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

• The chloride intracellular channel (CLIC) gene family has been implicated in chloride ion transport within various subcellular compartments [8].
• Our results provide the basis for new hypotheses concerning novel ways in which CLIC proteins might be associated with cell membrane remodelling, the control of cell shape, and anion channel activity [9].
• The structure of the soluble form of CLIC1 is typical of a soluble glutathione S-transferase superfamily protein but contains a glutaredoxin-like active site [10].
• By contrast, upregulation of CLIC1 was not observed in one-dimensional Western blotting, unlike the 2-DE results [11].
• We demonstrate that reducing CLIC1 chloride conductance by a specific blocker [IAA-94 (R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy] acetic acid)] prevents neuronal apoptosis in neurons cocultured with Abeta-treated microglia [12].

Anatomical context of CLIC1

• Moreover, in contrast to CLIC1 and CLIC4, CLIC5 is associated with the detergent-insoluble cytoskeletal fraction of microvilli [8].
• Indirect immunofluorescence microscopy revealed that CLIC4 and CLIC5 are concentrated within the apical region of the trophoblast, whereas CLIC1 is distributed throughout the cytoplasm [8].
• Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts [13].
• Identification of a novel member of the chloride intracellular channel gene family (CLIC5) that associates with the actin cytoskeleton of placental microvilli [8].
• Identification of chloride intracellular channel proteins in spermatozoa [14].

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

• All CLIC family members were able to bind a 133-amino acid domain within AKAP350 through the last 120 amino acids in the conserved CLIC carboxyl termini [1].
• Green fluorescence protein-CLIC1 readily co-immunoprecipitated with FLAG-Sedlin [19].

Regulatory relationships of CLIC1

• Reduction of CLIC4 and several other CLIC family members by expressing a doxycycline-regulated CLIC4 antisense also causes apoptosis in squamous cancer cell lines [20].

Other interactions of CLIC1

• While the human NCC27 and XAP121 homologs encode small peptides of 241 and 243 amino acids, respectively, the bovine peptide has a length of 437 amino acids [21].
• Taken together, these results suggest that CLIC3 is a new member of the human CLIC family [22].
• Interaction of Sedlin with chloride intracellular channel proteins [19].
• Purified CLIC1 can integrate into synthetic lipid bilayers forming a chloride channel with similar properties to those observed in vivo [15].
• We identified SRp20, a splicing factor, and CLIC1, an intracellular chloride ion channel, as novel downstream effectors besides previously reported effectors of Rho-guanine nucleotide dissociation inhibitor 2 and glutathione S-transferase-pi [11].

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].

References