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CLIC4 (chloride intracellular channel 4)

Written2009-07Velayuthan C Padmakumar, Stuart H Yuspa
Laboratory of Cancer Biology, Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)DKFZP566G223
CLIC4L
P64H1
H1
huH1
p64H1
Other aliasMTCLIC
HGNC (Hugo) CLIC4
LocusID (NCBI) 25932
Atlas_Id 40102
Location 1p36.11  [Link to chromosome band 1p36]
Location_base_pair Starts at 24745269 and ends at 24844324 bp from pter ( according to hg19-Feb_2009)  [Mapping CLIC4.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)
CACHD1 (1p31.3) / CLIC4 (1p36.11)CLIC4 (1p36.11) / GRHL3 (1p36.11)CLIC4 (1p36.11) / PLOD1 (1p36.22)
CLIC4 (1p36.11) / RPS25 (11q23.3)CLIC4 (1p36.11) / SRRM1 (1p36.11)COL2A1 (12q13.11) / CLIC4 (1p36.11)
HERC1 (15q22.31) / CLIC4 (1p36.11)

DNA/RNA

 
  CLIC4 gene consists of 6 exons. The number between the exons indicate the length in kilo bases of intervening introns.
Description CLIC4 gene comprises of 6 exons spanning a region of about 99 kb on human chromosome 1p36.
Transcription CLIC4 gene codes for a protein of 253 amino acids length corresponding to molecular weight of about 29 kDa. No alternative isoforms of CLIC4 has been reported.

Protein

 
  Domain organisation of CLIC4. TM indicates transmembrane domain and NLS represents nuclear localisation signal.
Description CLIC4 is a putative chloride channel for intracellular organelles. The human protein consists of 253 amino acids with an N-terminal transmembrane domain and C-terminal nuclear localisation signal.
Expression Ubiquitous and induced by p53, TNF-alpha and c-myc.
Localisation It is localised in cytoplasm and mitochondria in primary keratinocytes and translocated to nucleus upon cellular stress.
Function CLIC4 has been shown to regulate TGF-beta signaling. It has been shown to translocate to the nucleus in a Schnurri-2 dependent manner and nuclear CLIC4 has been shown to subsequently stabilise phospho- Smad2 and Smad3.
CLIC4 has been implicated in angiogenesis. It has been shown to be involved in acidification of vacuoles along the cell hollowing tubulogenic pathway.
CLIC4 has been shown to be expressed in myofibroblasts and inhibit motility of MEF/3T3 cells.
CLIC4 has been implicated in Myc-induced apoptosis. It was identified as a candidate gene after protein expression analysis during Myc-induced apoptosis. Myc has been shown to bind to CLIC4 promotor and activate its transcription.
Homology CLIC1, CLIC2, CLIC3, CLIC5 and CLIC6.

Implicated in

Note
  
Entity Various cancer
Note Expression analysis on a human tumour array has shown that CLIC4 expression is dimished in several tumour types including breast, ovary and kidney. CLIC4 expression has also been shown to be upregulated in some tumours.
In matched tissue arrays, CLIC4 was predominantly nuclear in normal epithelial tissues but not cancers. As tumours progressed CLIC4 expression became undetectable in tumour cells but increased in stromal cells.
Sequence analysis of CLIC4 cDNA of 60 human cancer cell lines (NCI60) and EST database analysis failed to reveal mutations in CLIC4 gene.
  

Bibliography

mtCLIC/CLIC4, an organellular chloride channel protein, is increased by DNA damage and participates in the apoptotic response to p53.
Fernandez-Salas E, Suh KS, Speransky VV, Bowers WL, Levy JM, Adams T, Pathak KR, Edwards LE, Hayes DD, Cheng C, Steven AC, Weinberg WC, Yuspa SH.
Mol Cell Biol. 2002 Jun;22(11):3610-20.
PMID 11997498
 
Overexpressed chloride intracellular channel protein CLIC4 (p64H1) is an essential component of novel plasma membrane anion channels.
Proutski I, Karoulias N, Ashley RH.
Biochem Biophys Res Commun. 2002 Sep 20;297(2):317-22.
PMID 12237120
 
Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts.
Ronnov-Jessen L, Villadsen R, Edwards JC, Petersen OW.
Am J Pathol. 2002 Aug;161(2):471-80.
PMID 12163372
 
Quantitative proteomic analysis of myc-induced apoptosis: a direct role for Myc induction of the mitochondrial chloride ion channel, mtCLIC/CLIC4.
Shiio Y, Suh KS, Lee H, Yuspa SH, Eisenman RN, Aebersold R.
J Biol Chem. 2006 Feb 3;281(5):2750-6. Epub 2005 Nov 29.
PMID 16316993
 
TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3.
Shukla A, Malik M, Cataisson C, Ho Y, Friesen T, Suh KS, Yuspa SH.
Nat Cell Biol. 2009 Jun;11(6):777-84. Epub 2009 May 17.
PMID 19448624
 
Chloride intracellular channel protein CLIC4 (p64H1) binds directly to brain dynamin I in a complex containing actin, tubulin and 14-3-3 isoforms.
Suginta W, Karoulias N, Aitken A, Ashley RH.
Biochem J. 2001 Oct 1;359(Pt 1):55-64.
PMID 11563969
 
Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers.
Suh KS, Crutchley JM, Koochek A, Ryscavage A, Bhat K, Tanaka T, Oshima A, Fitzgerald P, Yuspa SH.
Clin Cancer Res. 2007 Jan 1;13(1):121-31.
PMID 17200346
 
The organellular chloride channel protein CLIC4/mtCLIC translocates to the nucleus in response to cellular stress and accelerates apoptosis.
Suh KS, Mutoh M, Nagashima K, Fernandez-Salas E, Edwards LE, Hayes DD, Crutchley JM, Marin KG, Dumont RA, Levy JM, Cheng C, Garfield S, Yuspa SH.
J Biol Chem. 2004 Feb 6;279(6):4632-41. Epub 2003 Nov 10.
PMID 14610078
 
Chloride intracellular channel protein-4 functions in angiogenesis by supporting acidification of vacuoles along the intracellular tubulogenic pathway.
Ulmasov B, Bruno J, Gordon N, Hartnett ME, Edwards JC.
Am J Pathol. 2009 Mar;174(3):1084-96. Epub 2009 Feb 5.
PMID 19197003
 

Citation

This paper should be referenced as such :
Padmakumar, VC ; Yuspa, SH
CLIC4 (chloride intracellular channel 4)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(6):536-537.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CLIC4ID40102ch1p36.html


External links

Nomenclature
HGNC (Hugo)CLIC4   13518
Cards
AtlasCLIC4ID40102ch1p36
Entrez_Gene (NCBI)CLIC4  25932  chloride intracellular channel 4
AliasesCLIC4L; H1; MTCLIC; huH1; 
p64H1
GeneCards (Weizmann)CLIC4
Ensembl hg19 (Hinxton)ENSG00000169504 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000169504 [Gene_View]  chr1:24745269-24844324 [Contig_View]  CLIC4 [Vega]
ICGC DataPortalENSG00000169504
TCGA cBioPortalCLIC4
AceView (NCBI)CLIC4
Genatlas (Paris)CLIC4
WikiGenes25932
SOURCE (Princeton)CLIC4
Genetics Home Reference (NIH)CLIC4
Genomic and cartography
GoldenPath hg38 (UCSC)CLIC4  -     chr1:24745269-24844324 +  1p36.11   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CLIC4  -     1p36.11   [Description]    (hg19-Feb_2009)
EnsemblCLIC4 - 1p36.11 [CytoView hg19]  CLIC4 - 1p36.11 [CytoView hg38]
Mapping of homologs : NCBICLIC4 [Mapview hg19]  CLIC4 [Mapview hg38]
OMIM606536   
Gene and transcription
Genbank (Entrez)AF097330 AF109196 AK001624 AK095959 AK301466
RefSeq transcript (Entrez)NM_013943
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CLIC4
Cluster EST : UnigeneHs.440544 [ NCBI ]
CGAP (NCI)Hs.440544
Alternative Splicing GalleryENSG00000169504
Gene ExpressionCLIC4 [ NCBI-GEO ]   CLIC4 [ EBI - ARRAY_EXPRESS ]   CLIC4 [ SEEK ]   CLIC4 [ MEM ]
Gene Expression Viewer (FireBrowse)CLIC4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)25932
GTEX Portal (Tissue expression)CLIC4
Human Protein AtlasENSG00000169504-CLIC4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y696   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9Y696  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9Y696
Splice isoforms : SwissVarQ9Y696
PhosPhoSitePlusQ9Y696
Domaine pattern : Prosite (Expaxy)GST_CTER (PS50405)   
Domains : Interpro (EBI)CLIC    Glutathione-S-Trfase_C-like    Thioredoxin-like_fold   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)CLIC4
DMDM Disease mutations25932
Blocks (Seattle)CLIC4
PDB (SRS)2AHE    2D2Z    3OQS   
PDB (PDBSum)2AHE    2D2Z    3OQS   
PDB (IMB)2AHE    2D2Z    3OQS   
PDB (RSDB)2AHE    2D2Z    3OQS   
Structural Biology KnowledgeBase2AHE    2D2Z    3OQS   
SCOP (Structural Classification of Proteins)2AHE    2D2Z    3OQS   
CATH (Classification of proteins structures)2AHE    2D2Z    3OQS   
SuperfamilyQ9Y696
Human Protein Atlas [tissue]ENSG00000169504-CLIC4 [tissue]
Peptide AtlasQ9Y696
HPRD05943
IPIIPI00001960   IPI00903323   IPI01010396   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y696
IntAct (EBI)Q9Y696
FunCoupENSG00000169504
BioGRIDCLIC4
STRING (EMBL)CLIC4
ZODIACCLIC4
Ontologies - Pathways
QuickGOQ9Y696
Ontology : AmiGOangiogenesis  endothelial cell morphogenesis  voltage-gated ion channel activity  chloride channel activity  protein binding  intracellular  cytoplasm  mitochondrion  centrosome  cytosol  plasma membrane  microvillus  cell-cell junction  chloride transport  vacuolar acidification  fertilization  cell surface  actin cytoskeleton  microtubule cytoskeleton  nuclear matrix  cell differentiation  keratinocyte differentiation  negative regulation of cell migration  midbody  cytoplasmic vesicle membrane  chloride channel complex  regulation of ion transmembrane transport  establishment or maintenance of apical/basal cell polarity  multicellular organism growth  apical part of cell  perinuclear region of cytoplasm  branching morphogenesis of an epithelial tube  regulation of cytoskeleton organization  retina vasculature morphogenesis in camera-type eye  extracellular exosome  cellular response to calcium ion  chloride transmembrane transport  
Ontology : EGO-EBIangiogenesis  endothelial cell morphogenesis  voltage-gated ion channel activity  chloride channel activity  protein binding  intracellular  cytoplasm  mitochondrion  centrosome  cytosol  plasma membrane  microvillus  cell-cell junction  chloride transport  vacuolar acidification  fertilization  cell surface  actin cytoskeleton  microtubule cytoskeleton  nuclear matrix  cell differentiation  keratinocyte differentiation  negative regulation of cell migration  midbody  cytoplasmic vesicle membrane  chloride channel complex  regulation of ion transmembrane transport  establishment or maintenance of apical/basal cell polarity  multicellular organism growth  apical part of cell  perinuclear region of cytoplasm  branching morphogenesis of an epithelial tube  regulation of cytoskeleton organization  retina vasculature morphogenesis in camera-type eye  extracellular exosome  cellular response to calcium ion  chloride transmembrane transport  
NDEx NetworkCLIC4
Atlas of Cancer Signalling NetworkCLIC4
Wikipedia pathwaysCLIC4
Orthology - Evolution
OrthoDB25932
GeneTree (enSembl)ENSG00000169504
Phylogenetic Trees/Animal Genes : TreeFamCLIC4
HOVERGENQ9Y696
HOGENOMQ9Y696
Homologs : HomoloGeneCLIC4
Homology/Alignments : Family Browser (UCSC)CLIC4
Gene fusions - Rearrangements
Fusion : MitelmanCACHD1/CLIC4 [1p31.3/1p36.11]  [t(1;1)(p31;p36)]  
Fusion : MitelmanCLIC4/GRHL3 [1p36.11/1p36.11]  [t(1;1)(p36;p36)]  
Fusion : MitelmanCLIC4/PLOD1 [1p36.11/1p36.22]  [t(1;1)(p36;p36)]  
Fusion: TCGA_MDACCCACHD1 1p31.3 CLIC4 1p36.11 BRCA
Fusion: TCGA_MDACCCLIC4 1p36.11 GRHL3 1p36.11 LUAD
Fusion: TCGA_MDACCCLIC4 1p36.11 PLOD1 1p36.22 GBM
Tumor Fusion PortalCLIC4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCLIC4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CLIC4
dbVarCLIC4
ClinVarCLIC4
1000_GenomesCLIC4 
Exome Variant ServerCLIC4
ExAC (Exome Aggregation Consortium)ENSG00000169504
GNOMAD BrowserENSG00000169504
Genetic variants : HAPMAP25932
Genomic Variants (DGV)CLIC4 [DGVbeta]
DECIPHERCLIC4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCLIC4 
Mutations
ICGC Data PortalCLIC4 
TCGA Data PortalCLIC4 
Broad Tumor PortalCLIC4
OASIS PortalCLIC4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCLIC4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCLIC4
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
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
BioMutasearch CLIC4
DgiDB (Drug Gene Interaction Database)CLIC4
DoCM (Curated mutations)CLIC4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CLIC4 (select a term)
intoGenCLIC4
NCG5 (London)CLIC4
Cancer3DCLIC4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606536   
Orphanet
DisGeNETCLIC4
MedgenCLIC4
Genetic Testing Registry CLIC4
NextProtQ9Y696 [Medical]
TSGene25932
GENETestsCLIC4
Target ValidationCLIC4
Huge Navigator CLIC4 [HugePedia]
snp3D : Map Gene to Disease25932
BioCentury BCIQCLIC4
ClinGenCLIC4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD25932
Chemical/Pharm GKB GenePA26591
Clinical trialCLIC4
Miscellaneous
canSAR (ICR)CLIC4 (select the gene name)
Probes
Litterature
PubMed58 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCLIC4
EVEXCLIC4
GoPubMedCLIC4
iHOPCLIC4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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