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| Description | CLIC1, also known as NCC27, is a member of the CLIC family. The family is defined by a C-terminal core segment of 230 amino acids, which has significant structural homology with glutathione-S-transferase (Harrop et al., 2001), and contains seven members, including CLIC1, CLIC2, CLIC3, CLIC4, CLIC5, p64, and parchorin. CLIC1 functions as a chloride channel, much like other CLIC family members, and possesses the biological activities needed to regulate the cell volume and acidity of intracellular organelles. CLIC1 exists in cells as an integral membrane protein as well as a soluble cytoplasm protein. These phenomena indicate that CLIC1 might cycle between membrane-inserted and soluble forms (Tulk et al., 2002). |
| Expression | CLIC1 can be expressed in various cell types. Expression is prominent in the heart, placenta, liver, kidney and pancreas (Berryman and Bretscher, 2000). To find the protein expression of various cell types and normal/cancer tissues, please refer to the database, The Human Protein Atlas. |
| Localisation | The protein localizes in the nucleus, nucleus membrane, cytoplasm, and cell membrane. Protein generally exists in the nucleus including the nuclear membrane and smaller amounts exist in the cytoplasm as well as the plasma membrane (Valenzuela et al., 1997; Berryman and Bretscher, 2000; Harrop et al., 2001). The Human Protein Atlas database reveals that CLIC1 has weak to strong immunofluorescence staining in various cell types in cytoplasm. |
| Function | 1. Ion channels
The CLIC family of proteins exhibits chloride channel activity when reconstituted in phospholipid vesicles. Due to its ability to spontaneously insert into preformed membranes, CLIC1 appears to cycle between membrane protein and soluble cytoplasmic protein forms, and sometimes functions as an anion-selective channel (chloride ion channels) (Tulk et al., 2000; Tulk et al., 2002; Berryman and Bretscher, 2000). Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including cell volume, stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH. In previous studies, CLIC1 ion channels were shown to be strongly and reversibly inhibited by cytosolic F-actin in the absence of other proteins. This effect can be reversed using cytochalasin, which disrupts F-actin. This represents a new possibility for which CLIC1 and other actin-regulated membrane CLICs could be used to modify solute transport at key stages during cellular events such as apoptosis, cell movement, cell-volume regulation, as well as cell and organelle division and fusion (Singh et al., 2007; Fanucchi et al., 2008; Stoychev et al., 2009). In an oxidized state, the crystal structure of CLIC1 drastically changes as a large hydrophobic surface is exposed, and forms a dimer interface. The oxidized CLIC1 dimer maintains its ability to form chloride ion channels in artificial bilayers and vesicles, whereas a reducing environment would inhibit the formation of ion channels by CLIC1 (Littler et al., 2004). Research suggest that oxidation of monomeric CLIC1, in the presence of membranes, promotes its insertion into the bilayer more effectively than the oxidized CLIC1 dimer (Goodchild et al., 2009). The crystal structure of CLIC1 classifies it as a member of the glutathione S-transferase superfamily. This detail helps explain why CLICs can exist in a water-soluble state, and also insert into membranes to form ion channels (Dulhunty et al., 2000; Cromer et al., 2002). As an ion channel, CLIC1 is likely to consist of a tetrameric assembly of subunits, and despite its size and unusual properties, there are indications of its ability to form an ion channel in the absence of any other ancillary proteins (Warton et al., 2002). The structure of CLIC1 with glutathione reveals that glutathione occupies the redox-active site, which is adjacent to an open, elongated slot lined with basic residues. Integration of CLIC1 into the membrane would require major structural changes, most likely within the N-domain (residues 1-90), with its transmembrane helix arising from residues near the redox-active site. The structure indicates that CLIC1 is likely to be controlled by redox-dependent processes (Harrop et al., 2001). In addition, CLIC1 translocates from the cytosol to the plasma membrane after microglial activation where it promotes chloride conductance. The charge generated by the active NADPH oxidase is balanced by the resulting anionic current. Removing the excess charge supports superoxide generation by the enzyme. CLIC1 exhibits an ability to act as both a second messenger and an executer (Averaimo et al., 2010).
2. Inflammation
At the cellular level, Alzheimer's disease is characterized as the accumulation of Aβ in neuritic plaques which have been infiltrated by astrocytes and reactive microglia. A decrease in the expression of CLIC1 could reverse this inflammation if the decrease was used to prevent pro-inflammatory TNF-a and neurotoxic products caused by Aβ-stimulated microglial cells (Novarino et al., 2004).
3. Apoptosis
A specific blocker may be used to reduce CLIC1 chloride conductance, and thereby prevent neural apoptosis in neurons co-cultured with Aβ-treated microglia. In doing so, the cellular process of apoptosis could be controlled, giving hope to possibly control diseases caused by the apoptosis of particular cells (Novarino et al., 2004).
4. Motility
CLIC1 overexpression can promote cell motility and invasion of gallbladder carcinoma cells (GBC-SD18L), whereas interference of CLIC1's RNA can significantly decrease the cell motility and invasive potency of GBC-SD18L in vitro (Wang et al., 2009). Additionally, by simply reducing the CLIC1 expression, the migration ability of endothelial cells can be reduced accordingly (Tung and Kitajewski, 2010).
5. Cell cycle regulation
Cl- ion channel blockers, known to block CLIC1, were shown to inhibit Chinese hamster ovary (CHO-K1) cells in the G2/M stage of the cell cycle. This is the stage in which the ion channel is selectively expressed on the plasma membrane. The prevention of CLIC1-mediated changes in cell volume may prevent cells from completing mitosis, thereby preventing the cells from physically dividing and/or the dissolution of the nuclear envelope. To the same effect, disruption of the CLIC1 function in ionic Cl- regulation may prevent other downstream events, in which case cell cycle checkpoint mechanisms prevent the cell from completing mitosis (Valenzuela et al., 2000). |
| Homology | CLIC1, CLIC2, CLIC3, CLIC5 and CLIC6. |
| Molecular cloning and expression of a chloride ion channel of cell nuclei. |
| Valenzuela SM, Martin DK, Por SB, Robbins JM, Warton K, Bootcov MR, Schofield PR, Campbell TJ, Breit SN. |
| J Biol Chem. 1997 May 9;272(19):12575-82. |
| PMID 9139710 |
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| 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 May;11(5):1509-21. |
| PMID 10793131 |
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| Functional characterization of the NCC27 nuclear protein in stable transfected CHO-K1 cells. |
| Tonini R, Ferroni A, Valenzuela SM, Warton K, Campbell TJ, Breit SN, Mazzanti M. |
| FASEB J. 2000 Jun;14(9):1171-8. |
| PMID 10834939 |
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| CLIC-1 functions as a chloride channel when expressed and purified from bacteria. |
| Tulk BM, Schlesinger PH, Kapadia SA, Edwards JC. |
| J Biol Chem. 2000 Sep 1;275(35):26986-93. |
| PMID 10874038 |
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| The nuclear chloride ion channel NCC27 is involved in regulation of the cell cycle. |
| Valenzuela SM, Mazzanti M, Tonini R, Qiu MR, Warton K, Musgrove EA, Campbell TJ, Breit SN. |
| J Physiol. 2000 Dec 15;529 Pt 3:541-52. |
| PMID 11195932 |
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| Crystal structure of a soluble form of the intracellular chloride ion channel CLIC1 (NCC27) at 1.4-A resolution. |
| Harrop SJ, DeMaere MZ, Fairlie WD, Reztsova T, Valenzuela SM, Mazzanti M, Tonini R, Qiu MR, Jankova L, Warton K, Bauskin AR, Wu WM, Pankhurst S, Campbell TJ, Breit SN, Curmi PM. |
| J Biol Chem. 2001 Nov 30;276(48):44993-5000. Epub 2001 Sep 10. |
| PMID 11551966 |
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| From glutathione transferase to pore in a CLIC. |
| Cromer BA, Morton CJ, Board PG, Parker MW. |
| Eur Biophys J. 2002 Sep;31(5):356-64. Epub 2002 May 23. (REVIEW) |
| PMID 12202911 |
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| CLIC1 inserts from the aqueous phase into phospholipid membranes, where it functions as an anion channel. |
| Tulk BM, Kapadia S, Edwards JC. |
| Am J Physiol Cell Physiol. 2002 May;282(5):C1103-12. |
| PMID 11940526 |
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| Recombinant CLIC1 (NCC27) assembles in lipid bilayers via a pH-dependent two-state process to form chloride ion channels with identical characteristics to those observed in Chinese hamster ovary cells expressing CLIC1. |
| Warton K, Tonini R, Fairlie WD, Matthews JM, Valenzuela SM, Qiu MR, Wu WM, Pankhurst S, Bauskin AR, Harrop SJ, Campbell TJ, Curmi PM, Breit SN, Mazzanti M. |
| J Biol Chem. 2002 Jul 19;277(29):26003-11. Epub 2002 Apr 26. |
| PMID 11978800 |
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| Diverse cellular transformation capability of overexpressed genes in human hepatocellular carcinoma. |
| Huang JS, Chao CC, Su TL, Yeh SH, Chen DS, Chen CT, Chen PJ, Jou YS. |
| Biochem Biophys Res Commun. 2004 Mar 19;315(4):950-8. |
| PMID 14985104 |
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| The intracellular chloride ion channel protein CLIC1 undergoes a redox-controlled structural transition. |
| Littler DR, Harrop SJ, Fairlie WD, Brown LJ, Pankhurst GJ, Pankhurst S, DeMaere MZ, Campbell TJ, Bauskin AR, Tonini R, Mazzanti M, Breit SN, Curmi PM. |
| J Biol Chem. 2004 Mar 5;279(10):9298-305. Epub 2003 Nov 12. |
| PMID 14613939 |
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| Involvement of the intracellular ion channel CLIC1 in microglia-mediated beta-amyloid-induced neurotoxicity. |
| Novarino G, Fabrizi C, Tonini R, Denti MA, Malchiodi-Albedi F, Lauro GM, Sacchetti B, Paradisi S, Ferroni A, Curmi PM, Breit SN, Mazzanti M. |
| J Neurosci. 2004 Jun 9;24(23):5322-30. |
| PMID 15190104 |
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| Overexpression of CLIC1 in human gastric carcinoma and its clinicopathological significance. |
| Chen CD, Wang CS, Huang YH, Chien KY, Liang Y, Chen WJ, Lin KH. |
| Proteomics. 2007 Jan;7(1):155-67. |
| PMID 17154271 |
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| Functional reconstitution of mammalian 'chloride intracellular channels' CLIC1, CLIC4 and CLIC5 reveals differential regulation by cytoskeletal actin. |
| Singh H, Cousin MA, Ashley RH. |
| FEBS J. 2007 Dec;274(24):6306-16. Epub 2007 Nov 19. |
| PMID 18028448 |
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| Formation of an unfolding intermediate state of soluble chloride intracellular channel protein CLIC1 at acidic pH. |
| Fanucchi S, Adamson RJ, Dirr HW. |
| Biochemistry. 2008 Nov 4;47(44):11674-81. Epub 2008 Oct 14. |
| PMID 18850721 |
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| Cell secretome analysis using hollow fiber culture system leads to the discovery of CLIC1 protein as a novel plasma marker for nasopharyngeal carcinoma. |
| Chang YH, Wu CC, Chang KP, Yu JS, Chang YC, Liao PC. |
| J Proteome Res. 2009 Dec;8(12):5465-74. |
| PMID 19845400 |
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| Oxidation promotes insertion of the CLIC1 chloride intracellular channel into the membrane. |
| Goodchild SC, Howell MW, Cordina NM, Littler DR, Breit SN, Curmi PM, Brown LJ. |
| Eur Biophys J. 2009 Dec;39(1):129-38. Epub 2009 Apr 23. |
| PMID 19387633 |
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| Structural dynamics of soluble chloride intracellular channel protein CLIC1 examined by amide hydrogen-deuterium exchange mass spectrometry. |
| Stoychev SH, Nathaniel C, Fanucchi S, Brock M, Li S, Asmus K, Woods VL Jr, Dirr HW. |
| Biochemistry. 2009 Sep 8;48(35):8413-21. |
| PMID 19650640 |
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| Identification of metastasis-associated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1. |
| Wang JW, Peng SY, Li JT, Wang Y, Zhang ZP, Cheng Y, Cheng DQ, Weng WH, Wu XS, Fei XZ, Quan ZW, Li JY, Li SG, Liu YB. |
| Cancer Lett. 2009 Aug 18;281(1):71-81. Epub 2009 Mar 18. |
| PMID 19299076 |
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| Chloride intracellular channel 1 (CLIC1): Sensor and effector during oxidative stress. |
| Averaimo S, Milton RH, Duchen MR, Mazzanti M. |
| FEBS Lett. 2010 May 17;584(10):2076-84. Epub 2010 Apr 10. (REVIEW) |
| PMID 20385134 |
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| Chloride intracellular channel 1 identified using proteomic analysis plays an important role in the radiosensitivity of HEp-2 cells via reactive oxygen species production. |
| Kim JS, Chang JW, Yun HS, Yang KM, Hong EH, Kim DH, Um HD, Lee KH, Lee SJ, Hwang SG. |
| Proteomics. 2010 Jul;10(14):2589-604. |
| PMID 20461716 |
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| Personalized medicine in psoriasis: developing a genomic classifier to predict histological response to Alefacept. |
| Suarez-Farinas M, Shah KR, Haider AS, Krueger JG, Lowes MA. |
| BMC Dermatol. 2010 Feb 12;10:1. |
| PMID 20152045 |
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| Chloride intracellular channel 1 functions in endothelial cell growth and migration. |
| Tung JJ, Kitajewski J. |
| J Angiogenes Res. 2010 Nov 1;2:23. |
| PMID 21040583 |
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| The expression and clinical significance of CLIC1 and HSP27 in lung adenocarcinoma. |
| Wang W, Xu X, Wang W, Shao W, Li L, Yin W, Xiu L, Mo M, Zhao J, He Q, He J. |
| Tumour Biol. 2011 Dec;32(6):1199-208. Epub 2011 Aug 20. |
| PMID 21858536 |
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