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Author (up) Baylis, H.A.; Furuichi, T.; Yoshikawa, F.; Mikoshiba, K.; Sattelle, D.B. file  url
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  Title Inositol 1,4,5-trisphosphate receptors are strongly expressed in the nervous system, pharynx, intestine, gonad and excretory cell of Caenorhabditis elegans and are encoded by a single gene (itr-1) Type Journal Article
  Year 1999 Publication Journal of Molecular Biology Abbreviated Journal J Mol Biol  
  Volume 294 Issue 2 Pages 467-476  
  Keywords Amino Acid Sequence; Animals; Animals, Genetically Modified; Binding Sites; Caenorhabditis elegans/*genetics; Calcium Channels/*genetics/*metabolism; Cell Membrane/genetics/metabolism; Conserved Sequence; Gene Expression Profiling; Gonads/metabolism; Helminth Proteins/*genetics/*metabolism; Inositol 1,4,5-Trisphosphate Receptors; Intestines/metabolism; Molecular Sequence Data; Nervous System/metabolism; Pharynx/metabolism; RNA, Messenger; Receptors, Cytoplasmic and Nuclear/*genetics/*metabolism; Rectum/cytology/metabolism  
  Abstract Inositol 1,4,5-trisphosphate (InsP3) activates receptors (InsP3Rs) that mediate intracellular Ca(2+ )release, thereby modulating intracellular calcium signals and regulating important aspects of cellular physiology and gene expression. To further our understanding of InsP3Rs we have characterised InsP3Rs and the InsP3R gene, itr-1, from the model organism Caenorhabditis elegans. cDNAs encoding InsP3Rs were cloned enabling us to: (a) identify three putative transcription start sites that result in alternative mRNA 5' ends: (b) detect alternative splicing at three sites and: (c) determine the full genomic organisation of the itr-1 gene. The InsP3R protein (ITR-1) is approximately 42 % identical with known InsP3Rs and possesses conserved structural features. When the putative InsP3 binding domain was expressed in Escherichia coli, specific binding of InsP3 was detected. Using antibodies against ITR-1 we detected a protein of 220 kDa in C. elegans membranes. These antibodies and itr-1::GFP (green fluorescent protein) reporter constructs were used to determine the expression pattern of itr-1 in C. elegans. Strong expression was observed in the intestine, pharynx, nerve ring, excretory cell and gonad. These results demonstrate the high degree of structural and functional conservation of InsP3Rs from nematodes to mammals and the utility of C. elegans as a system for studies on InsP3R mediated signalling.  
  Call Number Serial 309  
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Author (up) Burak, M.F.; Inouye, K.E.; White, A.; Lee, A.; Tuncman, G.; Calay, E.S.; Sekiya, M.; Tirosh, A.; Eguchi, K.; Birrane, G.; Lightwood, D.; Howells, L.; Odede, G.; Hailu, H.; West, S.; Garlish, R.; Neale, H.; Doyle, C.; Moore, A.; Hotamisligil, G.S. file  url
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  Title Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes Type Journal Article
  Year 2015 Publication Science Translational Medicine Abbreviated Journal Sci Transl Med  
  Volume 7 Issue 319 Pages 319ra205  
  Keywords Adipose Tissue/drug effects; Amino Acid Sequence; Animals; Antibodies, Monoclonal/*therapeutic use; Body Composition/drug effects; Diabetes Mellitus, Type 2/complications/*drug therapy; Diet, High-Fat; Fatty Acid-Binding Proteins/chemistry/*immunology; Fatty Liver/complications/pathology; Glucose/metabolism; Humans; Insulin/pharmacology; Male; Metabolome/drug effects; Mice, Inbred C57BL; Mice, Obese  
  Abstract The lipid chaperone aP2/FABP4 has been implicated in the pathology of many immunometabolic diseases, including diabetes in humans, but aP2 has not yet been targeted for therapeutic applications. aP2 is not only an intracellular protein but also an active adipokine that contributes to hyperglycemia by promoting hepatic gluconeogenesis and interfering with peripheral insulin action. Serum aP2 levels are markedly elevated in mouse and human obesity and strongly correlate with metabolic complications. These observations raise the possibility of a new strategy to treat metabolic disease by targeting serum aP2 with a monoclonal antibody (mAb) to aP2. We evaluated mAbs to aP2 and identified one, CA33, that lowered fasting blood glucose, improved systemic glucose metabolism, increased systemic insulin sensitivity, and reduced fat mass and liver steatosis in obese mouse models. We examined the structure of the aP2-CA33 complex and resolved the target epitope by crystallographic studies in comparison to another mAb that lacked efficacy in vivo. In hyperinsulinemic-euglycemic clamp studies, we found that the antidiabetic effect of CA33 was predominantly linked to the regulation of hepatic glucose output and peripheral glucose utilization. The antibody had no effect in aP2-deficient mice, demonstrating its target specificity. We conclude that an aP2 mAb-mediated therapeutic constitutes a feasible approach for the treatment of diabetes.  
  Call Number Serial 2042  
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Author (up) Cho, J.H.; Bandyopadhyay, J.; Lee, J.; Park, C.S.; Ahnn, J. file  url
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  Title Two isoforms of sarco/endoplasmic reticulum calcium ATPase (SERCA) are essential in Caenorhabditis elegans Type Journal Article
  Year 2000 Publication Gene Abbreviated Journal Gene  
  Volume 261 Issue 2 Pages 211-219  
  Keywords Alternative Splicing; Amino Acid Sequence; Animals; Caenorhabditis elegans/embryology/enzymology/*genetics; Calcium-Transporting ATPases/*genetics/metabolism; Embryo, Nonmammalian/drug effects/enzymology; Embryonic Development; Gene Expression Regulation, Enzymologic; Green Fluorescent Proteins; Isoenzymes/genetics/metabolism; Luminescent Proteins/genetics/metabolism; Microscopy, Fluorescence; Molecular Sequence Data; Phenotype; Promoter Regions, Genetic/genetics; RNA, Double-Stranded/administration & dosage/genetics; Recombinant Fusion Proteins/genetics/metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sequence Homology, Amino Acid; Tissue Distribution  
  Abstract SERCA (Sarco/Endoplasmic Reticulum Calcium ATPase), a membrane bound Ca(2+)- /Mg(2+)- dependent ATPase that sequesters Ca(2+) into the SR/ER lumen, is one of the essential components for the maintenance of intracellular Ca(2+) homeostasis. Here we describe the identification and functional characterization of a C. elegans SERCA gene (ser-1). ser-1 is a single gene alternatively spliced at its carboxyl terminus to form two isoforms (SER-1A and SER-1B) and displays a high homology (70% identity, 80% similarity) with mammalian SERCAs. Green fluorescent protein (GFP) and whole-mount immunostaining analyses reveal that SER-1 expresses in neuronal cells, body-wall muscles, pharyngeal and vulval muscles, excretory cells, and vulva epithelial cells. Furthermore, SER-1::GFP expresses during embryonic stages and the expression is maintained through the adult stages. Double-stranded RNA injection (also known as RNAi) targeted to each SER-1 isoform results in severe phenotypic defects: ser-1A(RNAi) animals show embryonic lethality, whereas ser-1B(RNAi) results in L1 larval arrest phenotype. These findings suggest that both isoforms of C. elegans SERCA, like in mammals, are essential for embryonic development and post-embryonic growth and survival.  
  Call Number Serial 451  
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Author (up) Fliss, H.; Menard, M. file  url
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  Title Hypochlorous acid-induced mobilization of zinc from metalloproteins Type Journal Article
  Year 1991 Publication Archives of Biochemistry and Biophysics Abbreviated Journal Arch Biochem Biophys  
  Volume 287 Issue 1 Pages 175-179  
  Keywords Amino Acid Sequence; Animals; Horses; Hypochlorous Acid--metabolism; Kinetics; Metalloproteins--metabolism; Molecular Sequence Data; Oligopeptides--metabolism; Resorcinols--metabolism; Zinc--metabolism  
  Abstract Hypochlorous acid (HOCl), a neutrophil oxidant, can contribute to tissue injury at sites of inflammation by its reactivity with protein sulfhydryls. The present study shows that physiological concentrations (50-200 microM) of HOCl can displace Zn2+ from metalloproteins, such as metallothionein and alcohol dehydrogenase, in which the metal is bound to sulfhydryls by means of thiolate (S-Zn) bonds. No mobilization of Zn2+ was observed from superoxide dismutase in which the metal is not bound to cysteine, suggesting that HOCl reacts selectively with thiolate bonds. Zn2+ mobilization, measured spectrophotometrically with the metallochromic indicator 4-(2-pyridylazo)resorcinol, was also observed from complexes of this metal with other thiol-containing compounds such as 2,3-dimercaptopropanol and metallothionein fragment 56-61. HOCl cleavage of the thiolate bonds was confirmed by the decrease in absorbance at 250 nm. This study shows for the first time that HOCl can mobilize protein-bound Zn2+ and suggests that neutrophil oxidant injury may be partially mediated by the mobilization of cellular Zn2+.  
  Call Number Serial 74  
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Author (up) Foltz, D.R.; Jansen, L.E.T.; Black, B.E.; Bailey, A.O.; Yates, J.R. 3rd; Cleveland, D.W. url  doi
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  Title The human CENP-A centromeric nucleosome-associated complex Type Journal Article
  Year 2006 Publication Nature Cell Biology Abbreviated Journal Nat Cell Biol  
  Volume 8 Issue 5 Pages 458-469  
  Keywords Amino Acid Sequence; Autoantigens--chemistry, isolation & purification; metabolism; Centromere--metabolism; Chromatin Assembly Factor-1; Chromatin Assembly and Disassembly--genetics; Chromosomal Proteins, Non-Histone--chemistry, isolation & purification, metabolism; Chromosomes, Human genetics; DNA-Binding Proteins--metabolism; HeLa Cells; Histones--chemistry; Humans; Mitosis--genetics; Molecular Sequence Data; Nucleosomes--metabolism; Protein Binding; Signal Transduction  
  Abstract The basic element for chromosome inheritance, the centromere, is epigenetically determined in mammals. The prime candidate for specifying centromere identity is the array of nucleosomes assembled with CENP-A, the centromere-specific histone H3 variant. Here, we show that CENP-A nucleosomes directly recruit a proximal CENP-A nucleosome associated complex (NAC) comprised of three new human centromere proteins (CENP-M, CENP-N and CENP-T), along with CENP-U(50), CENP-C and CENP-H. Assembly of the CENP-A NAC at centromeres is dependent on CENP-M, CENP-N and CENP-T. Facilitates chromatin transcription (FACT) and nucleophosmin-1 (previously implicated in transcriptional chromatin remodelling and as a multifunctional nuclear chaperone, respectively) are absent from histone H3-containing nucleosomes, but are stably recruited to CENP-A nucleosomes independent of CENP-A NAC. Seven new CENP-A-nucleosome distal (CAD) centromere components (CENP-K, CENP-L, CENP-O, CENP-P, CENP-Q, CENP-R and CENP-S) are identified as assembling on the CENP-A NAC. The CENP-A NAC is essential, as disruption of the complex causes errors of chromosome alignment and segregation that preclude cell survival despite continued centromere-derived mitotic checkpoint signalling.  
  Call Number Serial 13  
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