O-GlcNAc cycling: A link between metabolism and chronic disease

Annual Review of Nutrition

Volumn 33, Issue , 2013, Pages 205-229

  Bond, Michelle R ^a   Hanover, John A ^a  

^a NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

Author keywords

Hexosamine biosynthetic pathway (HBP); O GlcNAc transferase (OGT); O GlcNAcase (OGA); Uridine diphospho N acetylglucosamine (UDP GlcNAc)

Indexed keywords

ALPHA CRYSTALLIN; AMYLOID PRECURSOR PROTEIN; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ESTROGEN RECEPTOR BETA; HEAT SHOCK PROTEIN 27; HEAT SHOCK PROTEIN 90; HISTONE H2B; HISTONE H3; INSULIN; INSULIN RECEPTOR; KERATIN; N ACETYLGLUCOSAMINE; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PROTEASOME; PROTEIN KINASE B; PROTEIN P53; RNA POLYMERASE II; SERINE; TAU PROTEIN; THREONINE; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FKHR; TRANSCRIPTION FACTOR IRS1; TRANSCRIPTION FACTOR PDX 1; TRANSCRIPTION FACTOR SP1; TRANSCRIPTION FACTOR TET; UNCLASSIFIED DRUG; URIDINE DIPHOSPHATE N ACETYLGLUCOSAMINE;

ARTICLE; CELL CYCLE PROGRESSION; CELL FUNCTION; CELLULAR DISTRIBUTION; CHRONIC DISEASE; ENZYME ACTIVITY; ENZYME METABOLISM; HOMEOSTASIS; HUMAN; METABOLIC STRESS; MOLECULAR DYNAMICS; MOLECULAR RECOGNITION; NEOPLASM; NERVE CELL PLASTICITY; NERVE DEGENERATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; NUTRIENT AVAILABILITY; NUTRIENT CYCLING; PRIORITY JOURNAL; PROTEIN FOLDING; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN STABILITY; PROTEIN SYNTHESIS; PROTEIN TARGETING; SIGNAL TRANSDUCTION;

ACETYLGLUCOSAMINE; ANIMALS; BETA-N-ACETYLHEXOSAMINIDASES; DIABETES MELLITUS, TYPE 2; DIET; ENERGY METABOLISM; GENE EXPRESSION REGULATION; HEALTH STATUS; HUMANS; N-ACETYLGLUCOSAMINYLTRANSFERASES; NEOPLASMS; NEURODEGENERATIVE DISEASES; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTEIN STABILITY; URIDINE DIPHOSPHATE N-ACETYLGLUCOSAMINE;

EID: 84880648662     PISSN: 01999885     EISSN: 15454312     Source Type: Book Series    
DOI: 10.1146/annurev-nutr-071812-161240     Document Type: Article

References (150)

1. Albert SG, Oiknine RF, Parseghian S, Mooradian AD, Haas MJ, McPherson T. 2007. The effect of glucosamine on serum HDL cholesterol and apolipoprotein AI levels in people with diabetes. Diabetes Care 30:2800-3
2. Anderson JW, Nicolosi RJ, Borzelleca JF. 2005. Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem. Toxicol. 43:187-201
3. Andrali SS, Qian Q, Ozcan S. 2007. Glucose mediates the translocation of NeuroD1 by O-linked glycosylation. J. Biol. Chem. 282:15589-96
4. Andrali SS, SampleyML, VanderfordNL, Ozcan S. 2008.Glucose regulation of insulin gene expression in pancreatic β-cells. Biochem. J. 415:1-10
5. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. 2006. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 5:64-74
6. Biggee BA, Blinn CM, McAlindon TE, Nuite M, Silbert JE. 2006. Low levels of human serum glucosamine after ingestion of glucosamine sulphate relative to capability for peripheral effectiveness. Ann. Rheum. Dis. 65:222-26
7. Biggee BA, Blinn CM, Nuite M, Silbert JE, McAlindon TE. 2007. Effects of oral glucosamine sulphate on serum glucose and insulin during an oral glucose tolerance test of subjects with osteoarthritis. Ann. Rheum. Dis. 66:260-62
8. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, et al. 2005. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947-56
9. Butkinaree C, Park K, Hart GW. 2010. O-linked β-N-acetylglucosamine (O-GlcNAc): extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stress. Biochim. Biophys. Acta 1800:96-106
10. Caldwell SA, Jackson SR, Shahriari KS, Lynch TP, Sethi G, et al. 2010. Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene 29:2831-42
11. Chen Q, Chen Y, Bian C, Fujiki R, Yu X. 2013. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493:561-64
12. Chen YX, Du JT, Zhou LX, Liu XH, Zhao YF, et al. 2006. Alternative O-GlcNAcylation/O-phosphorylation of Ser16 induce different conformational disturbances to the N terminus of murine estrogen receptor beta. Chem. Biol. 13:937-44
13. Cheng X, Hart GW. 2001. Alternative O-glycosylation/O-phosphorylation of serine-16 in murine estrogen receptor β: post-translational regulation of turnover and transactivation activity. J. Biol. Chem. 276:10570-75
14. Cheung EC, Vousden KH. 2010. The role of p53 in glucosemetabolism. Curr. Opin. Cell Biol. 22:186-91
15. Cheung WD, Sakabe K, Housley MP, Dias WB, Hart GW. 2008. O-linked β-Nacetylglucosaminyltransferase substrate specificity is regulated by myosin phosphatase targeting and other interacting proteins. J. Biol. Chem. 283:33935-41
16. Chikanishi T, Fujiki R, Hashiba W, Sekine H, Yokoyama A, Kato S. 2010. Glucose-induced expression of MIP-1 genes requiresO-GlcNAc transferase inmonocytes. Biochem. Biophys. Res. Commun. 394:865-70
17. Chou TY, Dang CV, Hart GW. 1995. Glycosylation of the c-Myc transactivation domain. Proc. Natl. Acad. Sci. USA 92:4417-21
18. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, et al. 2003. Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J. Biol. Chem. 278:44230-37
19. Comer FI, Hart GW. 2001. Reciprocity between O-GlcNAc and O-phosphate on the carboxyl terminal domain of RNA polymerase II. Biochemistry 40:7845-52
20. Daly NL, Hoffmann R, Otvos LJ, Craik DJ. 2000. Role of phosphorylation in the conformation of peptides implicated in Alzheimer?s disease. Biochemistry 39:9039-46
21. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. 2008. Brick by brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev. 18:54-61
22. DeFronzo RA, Ferrannini E. 1991. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173-94
23. DejosezM, Krumenacker JS, Zitur LJ, Passeri M, Chu LF, et al. 2008. Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell 133:1162-74
24. Dejosez M, Levine SS, Frampton GM, Whyte WA, Stratton SA, et al. 2010. Ronin/Hcf-1 binds to a hyperconserved enhancer element and regulates genes involved in the growth of embryonic stem cells. Genes Dev. 24:1479-84
25. Dell A. 1992. Vertebrate lens alpha-crystallins are modified by O-linked N-acetylglucosamine. J. Biol. Chem. 267:555-63
26. Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX. 2009. Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: implication for Alzheimer?s disease. Am. J. Pathol. 175:2089-98
27. Dentin R, Hedrick S, Xie J, Yates J 3rd, Montminy M. 2008. Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319:1402-5
28. Deplus R, Delatte B, Schwinn MK, Defrance M, Mendez J, et al. 2013. TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. 32:645-55
29. Donohoe ME, Silva SS, Pinter SF, Xu N, Lee JT. 2009. The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting. Nature 460:128-32
30. DrzezgaA, Lautenschlager N, SiebnerH, RiemenschneiderM, Willoch F, et al. 2003. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer?s disease: a PET followup study. Eur. J. Nucl. Med. Mol. Imaging 30:1104-13
31. Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. 2001. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslationalmodification at the Akt site. J. Clin. Invest. 108:1341-48
32. Durgan DJ, Pat BM, Laczy B, Bradley JA, Tsai JY, et al. 2011. O-GlcNAcylation, novel posttranslational modification linking myocardial metabolism and cardiomyocyte circadian clock. J. Biol. Chem. 286:44606-19
33. Federici M, Menghini R, Mauriello A, Hribal ML, Ferrelli F, et al. 2002. Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylationmodification of signaling proteins in human coronary endothelial cells. Circulation 106:466-72
34. Fleming AB, Pennings S. 2001. Antagonistic remodelling by Swi-Snf and Tup1-Ssn6 of an extensive chromatin region forms the background for FLO1 gene regulation. EMBO J. 20:5219-31
35. Fong JJ, Nguyen BL, Bridger R, Medrano EE, Wells L, et al. 2012.β-N-acetylglucosamine (O-GlcNAc) is a novel regulator of mitosis-specific phosphorylations on histone H3. J. Biol. Chem. 287:12195-203
36. Forsythe ME, Love DC, Lazarus BD, Kim EJ, Prinz WA, et al. 2006. Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer. Proc. Natl. Acad. Sci. USA 103:11952-57
37. Fujiki R, Chikanishi T, Hashiba W, Ito H, Takada I, et al. 2009. GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature 459:455-59
38. Fujiki R, HashibaW, Sekine H, Yokoyama A, Chikanishi T, et al. 2011. GlcNAcylation of histone H2B facilitates its monoubiquitination. Nature 480:557-60
39. Gambetta MC, Oktaba K, Muller J. 2009. Essential role of the glycosyltransferase sxc/Ogt in polycomb repression. Science 325:93-96
40. Gao Y, Miyazaki J, Hart GW. 2003. The transcription factor PDX-1 is post-translationally modified by O-linked N-acetylglucosamine and this modification is correlated with its DNA binding activity and insulin secretion in min6 β-cells. Arch. Biochem. Biophys. 415:155-63
41. Garaulet M, Madrid JA. 2010. Chronobiological aspects of nutrition, metabolic syndrome and obesity. Adv. Drug Deliv. Rev. 62:967-78
42. Gu Y, Mi W, Ge Y, Liu H, Fan Q, et al. 2010. GlcNAcylation plays an essential role in breast cancer metastasis. Cancer Res. 70:6344-51
43. Guo K, Gan L, Zhang S, Cui FJ, Cun W, et al. 2012. Translocation of HSP27 into liver cancer cell nucleus may be associated with phosphorylation and O-GlcNAc glycosylation. Oncol. Rep. 28:494-500
44. Han I, Kudlow JE. 1997. Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility. Mol. Cell. Biol. 17:2550-58
45. Han I, Roos MD, Kudlow JE. 1998. Interaction of the transcription factor Sp1 with the nuclear pore protein p62 requires the C-terminal domain of p62. J. Cell. Biochem. 68:50-61
46. Hanover JA. 2010. Epigenetics gets sweeter: O-GlcNAc joins the "histone code." Chem. Biol. 17:1272-74
47. Hanover JA, ForsytheME, Hennessey PT, Brodigan TM, Love DC, et al. 2005. A Caenorhabditis elegans model of insulin resistance: altered macronutrient storage and dauer formation in an OGT-1 knockout. Proc. Natl. Acad. Sci. USA 102:11266-71
48. Hanover JA, Krause MW, Love DC. 2010. The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Biochim. Biophys. Acta 1800:80-95
49. Hanover JA, Krause MW, Love DC. 2012. Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat. Rev. Mol. Cell. Biol. 13:312-21
50. Hanover JA, Yu S, Lubas WB, Shin SH, Ragano-Caracciola M, et al. 2003. Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene. Arch. Biochem. Biophys. 409:287-97
51. Hart GW, Slawson C, Ramirez-Correa G, Lagerlof O. 2011. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu. Rev. Biochem. 80:825-58
52. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, et al. 2008. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl. Acad. Sci. USA 105:17046-49
53. Heiss WD, Szelies B, Kessler J, Herholz K. 1991. Abnormalities of energy metabolism in Alzheimer?s disease studied with PET. Ann. N. Y. Acad. Sci. 640:65-71
54. Henrotin Y, Chevalier X, Herrero-Beaumont G, McAlindon T, Mobasheri A, et al. 2013. Physiological effects of oral glucosamine on joint health: current status and consensus on future research priorities. BMC Res. Notes 6:115
55. Hewagama A, Patel D, Yarlagadda S, Strickland FM, Richardson BC. 2009. Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun. 10:509-16
56. Hewagama A, Richardson B. 2009. The genetics and epigenetics of autoimmune diseases. J. Autoimmun. 33:3-11
57. Hotamisligil GS, Erbay E. 2008. Nutrient sensing and inflammation in metabolic diseases. Nat. Rev. Immunol. 8:923-24
58. HousleyMP, Rodgers JT, Udeshi ND, Kelly TJ, Shabanowitz J, et al. 2008. O-GlcNAc regulates FoxO activation in response to glucose. J. Biol. Chem. 283:16283-92
59. IssadT, Kuo M. 2008.O-GlcNAc modification of transcription factors, glucose sensing and glucotoxicity. Trends Endocrinol. Metab. 19:380-89
60. IssadT, MassonE, Pagesy P. 2010.O-GlcNAc modification, insulin signaling and diabetic complications. Diabetes Metab. 36:423-35
61. Jackson SP, Tjian R. 1988. O-glycosylation of eukaryotic transcription factors: implications for mechanisms of transcriptional regulation. Cell 55:125-33
62. Jacobsen KT, Iverfeldt K. 2011. O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-beta precursor protein (APP). Biochem. Biophys. Res. Commun. 404:882-86
63. Kawauchi K, Araki K, Tobiume K, Tanaka N. 2009. Loss of p53 enhances catalytic activity of IKKβ through O-linked β-N-acetyl glucosamine modification. Proc. Natl. Acad. Sci. USA 106:3431-36
64. Kebede M, Ferdaoussi M, Mancini A, Alquiera T, Kulkarnic RN, et al. 2012. Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O-GlcNAcylation of pancreas-duodenum homeobox-1. Proc. Natl. Acad. Sci. USA 109:2376-81
65. Kim EY, Jeong EH, Park S, Jeong HJ, Edery I, Cho JW. 2012. A role for O-GlcNAcylation in setting circadian clock speed. Genes Dev. 26:490-502
66. Kim HS, Park SY, Choi YR, Kang JG, Joo HJ, et al. 2009. Excessive O-GlcNAcylation of proteins suppresses spontaneous cardiogenesis in ES cells. FEBS Lett. 583:2474-78
67. Kim JW, Dang CV. 2006. Cancer?s molecular sweet tooth and theWarburg effect. Cancer Res. 66:8927-30
68. Kreppel LK, Hart GW. 1999. Regulation of a cytosolic and nuclear O-GlcNAc transferase: role of the tetratricopeptide repeats. J. Biol. Chem. 274:32015-22
69. Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T. 2008. O-GlcNAc modification of FoxO1 increases its transcriptional activity: a role in the glucotoxicity phenomenon? Biochimie 90:679-85
70. Lazarus MB, Nam Y, Jiang J, Sliz P, Walker S. 2011. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 469:564-67
71. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, et al. 2006. Control of developmental regulators by polycomb in human embryonic stem cells. Cell 125:301-13
72. Lefebvre T, Dehennaut V, Guinez C, Olivier S, Drougat L, et al. 2010. Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer?s disease. Biochim. Biophys. Acta 1800:67-79
73. Lehman DM, Fu DJ, Freeman AB, Hunt KJ, Leach RJ, et al. 2005. A single nucleotide polymorphism in MGEA5 encoding O-GlcNAc-selective N-acetyl-beta-D glucosaminidase is associated with type 2 diabetes in Mexican Americans. Diabetes 54:1214-21
74. Lemischka IR. 2010. Hooking up with Oct4. Cell Stem Cell 6:291-92
75. Li MD, RuanHB, Hughes ME, Lee JS, Singh JP, et al. 2013. O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab. 17:303-10
76. Lima VV, Giachini FR, Carneiro FS, Carneiro ZN, Fortes ZB, et al. 2008. Increased vascular O-GlcNAcylation augments reactivity to constrictor stimuli-Vasoactive Peptide Symposium. J. Am. Soc. Hypertens 2:410-17
77. Lima VV, Rigsby CS, Hardy DM, Webb RC, Tostes RC. 2009. O-GlcNAcylation: a novel posttranslational mechanism to alter vascular cellular signaling in health and disease: focus on hypertension. J. Am. Soc. Hypertens. 3:374-87
78. Lin H, Gupta V, Vermilyea MD, Falciani F, Lee JT, et al. 2007. Dosage compensation in the mouse balances up-regulation and silencing of X-linked genes. PLoS Biol. 5:e326
79. Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. 2004. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer?s disease. Proc. Natl. Acad. Sci. USA 101:10804-9
80. Love DC, Ghosh S, Mondoux MA, Fukushige T, Wang P, et al. 2010. Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity. Proc. Natl. Acad. Sci. USA 107:7413-18
81. Love DC, Hanover JA. 2005. The hexosamine signaling pathway: deciphering the "O-GlcNAc code." Sci. STKE 2005:re13
82. Love DC, Krause MW, Hanover JA. 2010. O-GlcNAc cycling: emerging roles in development and epigenetics. Semin. Cell Dev. Biol. 21:646-54
83. Lubas WA, Frank DW, Krause M, Hanover JA. 1997. O-Linked GlcNAc transferase is a conserved nucleocytoplasmic protein containing tetratricopeptide repeats. J. Biol. Chem. 272:9316-24
84. Luo B, Soesanto Y, McClain DA. 2008. Protein modification by O-linked GlcNAc reduces angiogenesis by inhibiting Akt activity in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 28:651-57
85. Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ. 2012. Critical role of O-linked β-N-acetylglucosamine transferase in prostate cancer invasion, angiogenesis, and metastasis. J. Biol. Chem. 287:11070-81
86. Malik VS, Schulze MB, Hu FB. 2006. Intake of sugar-sweetened beverages and weight gain: a systematic review. Am. J. Clin. Nutr. 84:274-88
87. Marshall S, Bacote V, Traxinger RR. 1991. Discovery of a metabolic pathwaymediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J. Biol. Chem. 266:4706-12
88. Medford HM, Chatham JC, Marsh SA. 2012. Chronic ingestion of a Western diet increases O-linked-β-N-acetylglucosamine (O-GlcNAc) protein modification in the rat heart. Life Sci. 90:883-88
89. Mendjan S, Taipale M, Kind J, Holz H, Gebhardt P, et al. 2006. Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. Mol. Cell. 21:811-23
90. Mielke R, Herholz K, Grond M, Kessler J, Heiss WD. 1994. Clinical deterioration in probable Alzheimer?s disease correlates with progressive metabolic impairment of association areas. Dementia 5:36-41
91. Mondoux MA, Love DC, Ghosh SK, Fukushige T, BondM, et al. 2011. O-linked-N-acetylglucosamine cycling and insulin signaling are required for the glucose stress response in Caenorhabditis elegans. Genetics 188:369-82
92. Myers SA, Panning B, Burlingame AL. 2011. Polycomb repressive complex 2 is necessary for the normal site-specific O-GlcNAc distribution inmouse embryonic stem cells. Proc. Natl. Acad. Sci. USA 108:9490-95
93. Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, et al. 2009. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature 460:287-91
94. O?Donnell N, Zachara NE, Hart GW, Marth JD. 2004. Ogt-dependent X-chromosome-linked protein glycosylation is a requisite modification in somatic cell function and embryo viability. Mol. Cell. Biol. 24:1680-90
95. Ozcan S, Andrali SS, Cantrell JE. 2010. Modulation of transcription factor function by O-GlcNAc modification. Biochim. Biophys. Acta 1799:353-64
96. Pardo M, Lang B, Yu L, Prosser H, Bradley A, et al. 2010. An expanded Oct4 interaction network: implications for stem cell biology, development, and disease. Cell Stem Cell 6:382-95
97. Park SY, Kim HS, Kim NH, Ji S, Cha SY, et al. 2010. Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition. EMBO J. 29:3787-96
98. Park SY, Ryu J, Lee W. 2005. O-GlcNAc modification on IRS-1 and Akt2 by PUGNAc inhibits their phosphorylation and induces insulin resistance in rat primary adipocytes. Exp. Mol. Med. 37:220-29
99. Patti ME, Virkamaki A, Landaker EJ, Kahn CR, Yki-Jarvinen H. 1999. Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle. Diabetes 48:1562-71
100. Pettitt DJ, Jovanovic L. 2007. The vicious cycle of diabetes and pregnancy. Curr. Diab. Rep. 7:295-97
101. Pham T, Cornea A, Blick KE, Jenkins A, Scofield RH. 2007. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am. J. Med. Sci. 333:333-39
102. Ragle RL, Sawitzke AD. 2012. Nutraceuticals in the management of osteoarthritis: a critical review. Drugs Aging 29:717-31
103. Rahman MM, Stuchlick O, El-Karim EG, Stuart R, Kipreos ET, Wells L. 2010. Intracellular protein glycosylation modulates insulin mediated lifespan in C. elegans. Aging 2:678-90
104. Ranuncolo SM, Ghosh S, Hanover JA, Hart GW, Lewis BA. 2012. Evidence of the involvement of O-GlcNAc-modified human RNA polymerase II CTD in transcription in vitro and in vivo. J. Biol. Chem. 287:23549-61
105. Reusch JE. 2003. Diabetes, microvascular complications, and cardiovascular complications: What is it about glucose? J. Clin. Invest. 112:986-88
106. Rexach JE, Clark PM, Mason DE, Neve RL, Peters EC, Hsieh-Wilson LC. 2012. Dynamic O-GlcNAc modification regulates CREB-mediated gene expression andmemory formation. Nat. Chem. Biol. 8:253-61
107. Richardson BC. 2008. Epigenetics and autoimmunity. Overview. Autoimmunity 41:243-44
108. Roos MD, Su K, Baker J.R., Kudlow JE. 1997. O glycosylation of an Sp1-derived peptide blocks known Sp1 protein interactions. Mol. Cell. Biol. 17:6472-80
109. Roperoa AB, Alonso-Magdalenab P, Quesadaa I, Nadal A. 2008. The role of estrogen receptors in the control of energy and glucose homeostasis. Steriods 73:874-79
110. Roquemore EP, ChevrierMR, Cotter RJ, Hart GW. 1996. Dynamic O-GlcNAcylation of the small heat shock protein αB-crystallin. Biochemistry 35:3578-86
111. Rossetti L. 2000. Perspective: hexosamines and nutrient sensing. Endocrinology 141:1922-25
112. Ruderman NB, Williamson J.R., Brownlee M. 1992. Glucose and diabetic vascular disease. FASEB J. 6:2905-14
113. Sakabe K, Hart GW. 2010. O-GlcNAc transferase regulates mitotic chromatin dynamics. J. Biol. Chem. 285:34460-68
114. Sakabe K, Wang Z, Hart GW. 2010. Beta-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc. Natl. Acad. Sci. USA 107:19915-20
115. Sakaidani Y, Nomura T, Matsuura A, Ito M, Suzuki E, et al. 2011. O-Linked-N-acetylglucosamine on extracellular protein domains mediates epithelial cell-matrix interactions. Nat. Commun. 13:583
116. Sayeski PP, Kudlow JE. 1996. Glucose metabolism to glucosamine is necessary for glucose stimulation of transforming growth factor-alpha gene transcription. J. Biol. Chem. 271:15237-43
117. Scroggie DA, Albright A, HarrisMD. 2003. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, doubleblinded, randomized clinical trial. Arch. Intern. Med. 163:1587-90
118. Sekine O, LoveDC, Rubenstein DS, Hanover JA. 2010. Blocking O-linkedGlcNAc cycling in Drosophila insulin-producing cells perturbs glucose-insulin homeostasis. J. Biol. Chem. 285:38684-91
119. Shafi R, Iyer SPN, Ellies LG, O?Donnell N, Marek KW, et al. 2000. The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc. Natl. Acad. Sci. USA 97:5735-39
120. Shi Y, Tomic J, Wen F, Shaha S, Bahlo A, et al. 2010. Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia. Leukemia 24:1588-98
121. Shin SH, Love DC, Hanover JA. 2011. Elevated O-GlcNAc-dependent signaling through inducible mOGT expression selectively triggers apoptosis. Amino Acids 40:885-93
122. Simanek EE, Huang D-H, Pasternack L, Machajewski TD, Seitz O, et al. 1998. Glycosylation of threonine of the repeating unit ofRNApolymerase II with beta-linkedN-acetylglucosamine leads to a turnlike structure. J. Am. Chem. Soc. 120:11567-75
123. Sinclair DA, Syrzycka M, MacauleyMS, RastgardaniT, Komljenovic I, et al. 2009. Drosophila O-GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs (sxc). Proc. Natl. Acad. Sci. USA 106:13427-32
124. Slawson C, Lakshmanan T, Knapp S, Hart GW. 2008. A mitotic GlcNAcylation/phosphorylation signaling complex alters the posttranslational state of the cytoskeletal protein vimentin. Mol. Biol. Cell. 19:4130-40
125. Slawson C, Zachara NE, Vosseller K, Cheung WD, Lane MD, Hart GW. 2005. Perturbations in O-linked beta-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J. Biol. Chem. 280:32944-56
126. Soesanto YA, Luo B, Jones D, Taylor R, Gabrielsen JS, et al. 2008. Regulation of Akt signaling by O-GlcNAc in euglycemia. Am. J. Physiol. Endocrinol. Metab. 295:E974-80
127. Srikanth B, Vaidya MM, Kalraiya RD. 2010. O-GlcNAcylation determines the solubility, filament organization, and stability of keratins 8 and 18. J. Biol. Chem. 285:34062-71
128. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, et al. 2005. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer?s disease-is this type 3 diabetes? J. Alzheimers Dis. 7:63-80
129. van den Berg DL, Snoek T, Mullin NP, Yates A, Bezstarosti K, et al. 2010. An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell 6:369-81
130. Vella P, Scelfo A, Jammula S, Chiacchiera F, Williams K, et al. 2013. TET proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol. Cell 49:645-56
131. Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L. 1998. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393:684-88
132. Wang P, Lazarus BD, Forsythe ME, Love DC, Krause MW, Hanover JA. 2012. O-GlcNAc cycling mutants modulate proteotoxicity in Caenorhabditis elegans models of human neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 109:17669-74
133. Wang Z, Udeshi ND, Slawson C, Compton PD, Sakabe K, et al. 2010. Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. Sci. Signal. 3:ra2
134. Warburg O. 1956. On respiratory impairment in cancer cells. Science 124:269-70
135. Wells L, Vosseller K, Cole RN, Cronshaw JM, Matunis MJ, Hart GW. 2002. Mapping sites of O-GlcNAc modification using affinity tags for serine and threonine post-translational modifications. Mol. Cell. Proteomics 1:791-804
136. Whelan SA, Dias WB, Thiruneelakantapillai L, Lane MD, HartGW. 2010. Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-linked beta-N-acetylglucosamine in 3T3-L1 adipocytes. J. Biol. Chem. 285:5204-11
137. Whelan SA, Lane MD, Hart GW. 2008. Regulation of the O-linked beta-N-acetylglucosamine transferase by insulin signaling. J. Biol. Chem. 283:21411-17
138. Wotton KR, Weierud FK, Juarez-Morales JL, Alvares LE, Dietrich S, Lewis KE. 2009. Conservation of gene linkage in dispersed vertebrate NK homeobox clusters. Dev. Genes Evol. 219:481-96
139. Yanagisawa M, Planel E, Ishiguro K, Fujita SC. 1999. Starvation induces tau hyperphosphorylation in mouse brain: implications for Alzheimer?s disease. FEBS Lett. 461:329-33
140. Yang WH, Kim JE, Nam HW, Ju JW, Kim HS, et al. 2006. Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat. Cell. Biol. 8:1074-83
141. Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, et al. 2008. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 451:964-69
142. Yang X, Zhang F, Kudlow JE. 2002. Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression. Cell 110:69-80
143. Yang YR, Song M, Lee H, Jeon Y, Choi EJ, et al. 2012. O-GlcNAcase is essential for embryonic development and maintenance of genomic stability. Aging Cell 11:439-48
144. Yki-Jarvinen H, Virkamaki A, DanielsMC, McClain D, Gottschalk WK. 1998. Insulin and glucosamine infusions increase O-linked N-acetyl-glucosamine in skeletal muscle proteins in vivo. Metabolism 47:449-55
145. Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, et al. 2012. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat. Chem. Biol. 8:393-99
146. Zachara NE, Hart GW. 2004. O-GlcNAc a sensor of cellular state: the role of nucleocytoplasmic glycosylation in modulating cellular function in response to nutrition and stress. Biochim. Biophys. Acta 1673:13-28
147. Zachara NE, Hart GW. 2004. O-GlcNAc modification: a nutritional sensor that modulates proteasome function. Trends Cell. Biol. 14:218-21
148. Zachara NE, O?Donnell N, Cheung WD, Mercer JJ, Marth JD, Hart GW. 2004. Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. J. Biol. Chem. 279:30133-42
149. Zhang F, Su K, Yang X, Bowe DB, Paterson AJ, Kudlow JE. 2003. O-GlcNAc modification is an endogenous inhibitor of the proteasome. Cell 115:715-25
150. Zhang S, Roche K, Nasheuer HP, Lowndes NF. 2011. Modification of histones by sugar β-N-acetylglucosamine (GlcNAc) occurs on multiple residues, including histone H3 serine 10, and is cell cycle-regulated. J. Biol. Chem. 286:37483-95