CLIC4 (chloride intracellular channel 4)

2009-07-01   Velayuthan C Padmakumar , Stuart H Yuspa 

Laboratory of Cancer Biology, Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

Identity

HGNC
LOCATION
1p36.11
LOCUSID
ALIAS
CLIC4L,H1,MTCLIC,huH1,p64H1
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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

Entity name
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

Pubmed IDLast YearTitleAuthors
119974982002mtCLIC/CLIC4, an organellular chloride channel protein, is increased by DNA damage and participates in the apoptotic response to p53.Fernández-Salas E et al
122371202002Overexpressed chloride intracellular channel protein CLIC4 (p64H1) is an essential component of novel plasma membrane anion channels.Proutski I et al
121633722002Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts.Rønnov-Jessen L et al
163169932006Quantitative proteomic analysis of myc-induced apoptosis: a direct role for Myc induction of the mitochondrial chloride ion channel, mtCLIC/CLIC4.Shiio Y et al
194486242009TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3.Shukla A et al
115639692001Chloride intracellular channel protein CLIC4 (p64H1) binds directly to brain dynamin I in a complex containing actin, tubulin and 14-3-3 isoforms.Suginta W et al
172003462007Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers.Suh KS et al
146100782004The organellular chloride channel protein CLIC4/mtCLIC translocates to the nucleus in response to cellular stress and accelerates apoptosis.Suh KS et al
191970032009Chloride intracellular channel protein-4 functions in angiogenesis by supporting acidification of vacuoles along the intracellular tubulogenic pathway.Ulmasov B et al

Other Information

Locus ID:

NCBI: 25932
MIM: 606536
HGNC: 13518
Ensembl: ENSG00000169504

Variants:

dbSNP: 25932
ClinVar: 25932
TCGA: ENSG00000169504
COSMIC: CLIC4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000169504ENST00000374379Q9Y696
ENSG00000169504ENST00000374379Q6FIC5
ENSG00000169504ENST00000488683Q9Y696
ENSG00000169504ENST00000488683Q6FIC5

Expression (GTEx)

0
100
200
300
400
500
600
700
800
900

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
255468392015Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets.43
162392242005Proteomic analysis of vascular endothelial growth factor-induced endothelial cell differentiation reveals a role for chloride intracellular channel 4 (CLIC4) in tubular morphogenesis.41
121633722002Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts.37
180284482007Functional reconstitution of mammalian 'chloride intracellular channels' CLIC1, CLIC4 and CLIC5 reveals differential regulation by cytoskeletal actin.35
192477892009Chloride intracellular channel 4 is involved in endothelial proliferation and morphogenesis in vitro.34
145695962003CLIC4 is enriched at cell-cell junctions and colocalizes with AKAP350 at the centrosome and midbody of cultured mammalian cells.31
196392012009CLIC4 mediates TGF-beta1-induced fibroblast-to-myofibroblast transdifferentiation in ovarian cancer.29
172003462007Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers.27
197135322009S100A4 and bone morphogenetic protein-2 codependently induce vascular smooth muscle cell migration via phospho-extracellular signal-regulated kinase and chloride intracellular channel 4.26

Citation

Velayuthan C Padmakumar ; Stuart H Yuspa

CLIC4 (chloride intracellular channel 4)

Atlas Genet Cytogenet Oncol Haematol. 2009-07-01

Online version: http://atlasgeneticsoncology.org/gene/40102/clic4