Academic literature on the topic 'KC1 cotransporter'
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Journal articles on the topic "KC1 cotransporter"
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Holtzman, Eli J., Sumit Kumar, Carol A. Faaland, Fern Warner, Paul J. Logue, Sara J. Erickson, Gesa Ricken, Jeremy Waldman, Shiv Kumar, and Philip B. Dunham. "Cloning, characterization, and gene organization of K-Cl cotransporter from pig and human kidney and C. elegans." American Journal of Physiology-Renal Physiology 275, no. 4 (October 1, 1998): F550—F564. http://dx.doi.org/10.1152/ajprenal.1998.275.4.f550.
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We isolated and characterized the cDNAs for the human, pig, and Caenorhabditis elegansK-Cl cotransporters. The pig and human homologs are 94% identical and contain 1,085 and 1,086 amino acids, respectively. The deduced protein of the C. elegans K-Cl cotransporter clone (CE-KCC1) contains 1,003 amino acids. The mammalian K-Cl cotransporters share ∼45% similarity with CE-KCC1. Hydropathy analyses of the three clones indicate typical KCC topology patterns with 12 transmembrane segments, large extracellular loops between transmembrane domains 5 and 6 (unique to KCC), and large COOH-terminal domains. Human KCC1 is widely expressed among various tissues. This KCC1 gene spans 23 kb and is organized in 24 exons, whereas the CE-KCC1 gene spans 3.5 kb and contains 10 exons. Transiently and stably transfected human embryonic kidney cells (HEK-293) expressing the human, pig, and C. elegans K-Cl cotransporter fulfilled two (pig) or five (human and C. elegans) criteria for increased expression of the K-Cl cotransporter. The criteria employed were basal K-Cl cotransport; stimulation of cotransport by swelling, N-ethylmaleimide, staurosporine, and reduced cell Mg concentration; and secondary stimulation of Na-K-Cl cotransport.
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Race, Joanne E., Fadi N. Makhlouf, Paul J. Logue, Frederick H. Wilson, Philip B. Dunham, and Eli J. Holtzman. "Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter." American Journal of Physiology-Cell Physiology 277, no. 6 (December 1, 1999): C1210—C1219. http://dx.doi.org/10.1152/ajpcell.1999.277.6.c1210.
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We isolated and characterized a novel K-Cl cotransporter, KCC3, from human placenta. The deduced protein contains 1,150 amino acids. KCC3 shares 75–76% identity at the amino acid level with human, pig, rat, and rabbit KCC1 and 67% identity with rat KCC2. KCC3 is 40 and 33% identical to two Caenorhabditis elegans K-Cl cotransporters and ∼20% identical to other members of the cation-chloride cotransporter family (CCC), two Na-K-Cl cotransporters (NKCC1, NKCC2), and the Na-Cl cotransporter (NCC). Hydropathy analysis indicates a typical KCC topology with 12 transmembrane domains, a large extracellular loop between transmembrane domains 5 and 6 (unique to KCCs), and large NH2 and COOH termini. KCC3 is predominantly expressed in kidney, heart, and brain, and is also expressed in skeletal muscle, placenta, lung, liver, and pancreas. KCC3 was localized to chromosome 15. KCC3 transiently expressed in human embryonic kidney (HEK)-293 cells fulfilled three criteria for increased expression of K-Cl cotransport: stimulation of cotransport by swelling, treatment with N-ethylmaleimide, or treatment with staurosporine.
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Gillen, Christopher M., and Bliss Forbush. "Functional interaction of the K-Cl cotransporter (KCC1) with the Na-K-Cl cotransporter in HEK-293 cells." American Journal of Physiology-Cell Physiology 276, no. 2 (February 1, 1999): C328—C336. http://dx.doi.org/10.1152/ajpcell.1999.276.2.c328.
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We have studied the regulation of the K-Cl cotransporter KCC1 and its functional interaction with the Na-K-Cl cotransporter. K-Cl cotransporter activity was substantially activated in HEK-293 cells overexpressing KCC1 (KCC1-HEK) by hypotonic cell swelling, 50 mM external K, and pretreatment with N-ethylmaleimide (NEM). Bumetanide inhibited 86Rb efflux in KCC1-HEK cells after cell swelling [inhibition constant ( K i) ∼190 μM] and pretreatment with NEM ( K i ∼60 μM). Thus regulation of KCC1 is consistent with properties of the red cell K-Cl cotransporter. To investigate functional interactions between K-Cl and Na-K-Cl cotransporters, we studied the relationship between Na-K-Cl cotransporter activation and intracellular Cl concentration ([Cl]i). Without stimulation, KCC1-HEK cells had greater Na-K-Cl cotransporter activity than controls. Endogenous Na-K-Cl cotransporter of KCC1-HEK cells was activated <2-fold by low-Cl hypotonic prestimulation, compared with 10-fold activation in HEK-293 cells and >20-fold activation in cells overexpressing the Na-K-Cl cotransporter (NKCC1-HEK). KCC1-HEK cells had lower resting [Cl]i than HEK-293 cells; cell volume was not different among cell lines. We found a steep relationship between [Cl]i and Na-K-Cl cotransport activity within the physiological range, supporting a primary role for [Cl]iin activation of Na-K-Cl cotransport and in apical-basolateral cross talk in ion-transporting epithelia.
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Crable, Scott C., Suzan M. Hammond, Richard Papes, R. Kirk Rettig, Guo-Ping Zhou, Patrick G. Gallagher, Clinton H. Joiner, and Kathleen P. Anderson. "Multiple isoforms of the KC1 cotransporter are expressed in sickle and normal erythroid cells." Experimental Hematology 33, no. 6 (June 2005): 624–31. http://dx.doi.org/10.1016/j.exphem.2005.02.006.
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Strange, Kevin, Thomas D. Singer, Rebecca Morrison, and Eric Delpire. "Dependence of KCC2 K-Cl cotransporter activity on a conserved carboxy terminus tyrosine residue." American Journal of Physiology-Cell Physiology 279, no. 3 (September 1, 2000): C860—C867. http://dx.doi.org/10.1152/ajpcell.2000.279.3.c860.
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K-Cl cotransporters (KCC) play fundamental roles in ionic and osmotic homeostasis. To date, four mammalian KCC genes have been identified. KCC2 is expressed exclusively in neurons. Injection of Xenopus oocytes with KCC2 cRNA induced a 20-fold increase in Cl−-dependent, furosemide-sensitive K+ uptake. Oocyte swelling increased KCC2 activity 2–3 fold. A canonical tyrosine phosphorylation site is located in the carboxy termini of KCC2 (R1081–Y1087) and KCC4, but not in other KCC isoforms. Pharmacological studies, however, revealed no regulatory role for phosphorylation of KCC2 tyrosine residues. Replacement of Y1087 with aspartate or arginine dramatically reduced K+ uptake under isotonic and hypotonic conditions. Normal or near-normal cotransporter activity was observed when Y1087 was mutated to phenylalanine, alanine, or isoleucine. A tyrosine residue equivalent to Y1087 is conserved in all identified KCCs from nematodes to humans. Mutation of the Y1087 congener in KCC1 to aspartate also dramatically inhibited cotransporter activity. Taken together, these results suggest that replacement of Y1087 and its congeners with charged residues disrupts the conformational state of the carboxy terminus. We postulate that the carboxy terminus plays an essential role in maintaining the functional conformation of KCC cotransporters and/or is involved in essential regulatory protein-protein interactions.
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Pan, Dao, Theodosia A. Kalfa, Daren Wang, Mary Risinger, Scott Crable, Peter Ciraolo, Robert S. Franco, and Clinton H. Joiner. "Change in Expressional Profile of KCl Cotransporter Genes during Human Erythroid Differentiation." Blood 110, no. 11 (November 16, 2007): 1709. http://dx.doi.org/10.1182/blood.v110.11.1709.1709.
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Abstract Maintenance of cell volume by regulated cation transport is a fundamental cellular process. The KCl cotransporter (KCC) contributes to red blood cell (RBC) volume regulation, especially in reticulocytes. Erythroid K-Cl cotransport activity is increased in sickle cells (SS RBC) and contribute to SS RBC dehydration, which potentiates sickling. Three cation cotransporter genes, SLC12A4 (KCC1), SLC12A6 (KCC3) and SLC12A7 (KCC4), and several splicing variants, mediate KCC activity in non-neuronal tissues. To determine which KCC isoform(s) predominates in human RBC we examined the quantitative expression patterns of KCC isoforms during erythroid differentiation. We developed a set of real-time RT-QPCR assays specific for KCC1, KCC1b, KCC3a, KCC3b or KCC4, over a 7-log quantitation range and sensitivity of 10 copies per reaction using multiplex amplification of GAPDH as internal controls. In human reticulocytes isolated by magnetic separation using anti-transferrin receptor coated beads, KCC3a mRNA levels were consistently the highest (4–24 fold of KCC1), while KCC4 levels varied from 1 to 7-fold of KCC1 levels (n=8). Message levels for KCC3b were relatively low (20–80% of KCC1), and for KCC1b were negligible (1–2% of KCC1). Substantial variability in the relative levels of KCC1, KCC3a, and KCC4 mRNA was observed among individual samples, but no consistent difference was apparent comparing sickle and normal reticulocytes. Western blot analysis of sickle and normal RBC ghost membranes confirmed the presence of KCC1, KCC3 and KCC4 at the protein level. To evaluate cells at various erythroid differentiation stages, human CD34+ cells were cultured under conditions favoring erythroid differentiation for 26 days. During early in vitro differentiation, KCC1 was the main mRNA species, followed by KCC4, with similar levels of KCC3a and KCC3b. RNA levels for KCC3a and KCC4 increased during maturation and became the most abundant at later stages. KCC1b mRNA remained low, and KCC3b levels decreased during erythroid development. To further define this temporal sequence of KCC expression, cells cultured for 10–17 days were sorted by FACS into four subpopulations (I to IV), characterized by immunostaining for relative expression of CD71 and glycophorin A, with enrichment of pronormoblasts basophilic normoblasts polychromatophilic normoblasts or orthrochromatic normoblasts and reticulocytes KCC1, KCC3a, KCC3b, and KCC4 were expressed in these populations, with KCC1 as the main KCC species in early precursors (I), KCC3b decreasing >80% during maturation, KCC4 and KCC3a becoming the most abundant in the most differentiated subpopulation (IV). In summary, we identified KCC3a as the predominant KCC isoform in human reticulocytes, followed by KCC4 and KCC1, consistent with the presence of KCC1, KCC3 and KCC4 proteins in RBC membranes. The expression of KCC3a and KCC4 increased during erythriod differentiation in vitro. Variations in relative expression of KCC species are a potential source of inter-individual differences in KCC function for volume regulation. These results also provide the foundation for the possibility of improving SS RBC hydration by reducing gene expression of the major KCC isoforms in RBC.
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Delpire, Eric, and Jiangtao Guo. "Cryo-EM structures of DrNKCC1 and hKCC1: a new milestone in the physiology of cation-chloride cotransporters." American Journal of Physiology-Cell Physiology 318, no. 2 (February 1, 2020): C225—C237. http://dx.doi.org/10.1152/ajpcell.00465.2019.
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New milestones have been reached in the field of cation-Cl− cotransporters with the recently released cryo-electron microscopy (EM) structures of the Danio rerio (zebrafish) Na+-K+-2Cl− cotransporter ( DrNKCC1) and the human K+-Cl− cotransporter (hKCC1). In this review we provide a brief timeline that identifies the multiple breakthroughs in the field of solute carrier 12 transporters that led to the structure resolution of two of its key members. While cation-Cl− cotransporters share the overall architecture of carriers belonging to the amino acid-polyamine-organocation (APC) superfamily and some of their substrate binding sites, several new insights are gained from the two individual structures. A first major feature relates to the largest extracellular domain between transmembrane domain (TMD) 5 and TMD6 of KCC1, which stabilizes the dimer and forms a cap that likely participates in extracellular gating. A second feature is the conservation of the K+ and Cl− binding sites in both structures and evidence of an unexpected second Cl− coordination site in the KCC1 structure. Structural data are discussed in the context of previously published studies that examined the basic and kinetics properties of these cotransport mechanisms. A third characteristic is the evidence of an extracellular gate formed by conserved salt bridges between charged residues located toward the end of TMD3 and TMD4 in both transporters and the existence of an additional neighboring bridge in the hKCC1 structure. A fourth feature of these newly solved structures relates to the multiple points of contacts between the monomer forming the cotransporter homodimer units. These involve the TMDs, the COOH-terminal domains, and the large extracellular loop for hKCC1.
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Joiner, Clinton H., Richard Papes, Scott Crable, Dao Pan, and David B. Mount. "Functional Comparison of Red Cell KCl Cotransporter Isoforms, KCC1, KCC3, and KCC4." Blood 108, no. 11 (November 16, 2006): 1245. http://dx.doi.org/10.1182/blood.v108.11.1245.1245.
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Abstract The KCl cotransporter mediates volume reduction in normal (AA) reticulocytes, and its abnormal regulation in sickle (SS) reticulocytes contributes to cellular dehydration that facilitates Hb S sickling. mRNA for three KCC genes - KCC1, KCC3, and KCC4 - as well as a splicing isoform, KCC1ex1b, is present in reticulocytes (Exp. Hem.2005; 33:624). Western blotting has demonstrated KCC1 in human RBC membranes (Su et al, AJPhysiol.1999;277:C899) and KCC3 in sheep (Lauf et al, CompBiochemPhysiol2001;130:499); KCC4 protein was found in hRBC membranes by proteomic analysis (Pasini et al, Blood2006;108:791). We confirm here the presence of KCC3 protein in hRBC via western blotting using an antibody to an exon 3 epitope distal to known N-terminal splicing sites. We sought to characterize and compare human KCC isoforms expressed in human cells (HEK 293) and assess their similarity to KCC activity in RBC. cDNAs for human KCC1, KCC1ex1b, KCC3a, and KCC4, with N-terminal c-myc epitope tags were expressed in HEK 293 cells. Stable cell lines were selected by growth in neomycin, and expression monitored by quantitative PCR analysis of the expressed construct and other endogenous isoforms and by western blotting (anti-myc) of plasma membranes. KCC activity was measured as N-ethylmaleimide(NEM)-stimulated, Cl-dependent Rb uptake in cells grown to 75–90 % confluency. Cells were incubated at 37°C in isotonic saline media with various concentrations of Rb (Na replacement), plus 0.1 mM ouabain and 0.01 mM bumetanide. At 2 and 4 min cells were washed with iced Rb-free media, then lysed and assayed for Rb by flame emission, normalized to sample protein. Flux rates were calculated from Rb uptake at 2 and 4 min. The flux rate in Cl-free sulfamate media was subtracted from that in Cl-media to yield the Cl-dependent flux rate. Wild-type HEK cells showed no increase in Cl-dependent Rb influx when exposed to 1 mM NEM, but Cl-dependent, NEM-stimulated Rb uptake was apparent in cells expressing KCC isoforms. All isoforms were stimulated by hypotonic conditions (75 mOsm), but relative to NEM-stimulated activity, KCC3 was most responsive. Kinetic characteristics of Cl-dependent, NEM-stimulated Rb influx in HEK cell expressing human KCC1, KCC3a, and KCC4 isoforms isoforms are given below, compared to RBC KCC fluxes. A splice variant, KCC1ex1b, coding for a protein with a truncated N-terminus, exhibited 48 ± 7% of the activity of the full-length KCC1 isoform, but did not alter transport activity of coexpressed KCC3a. Thus, KCC isoforms expressed in HEK cells share some, but not all, characteristics with RBC KCC fluxes. The isoform kinetics also differ from those previously published in xenopus oocyte expression systems, suggesting that the membrane milieu in which KCC proteins are expressed may influence their functional characteristics. Likewise, KCC activity in RBC may represent an average of several transporters operating in parallel. The truncated KCC1ex1b isoform, expressed at higher levels in normal than in sickle reticulocytes, has lower activity than KCC1. KCC3 and KCC4 exhibit more robust transport activity than KCC1 and may mediate a substantial part of KCC activity in RBC. KCC Kinetic Characteristics VMax (μmol/mgprot./min) Km (ext. Rb, mM) Anion Selectivity hKCC1 28.9 ± 5.6 16.7 ± 5.4 Cl > Br > I > SCN hKCC3a 107 ± 45 11.0 ± 7.1 Cl = Br > I > SCN hKCC4 206 ± 16 15.6 ± 8.2 Cl > Br >> I = SCN RBC NA 12 - 20 Cl = Br >> I = SCN
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Risinger, Mary, Jesse Rinehart, Scott Crable, Anna Ottlinger, Richard Winkelmann, Dao Pan, Christian Huebner, Patrick G. Gallagher, and Clinton H. Joiner. "Structural and Functional Interactions of KCl Cotransport Proteins KCC1 and KCC3 in Sickle and Normal Erythrocyte Membranes." Blood 112, no. 11 (November 16, 2008): 2474. http://dx.doi.org/10.1182/blood.v112.11.2474.2474.
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Abstract The KCl cotransporter (KCC) mediates volume reduction in normal reticulocytes and exaggerated KCC activity in sickle red blood cells (SS RBC) (Joiner et al, Blood109:1728, 2007) contributes to pathological dehydration that potentiates sickling. Three separate genes (KCC1, KCC3, KCC4) are expressed in RBC (Crable et al, Exp. Hem.33:624, 2005). KCC1 and KCC3 proteins have been shown to interact in ex vivo expression systems (Simard et al, JBC282(25):18083, 2007), and co-expression of an N-terminal truncation of KCC1 reduces KCC activity mediated by full-length KCC1 or KCC3 (Casula et al. JBC276:41870, 2001), suggesting functional interaction. We show here via western blot analysis that SS RBC membranes contain more KCC1 protein (relative to KCC3) than AA RBC, independent of the reticulocytosis of sickle blood. Immunoprecipitation of solubilized SS RBC membranes with KCC3-specific antibody yielded a band at 125 kD on SDS PAGE which contained KCC1, as identified by western blotting with KCC1-specific antibody and by TOF mass spectroscopy. The effect of co-expression of KCC1 and KCC3 on KCC activity was assessed by measuring NEM-stimulated, Cl-dependent, (ouabain + bumetanide)-insensitive Rb uptake in HEK 293 cells. The Flip-In T-rex HEK 293 cell line (Invitrogen) containing a tetracycline-response promoter was transfected with a pcDNA5a plasmid containing KCC3a cDNA. Recombination of the plasmid with the integrated tet-promoter construct inserts the KCC3a gene under control of a tetracycline-responsive promoter. These cells were subsequently transduced with a retroviral vector (SF-91. Hildinger et at, Gene Ther. 5:1575, 1998) containing KCC1 cDNA linked to a GFP cassette. Control cells contained SF-91 vector lacking KCC1. Cells were selected for GFP expression and grown in the absence (un-induced, no KCC3a expression) or presence of tetracycline (induced, KCC3a expression). From this binary matrix, four types of cells were obtained: Cells with no additional KCC expression, representing endogenous KCC activity; cells with only KCC1 or KCC3a expression; cells with both KCC1 and KCC3a expression. Western blots indicated similar KCC1 expression in cells with KCC1 only and [KCC1 + KCC3] and similar KCC3 expression in cells with KCC3 only and [KCC1 + KCC3]. Thus, the expression of neither isoform was affected by the presence of the other. KCC activity in cells overexpressing KCC1 only was similar to endogenous activity in HEK 293 cells; i.e., transport activity of KCC1 alone was minimal. Cells overexpressing KCC3 only had a 5-fold increase in KCC activity over endogenous levels. When KCC1 was co-expressed with KCC3 in [KCC1 + KCC3] cells, an additional 50% increase in KCC activity was observed (p < 0.05 by paired t-test, N=4), despite similar levels of KCC3 expression by western blot analysis. This synergistic effect was dependent on the cytoplasmic N-terminus of KCC1, as it was not seen when the first 39 amino acids of KCC1 were removed. Interestingly, removal of the entire cytoplasmic N-terminal domain (117 aa) produced an inhibitory effect when co-expressed with KCC3a in HEK cells, as previously reported in Xenopus oocytes (Casula et al.). These data indicate that KCC1 and KCC3 interact structurally and functionally in RBC membranes, and provide another potential mechanism for regulation of KCC activity via multimeric associations between KCC isoforms. Thus, KCC activity could be modulated not only by transcriptional mechanisms and post-translational modification (phosphorylation), but also by altering the ratios of KCC isoforms or the kinetics of their association. We speculate that higher levels of KCC1 protein relative to KCC3 in SS RBC membranes could account for higher KCC activity in these cells relative to AA RBC.
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Mercado, Adriana, Paola de los Heros, Zesergio Melo, María Chávez-Canales, Adrián R. Murillo-de-Ozores, Erika Moreno, Silvana Bazúa-Valenti, Norma Vázquez, Juliette Hadchouel, and Gerardo Gamba. "With no lysine L-WNK1 isoforms are negative regulators of the K+-Cl− cotransporters." American Journal of Physiology-Cell Physiology 311, no. 1 (July 1, 2016): C54—C66. http://dx.doi.org/10.1152/ajpcell.00193.2015.
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The K+-Cl− cotransporters (KCC1-KCC4) encompass a branch of the SLC12 family of electroneutral cation-coupled chloride cotransporters that translocate ions out of the cell to regulate various factors, including cell volume and intracellular chloride concentration, among others. L-WNK1 is an ubiquitously expressed kinase that is activated in response to osmotic stress and intracellular chloride depletion, and it is implicated in two distinct hereditary syndromes: the renal disease pseudohypoaldosteronism type II (PHAII) and the neurological disease hereditary sensory neuropathy 2 (HSN2). The effect of L-WNK1 on KCC activity is unknown. Using Xenopus laevis oocytes and HEK-293 cells, we show that the activation of KCCs by cell swelling was prevented by L-WNK1 coexpression. In contrast, the activity of the Na+-K+-2Cl− cotransporter NKCC1 was remarkably increased with L-WNK1 coexpression. The negative effect of L-WNK1 on the KCCs is kinase dependent. Elimination of the STE20 proline-alanine rich kinase (SPAK)/oxidative stress-responsive kinase (OSR1) binding site or the HQ motif required for the WNK-WNK interaction prevented the effect of L-WNK1 on KCCs, suggesting a required interaction between L-WNK1 molecules and SPAK. Together, our data support that NKCC1 and KCCs are coordinately regulated by L-WNK1 isoforms.
Dissertations / Theses on the topic "KC1 cotransporter"
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Drew, Clare G. "Membrane transport in red blood cells." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275332.
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Godart, Helene. "KCI cotransport regulation in mammalian erythrocyctes." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318547.
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Yih-FungChen and 陳宜芳. "The emerging role of KCl cotransport in tumor biology." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/34372627312940774359.
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博士國立成功大學
基礎醫學研究所
98
The KCl cotransporter (KCC) is a major determinant of osmotic homeostasis and plays an important role in cancer development and progression. My thesis focuses on the emerging role for KCl cotransport in tumor biology and the novel mechanisms by which KCl cotransport regulates cancer malignant behaviors. My thesis includes four parts. (1) KCC4 expression is associated with cancer metastasis and clinical outcome. This part of study aims to investigate the contribution of individual KCC isoforms in cancer metastasis using cervical cancer and ovarian cancer as the model. The results indicate that metastatic cancer tissues express abundant KCC4 which benefits cancer cells in invasiveness. In the metastatic cancer tissues, KCC4 colocalizes with IGF-1 or EGF, indicating a likely in vivo stimulation of KCC4 function by growth factors. (2) Membrane trafficking of KCC4 is important for cancer cell invasion. Here I test the hypothesis that the regulation of specific KCC activation in cancer cells is a dynamic process which can be significantly upregulated by IGF-1 or EGF. The results indicate that IGF-1 and EGF stimulate the membrane recruitment of KCC4, in which KCC4 interacts with an actin-binding protein, ezrin, at lamellipodia. In addition to ion transport, KCC4 can function as a membrane scaffold to facilitate the modulation of cytoskeletal reorganization that is required for the invasive migration of cancer cells. (3) KCl cotransporter is an evolutionarily conserved assembly factor for actin-containing cellular protrusions. The novel functions of KCC in epithelial development were investigated using Drosophila melanogaster as a model. With the generation of KCC null mutants, it is suggested that fly KCC has essential role in the embryonic development and in the regulation of neural activity and salt homeostasis. Moreover, KCC is present in actin-bundle containing cellular protrusions of wing hairs and may play a role in the development of wing epithelium. (4) KCl cotransport is important for actin reorganization and focal adhesion dynamics during cancer cell migration. Here I test the hypothesis that KCl cotransport regulates cancer cell invasive migration is via the modulation of actin cytoskeleton and focal adhesions. The results suggest that KCl cotransport is necessary for actin reorganization and focal adhesion dynamics during cancer cell migration. Taken together, the results of my thesis provide the rationale for the clinical application of KCC as the therapeutic target and the prognostic biomarkers of metastatic cancers.
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Hsu, Yueh-Mei, and 徐月梅. "The important role of KCl cotransporters in the development and progression of human epithelial cancer." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/52135509117388502832.
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博士國立成功大學
基礎醫學研究所
96
The KCl cotransporter family (KCC) is responsible for electroneutral K-Cl co-transportation and plays important roles in cell volume regulation, transepithelial transport, and in the regulation of intracellular chloride concentration ([Cl-]i). Of the four mammalian KCl cotransporters, KCC1, KCC3 and KCC4 are widely expressed, whereas KCC2 is neuron specific. Our previous studies have begun to emerge the important roles of KCl cotransporters in tumor development and progression. In this thesis, we first demonstrated that the growth and invasion of cervical cancer cells are strongly linked the expression and activity of the KCl cotransporter (KCC). Reduced cellular invasiveness in loss-of-function KCC mutant cervical cancer cells is in parallel by reduced expression of 脉v刍3 and 脉6刍4 integrins, accompanied by decreased activity of matrix metalloproteinase 2 and 9. Inhibition of tumor growth in severe combined immunodeficiency (SCID) mice confirms the crucial role of KCC in promoting cervical cancer growth and invasion. In addition, KCC activation by insulin-like growth factor 1 (IGF-1) stimulation plays an important role in IGF-1 signaling to promote the growth and spread of gynecological cancers. Furthermore, overexpression of KCC3 in cervical cancer cells downregulates E-cadherin/刍-catenin complex formation by inhibiting transcription of E-cadherin gene and accelerating proteosome-dependent degradation of 刍-catenin protein. The disruption of E-cadherin/刍-catenin complex formation promotes EMT, thereby stimulating tumor progression. These evidences suggest that KCC may aid the invasive biology of cancer cells through new features of KCC function. Thus, blockade of KCl cotransport may be a useful therapeutic adjunctive strategy to retard or prevent gynecological cancer development and progression.
Book chapters on the topic "KC1 cotransporter"
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Ellory, J. Clive, Andrew C. Hall, Susan A. Ody, Carlos E. Poli de Figueiredos, Susan Chalder, and John Stuart. "KCl Cotransport in HbAA and HbSS Red Cells: Activation by Intracellular Acidity and Disappearance During Maturation." In Advances in Experimental Medicine and Biology, 47–57. Boston, MA: Springer US, 1991. http://dx.doi.org/10.1007/978-1-4684-5985-2_5.
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