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Gene Review

CLIC1  -  chloride intracellular channel 1

Homo sapiens

Synonyms: Chloride channel ABP, Chloride intracellular channel protein 1, G6, NCC27, Nuclear chloride ion channel 27, ...
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Disease relevance of CLIC1

  • Antibodies developed against a bovine CLIC, p64, immunoprecipitated AKAP350 from HCA-7 colonic adenocarcinoma cell extracts [1].
  • Experimental results indicate that overexpression of CLIC1 is a potential prognostic marker for gastric cancer [2].
  • Elevated CLIC1 expression was strongly correlated with lymph node metastasis, lymphatic invasion, perineural invasion, and pathological staging [2].
  • Cell lines expressing an inducible CLIC4-antisense construct that also reduces the expression of several other chloride intracellular channel (CLIC) family proteins were established in the human osteosarcoma lines SaOS and U2OS cells and a malignant derivative of the mouse squamous papilloma line SP1 [3].
  • Genetic variability among serotype G6 human rotaviruses: identification of a novel lineage isolated in Hungary [4].

High impact information on CLIC1

  • The intracellular chloride ion channel CLIC1 adopts the canonical glutathione transferase fold in its soluble form and appears to undergo radical structural modification as part of its membrane insertion process [5].
  • Antisense suppression of the chloride intracellular channel family induces apoptosis, enhances tumor necrosis factor {alpha}-induced apoptosis, and inhibits tumor growth [3].
  • Reducing CLIC proteins in tumor grafts of SP1 cells expressing a tetracycline-regulated CLIC4-antisense substantially inhibited tumor growth and induced tumor apoptosis [3].
  • In CHO-K1 cells transfected with epitope-tagged NCC27 constructs, we have demonstrated that the NCC27 conductance is chloride dependent and that the electrophysiological characteristics of the channels are essentially identical whether expressed on plasma or nuclear membranes [6].
  • They include: (a) the protein kinase C inhibitor 1, or histidine triad nucleotide-binding motif (HINT) protein; (b) substrates for protein kinase C activity including the chloride intracellular channel protein 1; and (c) a cytoskeletal protein degraded during apoptosis [7].

Biological context of CLIC1


Anatomical context of CLIC1


Associations of CLIC1 with chemical compounds

  • One of the clones, identified as CLIC4, a member of the CLIC family of chloride channels, was up-regulated more than 16 times in myofibroblasts and was therefore chosen for further analysis [13].
  • The structure of the complex of CLIC1 with glutathione shows that glutathione occupies the redox-active site, which is adjacent to an open, elongated slot lined by basic residues [15].
  • Redox regulation of CLIC1 by cysteine residues associated with the putative channel pore [16].
  • The activity is dependent on the amount of CLIC1 added, appears rapidly on mixing of protein and lipid, is inhibited by indanyloxyacetic acid-94, N-ethylmaleimide, and glutathione, is inactivated by heat, and shows sensitivity to pH and to membrane lipid composition [17].
  • Double staining with nephron segment-specific lectins indicates that the NCC27-expressing cells are proximal tubule cells [18].

Physical interactions of CLIC1


Regulatory relationships of CLIC1


Other interactions of CLIC1


Analytical, diagnostic and therapeutic context of CLIC1

  • Northern blot analysis showed that CLIC5 has a distinct pattern of expression compared with CLIC1 and CLIC4 [8].
  • We carried out covalent functional modification and site-directed mutagenesis of this controversial ion channel to test the idea that cysteine 24 is a critical redox-sensitive residue located on the extracellular (or luminal) side of membrane CLIC1 subunits, in a cysteine-proline motif close to the putative channel pore [16].
  • In addition to the SRT-NCC27/CLIC1, SRT10 could detect N-terminal-tagged MEF2D and C-terminal-tagged CD4 by immunocytochemistry [23].
  • In this study we describe the molecular cloning and characterization of a nuclear ion channel protein, designated nuclear chloride channel-27 (NCC27), from the human myelomonocytic cell line, U937 [24].
  • The structure of CLIC4, a member of the CLIC family of putative intracellular chloride ion channel proteins, has been determined at 1.8 Angstroms resolution by X-ray crystallography [25].


  1. AKAP350 at the Golgi apparatus. II. Association of AKAP350 with a novel chloride intracellular channel (CLIC) family member. Shanks, R.A., Larocca, M.C., Berryman, M., Edwards, J.C., Urushidani, T., Navarre, J., Goldenring, J.R. J. Biol. Chem. (2002) [Pubmed]
  2. Overexpression of CLIC1 in human gastric carcinoma and its clinicopathological significance. Chen, C.D., Wang, C.S., Huang, Y.H., Chien, K.Y., Liang, Y., Chen, W.J., Lin, K.H. Proteomics (2007) [Pubmed]
  3. Antisense suppression of the chloride intracellular channel family induces apoptosis, enhances tumor necrosis factor {alpha}-induced apoptosis, and inhibits tumor growth. Suh, K.S., Mutoh, M., Gerdes, M., Crutchley, J.M., Mutoh, T., Edwards, L.E., Dumont, R.A., Sodha, P., Cheng, C., Glick, A., Yuspa, S.H. Cancer Res. (2005) [Pubmed]
  4. Genetic variability among serotype G6 human rotaviruses: identification of a novel lineage isolated in Hungary. Bányai, K., Gentsch, J.R., Griffin, D.D., Holmes, J.L., Glass, R.I., Szücs, G. J. Med. Virol. (2003) [Pubmed]
  5. Glutathione transferases: new functions. Oakley, A.J. Curr. Opin. Struct. Biol. (2005) [Pubmed]
  6. Functional characterization of the NCC27 nuclear protein in stable transfected CHO-K1 cells. Tonini, R., Ferroni, A., Valenzuela, S.M., Warton, K., Campbell, T.J., Breit, S.N., Mazzanti, M. FASEB J. (2000) [Pubmed]
  7. Expression of proteins coincident with inducible radioprotection in human lung epithelial cells. Gamble, S.C., Dunn, M.J., Wheeler, C.H., Joiner, M.C., Adu-Poku, A., Arrand, J.E. Cancer Res. (2000) [Pubmed]
  8. Identification of a novel member of the chloride intracellular channel gene family (CLIC5) that associates with the actin cytoskeleton of placental microvilli. Berryman, M., Bretscher, A. Mol. Biol. Cell (2000) [Pubmed]
  9. 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, R.H. Biochem. J. (2001) [Pubmed]
  10. The intracellular chloride ion channel protein CLIC1 undergoes a redox-controlled structural transition. Littler, D.R., Harrop, S.J., Fairlie, W.D., Brown, L.J., Pankhurst, G.J., Pankhurst, S., DeMaere, M.Z., Campbell, T.J., Bauskin, A.R., Tonini, R., Mazzanti, M., Breit, S.N., Curmi, P.M. J. Biol. Chem. (2004) [Pubmed]
  11. Proteomic analysis on insulin signaling in human hematopoietic cells: identification of CLIC1 and SRp20 as novel downstream effectors of insulin. Saeki, K., Yasugi, E., Okuma, E., Breit, S.N., Nakamura, M., Toda, T., Kaburagi, Y., Yuo, A. Am. J. Physiol. Endocrinol. Metab. (2005) [Pubmed]
  12. Involvement of the intracellular ion channel CLIC1 in microglia-mediated beta-amyloid-induced neurotoxicity. Novarino, G., Fabrizi, C., Tonini, R., Denti, M.A., Malchiodi-Albedi, F., Lauro, G.M., Sacchetti, B., Paradisi, S., Ferroni, A., Curmi, P.M., Breit, S.N., Mazzanti, M. J. Neurosci. (2004) [Pubmed]
  13. Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts. Rønnov-Jessen, L., Villadsen, R., Edwards, J.C., Petersen, O.W. Am. J. Pathol. (2002) [Pubmed]
  14. Identification of chloride intracellular channel proteins in spermatozoa. Myers, K., Somanath, P.R., Berryman, M., Vijayaraghavan, S. FEBS Lett. (2004) [Pubmed]
  15. Crystal structure of a soluble form of the intracellular chloride ion channel CLIC1 (NCC27) at 1.4-A resolution. Harrop, S.J., DeMaere, M.Z., Fairlie, W.D., Reztsova, T., Valenzuela, S.M., Mazzanti, M., Tonini, R., Qiu, M.R., Jankova, L., Warton, K., Bauskin, A.R., Wu, W.M., Pankhurst, S., Campbell, T.J., Breit, S.N., Curmi, P.M. J. Biol. Chem. (2001) [Pubmed]
  16. Redox regulation of CLIC1 by cysteine residues associated with the putative channel pore. Singh, H., Ashley, R.H. Biophys. J. (2006) [Pubmed]
  17. CLIC1 inserts from the aqueous phase into phospholipid membranes, where it functions as an anion channel. Tulk, B.M., Kapadia, S., Edwards, J.C. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  18. NCC27, a homolog of intracellular Cl- channel p64, is expressed in brush border of renal proximal tubule. Tulk, B.M., Edwards, J.C. Am. J. Physiol. (1998) [Pubmed]
  19. Interaction of Sedlin with chloride intracellular channel proteins. Fan, L., Yu, W., Zhu, X. FEBS Lett. (2003) [Pubmed]
  20. CLIC4, an intracellular chloride channel protein, is a novel molecular target for cancer therapy. Suh, K.S., Mutoh, M., Gerdes, M., Yuspa, S.H. J. Investig. Dermatol. Symp. Proc. (2005) [Pubmed]
  21. Genomic structure of a novel chloride channel gene, CLIC2, in Xq28. Heiss, N.S., Poustka, A. Genomics (1997) [Pubmed]
  22. Molecular cloning and characterization of a mitogen-activated protein kinase-associated intracellular chloride channel. Qian, Z., Okuhara, D., Abe, M.K., Rosner, M.R. J. Biol. Chem. (1999) [Pubmed]
  23. Development of a new epitope tag recognized by a monoclonal antibody to Rickettsia typhi. Lee, J.R., Chang, Y.Y., Hahn, M.J. BioTechniques (2001) [Pubmed]
  24. Molecular cloning and expression of a chloride ion channel of cell nuclei. Valenzuela, S.M., Martin, D.K., Por, S.B., Robbins, J.M., Warton, K., Bootcov, M.R., Schofield, P.R., Campbell, T.J., Breit, S.N. J. Biol. Chem. (1997) [Pubmed]
  25. Crystal structure of the soluble form of the redox-regulated chloride ion channel protein CLIC4. Littler, D.R., Assaad, N.N., Harrop, S.J., Brown, L.J., Pankhurst, G.J., Luciani, P., Aguilar, M.I., Mazzanti, M., Berryman, M.A., Breit, S.N., Curmi, P.M. FEBS J. (2005) [Pubmed]
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