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Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study.
Manichaikul A, Hoffman EA, Smolonska J, Gao W, Cho MH, Baumhauer H, Budoff M, Austin JH, Washko GR, Carr JJ, Kaufman JD, Pottinger T, Powell CA, Wijmenga C, Zanen P, Groen HJ, Postma DS, Wanner A, Rouhani FN, Brantly ML, Powell R, Smith BM, Rabinowitz D, Raffel LJ, Hinckley Stukovsky KD, Crapo JD, Beaty TH, Hokanson JE, Silverman EK, Dupuis J, O'Connor GT, Boezen HM, Rich SS, Barr RG
(2014) Am J Respir Crit Care Med 189: 408-18
MeSH Terms: Aged, Aged, 80 and over, Female, Follow-Up Studies, Genetic Markers, Genome-Wide Association Study, Genotyping Techniques, Humans, Male, Mannosidases, Middle Aged, N-Acetylglucosaminyltransferases, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Pulmonary Emphysema, RNA Helicases, Thiolester Hydrolases, Tomography, X-Ray Computed, United States, alpha-Mannosidase, snRNP Core Proteins
Show Abstract · Added February 15, 2014
RATIONALE - Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.
OBJECTIVES - To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.
METHODS - We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than -950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.
MEASUREMENTS AND MAIN RESULTS - Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10(-8)) and PPT2 (rs10947233; P = 3.2 × 10(-8)), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 × 10(-9); minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10(-8); MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 10(-6); MAF, 13.3%) was associated with percent emphysema.
CONCLUSIONS - Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
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21 MeSH Terms
N-glycosylation requirements in neuromuscular synaptogenesis.
Parkinson W, Dear ML, Rushton E, Broadie K
(2013) Development 140: 4970-81
MeSH Terms: Animals, Animals, Genetically Modified, Carrier Proteins, Drosophila Proteins, Drosophila melanogaster, Glycosylation, N-Acetylglucosaminyltransferases, Nervous System, Neurogenesis, Neuromuscular Junction, Receptors, AMPA, Signal Transduction, Synapses, Synaptic Transmission, Tumor Suppressor Proteins
Show Abstract · Added March 29, 2017
Neural development requires N-glycosylation regulation of intercellular signaling, but the requirements in synaptogenesis have not been well tested. All complex and hybrid N-glycosylation requires MGAT1 (UDP-GlcNAc:α-3-D-mannoside-β1,2-N-acetylglucosaminyl-transferase I) function, and Mgat1 nulls are the most compromised N-glycosylation condition that survive long enough to permit synaptogenesis studies. At the Drosophila neuromuscular junction (NMJ), Mgat1 mutants display selective loss of lectin-defined carbohydrates in the extracellular synaptomatrix, and an accompanying accumulation of the secreted endogenous Mind the gap (MTG) lectin, a key synaptogenesis regulator. Null Mgat1 mutants exhibit strongly overelaborated synaptic structural development, consistent with inhibitory roles for complex/hybrid N-glycans in morphological synaptogenesis, and strengthened functional synapse differentiation, consistent with synaptogenic MTG functions. Synapse molecular composition is surprisingly selectively altered, with decreases in presynaptic active zone Bruchpilot (BRP) and postsynaptic Glutamate receptor subtype B (GLURIIB), but no detectable change in a wide range of other synaptic components. Synaptogenesis is driven by bidirectional trans-synaptic signals that traverse the glycan-rich synaptomatrix, and Mgat1 mutation disrupts both anterograde and retrograde signals, consistent with MTG regulation of trans-synaptic signaling. Downstream of intercellular signaling, pre- and postsynaptic scaffolds are recruited to drive synaptogenesis, and Mgat1 mutants exhibit loss of both classic Discs large 1 (DLG1) and newly defined Lethal (2) giant larvae [L(2)GL] scaffolds. We conclude that MGAT1-dependent N-glycosylation shapes the synaptomatrix carbohydrate environment and endogenous lectin localization within this domain, to modulate retention of trans-synaptic signaling ligands driving synaptic scaffold recruitment during synaptogenesis.
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15 MeSH Terms
Enhanced cardiac protein glycosylation (O-GlcNAc) of selected mitochondrial proteins in rats artificially selected for low running capacity.
Johnsen VL, Belke DD, Hughey CC, Hittel DS, Hepple RT, Koch LG, Britton SL, Shearer J
(2013) Physiol Genomics 45: 17-25
MeSH Terms: Absorptiometry, Photon, Analysis of Variance, Animals, Carbon Radioisotopes, Citrate (si)-Synthase, Fatty Acids, Nonesterified, Glucose, Glucose Clamp Technique, Glycosylation, Immunoblotting, Insulin Resistance, Kinetics, Mitochondrial Proteins, Models, Animal, Myocardium, N-Acetylglucosaminyltransferases, Oxidative Phosphorylation, Rats, Rats, Inbred Strains, Running
Show Abstract · Added April 24, 2014
O-linked β-N-acetyl glucosamine (O-GlcNAc) is a posttranslational modification consisting of a single N-acetylglucosamine moiety attached by an O-β-glycosidic linkage to serine and threonine residues of both nuclear and cytosolic proteins. Analogous to phosphorylation, the modification is reversible and dynamic, changing in response to stress, nutrients, hormones, and exercise. Aims of this study were to examine differences in O-GlcNAc protein modification in the cardiac tissue of rats artificially selected for low (LCR) or high (HCR) running capacity. Hyperinsulinemic-euglycemic clamps in conscious animals assessed insulin sensitivity while 2-[(14)C] deoxyglucose tracked both whole body and tissue-specific glucose disposal. Immunoblots of cardiac muscle examined global O-GlcNAc modification, enzymes that control its regulation (OGT, OGA), and specific proteins involved in mitochondrial oxidative phosphorylation. LCR rats were insulin resistant disposing of 65% less glucose than HCR. Global tissue O-GlcNAc, OGT, OGA, and citrate synthase were similar between groups. Analysis of cardiac proteins revealed enhanced O-GlcNAcylation of mitochondrial Complex I, Complex IV, VDAC, and SERCA in LCR compared with HCR. These results are the first to establish an increase in specific protein O-GlcNAcylation in LCR animals that may contribute to progressive mitochondrial dysfunction and the pathogenesis of insulin resistance observed in the LCR phenotype.
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20 MeSH Terms
Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis.
Mkhikian H, Grigorian A, Li CF, Chen HL, Newton B, Zhou RW, Beeton C, Torossian S, Tatarian GG, Lee SU, Lau K, Walker E, Siminovitch KA, Chandy KG, Yu Z, Dennis JW, Demetriou M
(2011) Nat Commun 2: 334
MeSH Terms: Animals, Antigens, CD, CTLA-4 Antigen, Case-Control Studies, Cholecalciferol, Cohort Studies, Down-Regulation, Female, Genetic Variation, Glycosylation, Haplotypes, Humans, Male, Mice, Mice, Inbred Strains, Multiple Sclerosis, N-Acetylglucosaminyltransferases, Receptors, Interleukin-2, Receptors, Interleukin-7, Risk Factors, Signal Transduction, Sunlight
Show Abstract · Added November 15, 2013
How environmental factors combine with genetic risk at the molecular level to promote complex trait diseases such as multiple sclerosis (MS) is largely unknown. In mice, N-glycan branching by the Golgi enzymes Mgat1 and/or Mgat5 prevents T cell hyperactivity, cytotoxic T-lymphocyte antigen 4 (CTLA-4) endocytosis, spontaneous inflammatory demyelination and neurodegeneration, the latter pathologies characteristic of MS. Here we show that MS risk modulators converge to alter N-glycosylation and/or CTLA-4 surface retention conditional on metabolism and vitamin D(3), including genetic variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IV(A)V(T-T)) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IV(A)V(T-T)) and vitamin D(3), optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17. Our data suggest a molecular mechanism in MS whereby multiple environmental and genetic inputs lead to dysregulation of a final common pathway, namely N-glycosylation.
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22 MeSH Terms
O-GlcNAcylation contributes to augmented vascular reactivity induced by endothelin 1.
Lima VV, Giachini FR, Carneiro FS, Carneiro ZN, Saleh MA, Pollock DM, Fortes ZB, Carvalho MH, Ergul A, Webb RC, Tostes RC
(2010) Hypertension 55: 180-8
MeSH Terms: Acetylglucosamine, Animals, Aorta, Thoracic, Atrasentan, Blood Pressure, Blotting, Western, Desoxycorticosterone, Drug Synergism, Endothelin-1, Glycoproteins, Glycosylation, Hypertension, In Vitro Techniques, Male, N-Acetylglucosaminyltransferases, Phenylephrine, Pyrrolidines, Rats, Rats, Wistar, Time Factors, Vasoconstriction, Vasoconstrictor Agents
Show Abstract · Added July 31, 2014
O-GlcNAcylation augments vascular contractile responses, and O-GlcNAc-proteins are increased in the vasculature of deoxycorticosterone-acetate salt rats. Because endothelin 1 (ET-1) plays a major role in vascular dysfunction associated with salt-sensitive forms of hypertension, we hypothesized that ET-1-induced changes in vascular contractile responses are mediated by O-GlcNAc modification of proteins. Incubation of rat aortas with ET-1 (0.1 mumol/L) produced a time-dependent increase in O-GlcNAc levels and decreased expression of O-GlcNAc transferase and beta-N-acetylglucosaminidase, key enzymes in the O-GlcNAcylation process. Overnight treatment of aortas with ET-1 increased phenylephrine vasoconstriction (maximal effect [in moles]: 19+/-5 versus 11+/-2 vehicle). ET-1 effects were not observed when vessels were previously instilled with anti-O-GlcNAc transferase antibody or after incubation with an O-GlcNAc transferase inhibitor (3-[2-adamantanylethyl]-2-[{4-chlorophenyl}azamethylene]-4-oxo-1,3-thiazaperhyd roine-6-carboxylic acid; 100 mumol/L). Aortas from deoxycorticosterone-acetate salt rats, which exhibit increased prepro-ET-1, displayed increased contractions to phenylephrine and augmented levels of O-GlcNAc proteins. Treatment of deoxycorticosterone-acetate salt rats with an endothelin A antagonist abrogated augmented vascular levels of O-GlcNAc and prevented increased phenylephrine vasoconstriction. Aortas from rats chronically infused with low doses of ET-1 (2 pmol/kg per minute) exhibited increased O-GlcNAc proteins and enhanced phenylephrine responses (maximal effect [in moles]: 18+/-2 versus 10+/-3 control). These changes are similar to those induced by O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate, an inhibitor of beta-N-acetylglucosaminidase. Systolic blood pressure (in millimeters of mercury) was similar between control and ET-1-infused rats (117+/-3 versus 123+/-4 mm Hg; respectively). We conclude that ET-1 indeed augments O-GlcNAc levels and that this modification contributes to the vascular changes induced by this peptide. Increased vascular O-GlcNAcylation by ET-1 may represent a mechanism for hypertension-associated vascular dysfunction or other pathological conditions associated with increased levels of ET-1.
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22 MeSH Terms
Altered gastric chief cell lineage differentiation in histamine-deficient mice.
Nozaki K, Weis V, Wang TC, Falus A, Goldenring JR
(2009) Am J Physiol Gastrointest Liver Physiol 296: G1211-20
MeSH Terms: Age Factors, Animals, Azetidines, Basic Helix-Loop-Helix Transcription Factors, Cell Count, Cell Differentiation, Chief Cells, Gastric, Chromogranin A, Enterochromaffin-like Cells, Enzyme Inhibitors, Gastric Fundus, Gastric Mucosa, Gastrins, Histamine, Histidine Decarboxylase, Hyperplasia, Hypertrophy, Intrinsic Factor, Metaplasia, Mice, Mice, Inbred BALB C, Mice, Knockout, Mucins, Muscle Proteins, N-Acetylglucosaminyltransferases, Parietal Cells, Gastric, Peptides, Piperazines, Trefoil Factor-2
Show Abstract · Added October 7, 2013
The orderly differentiation of cell lineages within gastric glands is regulated by a complicated interplay of local mucosal growth factors and hormones. Histamine secreted from enterochromaffin-like cells plays an important role in not only stimulated gastric acid secretion but also coordination of intramucosal growth and lineage differentiation. We have examined histidine-decarboxylase (HDC)-deficient mice, which lack endogenous histamine synthesis, to evaluate the influence of histamine on differentiation of fundic mucosal lineages and the development of metaplasia following induction of acute oxyntic atrophy. Stomachs from HDC-deficient mice and wild-type mice were evaluated at 8 wk and 12 mo of age. DMP-777 was administrated orally to 6-wk-old mice for 1 to 14 days. Sections of gastric mucosa were stained with antibodies against Mist1, intrinsic factor, H/K-ATPase, trefoil factor 2 (TFF2), chromogranin A, and Ext1 and for the cell cycle marker phospho-histone H3. HDC-deficient mice at 8 wk of age demonstrated a prominent increase in chief cells expressing Mist1 and intrinsic factor. Importantly Mist1-positive mature chief cells were present in the midgland region as well as at the bases of fundic glands, indicating a premature differentiation of chief cells. Mice dually deficient for both HDC and gastrin showed a normal distribution of chief cells in fundic glands. Treatment of HDC-deficient mice with DMP-777 led to loss of parietal cells and an accelerated and exaggerated emergence of mucous cell metaplasia with the presence of dual intrinsic factor and TFF2-expressing cells throughout the gland length, indicative of the emergence of spasmolytic polypeptide-expressing metaplasia (SPEM) from chief cells. These findings indicate that histamine, in concert with gastrin, regulates the appropriate differentiation of chief cells from mucous neck cells as they migrate toward the bases of fundic glands. Nevertheless, histamine is not required for emergence of SPEM following acute oxyntic atrophy.
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29 MeSH Terms
N-Glycans in cancer progression.
Lau KS, Dennis JW
(2008) Glycobiology 18: 750-60
MeSH Terms: Animals, Disease Progression, Humans, N-Acetylglucosaminyltransferases, Neoplasms, Polysaccharides, Protein Binding, Signal Transduction
Show Abstract · Added November 15, 2013
N-Glycan branching in the medial-Golgi generates ligands for lattice-forming lectins (e.g., galectins) that regulate surface levels of glycoproteins including epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) receptors. Moreover, functional classes of glycoproteins differ in N-glycan multiplicities (number of N-glycans/peptide), a genetically encoded feature of glycoproteins that interacts with metabolic flux (UDP-GlcNAc) and N-glycan branching to differentially regulate surface levels. Oncogenesis increases beta1,6-N-acetylglucosaminyltransferase V (encoded by Mgat5) expression, and its high-affinity galectin ligands promote surface retention of growth receptors with a reduced dependence on UDP-GlcNAc. Mgat5(-/-) tumor cells are less metastatic in vivo and less responsive to cytokines in vitro, but undergo secondary changes that support tumor cell proliferation. These include loss of Caveolin-1, a negative regulator of EGF signaling, and increased reactive oxygen species, an inhibitor of phosphotyrosine phosphatases. These studies suggest a systems approach to cancer treatment where the surface distribution of receptors is targeted through metabolism and N-glycan branching to induce growth arrest.
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8 MeSH Terms
Complex N-glycan and metabolic control in tumor cells.
Mendelsohn R, Cheung P, Berger L, Partridge E, Lau K, Datti A, Pawling J, Dennis JW
(2007) Cancer Res 67: 9771-80
MeSH Terms: Animals, Antigens, Polyomavirus Transforming, Cell Growth Processes, Cell Line, Tumor, Glucose, Golgi Apparatus, MAP Kinase Signaling System, Mammary Neoplasms, Experimental, Mice, Mice, Transgenic, Mitochondria, Mitogen-Activated Protein Kinase Kinases, N-Acetylglucosaminyltransferases, Polysaccharides, Proto-Oncogene Proteins c-akt, Reactive Oxygen Species, Uridine Diphosphate N-Acetylglucosamine
Show Abstract · Added November 15, 2013
Golgi beta1,6N-acetylglucosaminyltransferase V (Mgat5) produces beta1,6GlcNAc-branched complex N-glycans on cell surface glycoproteins that bind to galectins and promote surface residency of glycoproteins, including cytokine receptors. Carcinoma cells from polyomavirus middle T (PyMT) transgenic mice on a Mgat5-/- background have reduced surface levels of epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) receptors and are less sensitive to acute stimulation by cytokines in vitro compared with PyMT Mgat5+/+ tumor cells but are nonetheless tumorigenic when injected into mice. Here, we report that PyMT Mgat5-/- cells are reduced in size, checkpoint impaired, and following serum withdrawal, fail to down-regulate glucose transport, protein synthesis, reactive oxygen species (ROS), and activation of Akt and extracellular signal-regulated kinase. To further characterize Mgat5+/+ and Mgat5-/- tumor cells, a screen of pharmacologically active compounds was done. Mgat5-/- tumor cells were comparatively hypersensitive to the ROS inducer 2,3-dimethoxy-1,4-naphthoquinone, hyposensitive to tyrosine kinase inhibitors, to Golgi disruption by brefeldin A, and to mitotic arrest by colcemid, hydroxyurea, and camptothecin. Finally, regulation of ROS, glucose uptake, and sensitivities to EGF and TGF-beta were rescued by Mgat5 expression or by hexosamine supplementation to complex N-glycan biosynthesis in Mgat5-/- cells. Our results suggest that complex N-glycans sensitize tumor cells to growth factors, and Mgat5 is required to balance responsiveness to growth and arrest cues downstream of metabolic flux.
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17 MeSH Terms
Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans.
An G, Wei B, Xia B, McDaniel JM, Ju T, Cummings RD, Braun J, Xia L
(2007) J Exp Med 204: 1417-29
MeSH Terms: Animals, Colitis, Colon, Colorectal Neoplasms, DNA Primers, Disease Susceptibility, Immunoblotting, Immunohistochemistry, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Mucin-2, Mucins, N-Acetylglucosaminyltransferases, Polysaccharides, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added August 24, 2017
Altered intestinal O-glycan expression has been observed in patients with ulcerative colitis and colorectal cancer, but the role of this alteration in the etiology of these diseases is unknown. O-glycans in mucin core proteins are the predominant components of the intestinal mucus, which comprises part of the intestinal mucosal barrier. Core 3-derived O-glycans, which are one of the major types of O-glycans, are primarily expressed in the colon. To investigate the biological function of core 3-derived O-glycans, we engineered mice lacking core 3 beta1,3-N-acetylglucosaminyltransferase (C3GnT), an enzyme predicted to be important in the synthesis of core 3-derived O-glycans. Disruption of the C3GnT gene eliminated core 3-derived O-glycans. C3GnT-deficient mice displayed a discrete, colon-specific reduction in Muc2 protein and increased permeability of the intestinal barrier. Moreover, these mice were highly susceptible to experimental triggers of colitis and colorectal adenocarcinoma. These data reveal a requirement for core 3-derived O-glycans in resistance to colonic disease.
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16 MeSH Terms
O-GlcNAc transferase is in a functional complex with protein phosphatase 1 catalytic subunits.
Wells L, Kreppel LK, Comer FI, Wadzinski BE, Hart GW
(2004) J Biol Chem 279: 38466-70
MeSH Terms: Animals, Blotting, Western, Brain, Catalytic Domain, Cell Nucleus, Chromatography, Chromatography, Gel, Chromatography, Liquid, Cytosol, Mass Spectrometry, N-Acetylglucosaminyltransferases, Phosphoprotein Phosphatases, Phosphoric Monoester Hydrolases, Phosphorylation, Precipitin Tests, Protein Binding, Protein Isoforms, Protein Phosphatase 1, Protein Structure, Tertiary, Rats, Serine, Signal Transduction, Threonine
Show Abstract · Added December 10, 2013
A hallmark of signal transduction is the dynamic and inducible post-translational modification of proteins. In addition to the well characterized phosphorylation of proteins, other modifications have been shown to be regulatory, including O-linked beta-N-acetylglucosamine (O-GlcNAc). O-GlcNAc modifies serine and threonine residues on a myriad of nuclear and cytosolic proteins, and for several proteins there appears to be a reciprocal relationship between phosphorylation and O-GlcNAc modification. Here we report further evidence of this yin-yang relationship by demonstrating that O-GlcNAc transferase, the enzyme that adds O-GlcNAc to proteins, exists in stable and active complexes with the serine/threonine phosphatases PP1beta and PP1gamma, enzymes that remove phosphate from proteins. The existence of this complex highlights the importance of understanding the dynamic relationship between O-GlcNAc and phosphate in modulating protein function in many cellular processes and disease states such as Alzheimer's disease and type II diabetes.
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23 MeSH Terms