient cells in Drosophila. | Krivy K et al |
| 25314060 | 2014 | TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations. | Labussière M et al |
| 17190598 | 2006 | ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. | Lam YC et al |
| 12393275 | 2002 | CIC, a member of a novel subfamily of the HMG-box superfamily, is transiently expressed in developing granule neurons. | Lee CJ et al |
| 22014525 | 2011 | ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization. | Lee Y et al |
| 18337722 | 2008 | Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. | Lim J et al |
| 21887471 | 2011 | Remarkable difference of somatic mutation patterns between oncogenes and tumor suppressor genes. | Liu H et al |
| 24801613 | 2014 | Round cell sarcomas - biologically important refinements in subclassification. | Mariño-Enríquez A et al |
| 8358429 | 1993 | Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. | Orr HT et al |
| 11861482 | 2002 | EGFR signalling inhibits Capicua-dependent repression during specification of Drosophila wing veins. | Roch F et al |
| 22588899 | 2012 | CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. | Sahm F et al |
| 25321332 | 2014 | Clinicopathologic features of a second patient with Ewing-like sarcoma harboring CIC-FOXO4 gene fusion. | Solomon DA et al |
| 21575214 | 2011 | The structural impact of cancer-associated missense mutations in oncogenes and tumor suppressors. | Stehr H et al |
| 25007147 | 2014 | A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. | Sugita S et al |
| 25848751 | 2015 | Mutational landscape and clonal architecture in grade II and III gliomas. | Suzuki H et al |
| 17398096 | 2007 | Capicua regulates cell proliferation downstream of the receptor tyrosine kinase/ras signaling pathway. | Tseng AS et al |
| 22072542 | 2012 | Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. | Yip S et al |
Other Information
Locus ID:
NCBI: 23152
MIM: 612082
HGNC: 14214
Ensembl: ENSG00000079432
Variants:
dbSNP: 23152
ClinVar: 23152
TCGA: ENSG00000079432
COSMIC: CIC
RNA/Proteins
Expression (GTEx)
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38278603 | 2024 | CIC-Rearranged Sarcoma. | 2 |
| 38278603 | 2024 | CIC-Rearranged Sarcoma. | 2 |
| 36647117 | 2023 | CIC reduces xCT/SLC7A11 expression and glutamate release in glioma. | 6 |
| 36788092 | 2023 | Expanding the Molecular Diversity of CIC-Rearranged Sarcomas With Novel and Very Rare Partners. | 3 |
| 36791667 | 2023 | A global collaboRAtive study of CIC-rearranged, BCOR::CCNB3-rearranged and other ultra-rare unclassified undifferentiated small round cell sarcomas (GRACefUl). | 6 |
| 36647117 | 2023 | CIC reduces xCT/SLC7A11 expression and glutamate release in glioma. | 6 |
| 36788092 | 2023 | Expanding the Molecular Diversity of CIC-Rearranged Sarcomas With Novel and Very Rare Partners. | 3 |
| 36791667 | 2023 | A global collaboRAtive study of CIC-rearranged, BCOR::CCNB3-rearranged and other ultra-rare unclassified undifferentiated small round cell sarcomas (GRACefUl). | 6 |
| 34525172 | 2022 | CIC-NUTM1 Sarcomas Affecting the Spine. | 8 |
| 34767259 | 2022 | Integrative multi-omic analysis reveals neurodevelopmental gene dysregulation in CIC-knockout and IDH1-mutant cells. | 3 |
| 36054333 | 2022 | CIC missense variants contribute to susceptibility for spina bifida. | 1 |
| 36198276 | 2022 | Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer. | 5 |
| 36383412 | 2022 | The CIC-ERF co-deletion underlies fusion-independent activation of ETS family member, ETV1, to drive prostate cancer progression. | 4 |
| 34525172 | 2022 | CIC-NUTM1 Sarcomas Affecting the Spine. | 8 |
| 34767259 | 2022 | Integrative multi-omic analysis reveals neurodevelopmental gene dysregulation in CIC-knockout and IDH1-mutant cells. | 3 |
Citation
Marlo Firme ; Marco Marra
CIC (capicua transcriptional repressor)
Atlas Genet Cytogenet Oncol Haematol. 2015-07-01
Online version: http://atlasgeneticsoncology.org/gene/46558/CIC%20(capicua%20transcriptional%20repressor)
