Journal of Molecular Medicine

, Volume 83, Issue 7, pp 504–513

SUMO wrestling with type 1 diabetes

  • Manyu Li
  • Dehuang Guo
  • Carlos M. Isales
  • Decio L. Eizirik
  • Mark Atkinson
  • Jin-Xiong She
  • Cong-Yi Wang
Review

Abstract

Post-translational modification of proteins by phosphorylation, methylation, acetylation, or ubiquitylation represent central mechanisms through which various biological processes are regulated. Reversible covalent modification (i.e., sumoylation) of proteins by the small ubiquitin-like modifier (SUMO) has also emerged as an important mechanism contributing to the dynamic regulation of protein function. Sumoylation has been linked to the pathogenesis of a variety of disorders including Alzheimer’s disease (AD), Huntington’s disease (HD), and type 1 diabetes (T1D). Advances in our understanding of the role of sumoylation suggested a novel regulatory mechanism for the regulation of immune responsive gene expression. In this review, we first update recent advances in the field of sumoylation, then specifically evaluate its regulatory role in several key signaling pathways for immune response and discuss its possible implication in T1D pathogenesis.

Keywords

SUMO Sumoylation Immune Regulation Transcription Autoimmunity 

Abbreviations

ERK

Extracellular signal-regulated protein kinase

JAK

Janus kinase

JNK

c-Jun N-terminal kinase

PIAS

Protein inhibitors of activated stats

RanBP

Ran binding protein

STAT

Signal transducers and activators of transcription

T1D

Type 1 diabetes

References

  1. 1.
    Seeler JS, Dejean A (2003) Nuclear and unclear functions of SUMO. Nat Rev Mol Cell Biol 4:690–699CrossRefPubMedGoogle Scholar
  2. 2.
    Su HL, Li SS (2002) Molecular features of human ubiquitin-like SUMO genes and their encoded proteins. Gene 296:65–73Google Scholar
  3. 3.
    Guo D, Li M, Zhang Y et al (2004) A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet 36:837–841Google Scholar
  4. 4.
    Bohren KM, Nadkarni V, Song JH, Gabbay KH, Owerbach D (2004) A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. J Biol Chem 279:27233–27238Google Scholar
  5. 5.
    Gill G (2004) SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev 18:2046–2059Google Scholar
  6. 6.
    Johnson ES (2004) Protein modification by SUMO. Annu Rev Biochem 73:355–382CrossRefPubMedGoogle Scholar
  7. 7.
    Muller S, Ledl A, Schmidt D (2004) SUMO: a regulator of gene expression and genome integrity. Oncogene 23:1998–2008CrossRefPubMedGoogle Scholar
  8. 8.
    Desterro JM, Rodriguez MS, Hay RT (1998) SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell 2:233–239Google Scholar
  9. 9.
    Pichler A, Knipscheer P, Saitoh H, Sixma TK, Melchior F (2004) The RanBP2 SUMO E3 ligase is neither. Nat Struct Mol Biol 11:984–991Google Scholar
  10. 10.
    Shuai K (2000) Modulation of STAT signaling by STAT-interacting proteins. Oncogene 19:2638–2644Google Scholar
  11. 11.
    Wong KA, Kim R, Christofk H, Gao J, Lawson G, Wu H (2004) Protein inhibitor of activated STAT Y (PIASy) and a splice variant lacking exon 6 enhance sumoylation but are not essential for embryogenesis and adult life. Mol Cell Biol 24:5577–5586Google Scholar
  12. 12.
    Roth W, Sustmann C, Kieslinger M et al (2004) PIASy-deficient mice display modest defects in IFN and Wnt signaling. J Immunol 173:6189–6199Google Scholar
  13. 13.
    Freiman RN, Tjian R (2003) Regulating the regulators: lysine modifications make their mark. Cell 112:11–17Google Scholar
  14. 14.
    Song J, Durrin LK, Wilkinson TA, Krontiris TG, Chen Y (2004) Identification of a SUMO-binding motif that recognizes SUMO-modified proteins. Proc Natl Acad Sci USA 101:14373–14378Google Scholar
  15. 15.
    Tatham MH, Jaffray E, Vaughan OA et al (2001) Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem 276:35368–35374Google Scholar
  16. 16.
    Li Y, Wang H, Wang S, Quon D, Liu YW, Cordell B (2003) Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci USA 100:259–264Google Scholar
  17. 17.
    Neve RL (2003) A new wrestler in the battle between alpha- and beta-secretases for cleavage of APP. Trends Neurosci 26:461–463Google Scholar
  18. 18.
    Pichler A, Gast A, Seeler JS, Dejean A, Melchior F (2002) The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108:109–120CrossRefPubMedGoogle Scholar
  19. 19.
    Matunis MJ, Coutavas E, Blobel G (1996) A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J Cell Biol 135:1457–1470CrossRefPubMedGoogle Scholar
  20. 20.
    Panse VG, Hardeland U, Werner T, Kuster B, Hurt E (2004) A proteome-wide approach identifies sumoylated substrate proteins in yeast. J Biol Chem 279:41346–41351Google Scholar
  21. 21.
    Wohlschlegel JA, Johnson ES, Reed SI, Yates JR III (2004) Global analysis of protein sumoylation in Saccharomyces cerevisiae. J Biol Chem 279:45662–45668Google Scholar
  22. 22.
    Zhou W, Ryan JJ, Zhou H (2004) Global analyses of sumoylated proteins in Saccharomyces cerevisiae. Induction of protein sumoylation by cellular stresses. J Biol Chem 279:32262–32268Google Scholar
  23. 23.
    Vertegaal AC, Ogg SC, Jaffray E et al (2004) A proteomic study of SUMO-2 target proteins. J Biol Chem 279:33791–33798Google Scholar
  24. 24.
    Zhao Y, Kwon SW, Anselmo A, Kaur K, White MA (2004) Broad spectrum identification of cellular small ubiquitin-related modifier (SUMO) substrate proteins. J Biol Chem 279:20999–21002Google Scholar
  25. 25.
    Li T, Evdokimov E, Shen RF et al (2004) Sumoylation of heterogeneous nuclear ribonucleoproteins, zinc finger proteins, and nuclear pore complex proteins: a proteomic analysis. Proc Natl Acad Sci USA 101:8551–8556Google Scholar
  26. 26.
    Rosas-Acosta G, Russell WK, Deyrieux A, Russell DH, Wilson VG (2005) A universal strategy for proteomic studies of SUMO and other ubiquitin-like modifiers. Mol Cell Proteomics 4:56–72Google Scholar
  27. 27.
    Saitoh H, Hinchey J (2000) Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem 275:6252–6258Google Scholar
  28. 28.
    Hilgarth RS, Murphy LA, Skaggs HS, Wilkerson DC, Xing H, Sarge KD (2004) Regulation and function of SUMO modification. J Biol Chem 279(52):53899–53902Google Scholar
  29. 29.
    Everett RD, Lomonte P, Sternsdorf T, van Driel R, Orr A (1999) Cell cycle regulation of PML modification and ND10 composition. J Cell Sci 112:4581–4588Google Scholar
  30. 30.
    Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A (2000) c-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem 275:13321–13329Google Scholar
  31. 31.
    Verger A, Perdomo J, Crossley M (2003) Modification with SUMO. A role in transcriptional regulation. EMBO Rep 4:137–142CrossRefPubMedGoogle Scholar
  32. 32.
    Caamano J, Hunter CA (2002) NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions. Clin Microbiol Rev 15:414–429Google Scholar
  33. 33.
    Takaesu G, Kishida S, Hiyama A et al (2000) TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell 5:649–658CrossRefPubMedGoogle Scholar
  34. 34.
    Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630–1635Google Scholar
  35. 35.
    Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421Google Scholar
  36. 36.
    Ihle JN (1996) STATs: signal transducers and activators of transcription. Cell 84:331–334Google Scholar
  37. 37.
    Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285:1–24Google Scholar
  38. 38.
    Wang T, Niu G, Kortylewski M et al (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48–54CrossRefGoogle Scholar
  39. 39.
    Aaronson DS, Horvath CM (2002) A road map for those who don’t know JAK-STAT. Science 296:1653–1655Google Scholar
  40. 40.
    Davoodi-Semiromi A, Laloraya M, Kumar GP, Purohit S, Jha RK, She JX (2004) A mutant Stat5b with weaker DNA binding affinity defines a key defective pathway in nonobese diabetic mice. J Biol Chem 279:11553–11561Google Scholar
  41. 41.
    Flodstrom-Tullberg M, Yadav D, Hagerkvist R et al (2003) Target cell expression of suppressor of cytokine signaling-1 prevents diabetes in the NOD mouse. Diabetes 52:2696–2700PubMedGoogle Scholar
  42. 42.
    Darville MI, Eizirik DL (1998) Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells. Diabetologia 41:1101–1108CrossRefPubMedGoogle Scholar
  43. 43.
    Chung CD, Liao J, Liu B et al (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science 278:1803–1805Google Scholar
  44. 44.
    Liu B, Gross M, Hoeve J ten, Shuai K (2001) A transcriptional corepressor of Stat1 with an essential LXXLL signature motif. Proc Natl Acad Sci USA 98:3203–3207Google Scholar
  45. 45.
    Liu B, Liao J, Rao X et al (1998) Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci USA 95:10626–10631Google Scholar
  46. 46.
    Arora T, Liu B, He H et al (2003) PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. J Biol Chem 278:21327–21330Google Scholar
  47. 47.
    Ungureanu D, Vanhatupa S, Kotaja N et al (2003) PIAS proteins promote SUMO-1 conjugation to STAT1. Blood 102:3311–3313Google Scholar
  48. 48.
    Rogers RS, Horvath CM, Matunis MJ (2003) SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. J Biol Chem 278:30091–30097Google Scholar
  49. 49.
    Wormald S, Hilton DJ (2004) Inhibitors of cytokine signal transduction. J Biol Chem 279:821–824CrossRefGoogle Scholar
  50. 50.
    Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3:859–868Google Scholar
  51. 51.
    Vogt PK (2002) Fortuitous convergences: the beginnings of JUN. Nat Rev Cancer 2:465–469Google Scholar
  52. 52.
    Ameyar M, Wisniewska M, Weitzman JB (2003) A role for AP-1 in apoptosis: the case for and against. Biochimie 85:747–752Google Scholar
  53. 53.
    Foletta VC, Segal DH, Cohen DR (1998) Transcriptional regulation in the immune system: all roads lead to AP-1. J Leukoc Biol 63:139–152Google Scholar
  54. 54.
    Eizirik DL, Mandrup-Poulsen T (2001) A choice of death—the signal transduction of immune-mediated beta-cell apoptosis. Diabetologia 44:2115–2133CrossRefPubMedGoogle Scholar
  55. 55.
    Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M (1999) Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev 13:1297–1308Google Scholar
  56. 56.
    Funakoshi-Tago M, Tago K, Sonoda Y, Tominaga S, Kasahara T (2003) TRAF6 and C-SRC induce synergistic AP-1 activation via PI3-kinase-AKT-JNK pathway. Eur J Biochem 270:1257–1268Google Scholar
  57. 57.
    Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4:E131–E136Google Scholar
  58. 58.
    Chanda SK, White S, Orth AP et al (2003) Genome-scale functional profiling of the mammalian AP-1 signaling pathway. Proc Natl Acad Sci USA 100:12153–12158Google Scholar
  59. 59.
    Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40CrossRefPubMedGoogle Scholar
  60. 60.
    Westwick JK, Weitzel C, Minden A, Karin M, Brenner DA (1994) Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. J Biol Chem 269:26396–26401Google Scholar
  61. 61.
    Lgssiar A, Hassan M, Schott-Ohly P et al (2004) Interleukin-11 inhibits NF-kappaB and AP-1 activation in islets and prevents diabetes induced with streptozotocin in mice. Exp Biol Med 229:425–436Google Scholar
  62. 62.
    Bennett BL, Satoh Y, Lewis AJ (2003) JNK: a new therapeutic target for diabetes. Curr Opin Pharmacol 3:420–425Google Scholar
  63. 63.
    Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A (2000) c-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem 275:13321–13329Google Scholar
  64. 64.
    Schmidt D, Muller S (2002) Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci USA 99:2872–2877Google Scholar
  65. 65.
    Kotaja N, Karvonen U, Janne OA, Palvimo JJ (2002) PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Mol Cell Biol 22:5222–5234Google Scholar
  66. 66.
    Salinas S, Briancon-Marjollet A, Bossis G et al (2004) SUMOylation regulates nucleo-cytoplasmic shuttling of Elk-1. J Cell Biol 165:767–773Google Scholar
  67. 67.
    Matsuzaki K, Minami T, Tojo M et al (2003) Serum response factor is modulated by the SUMO-1 conjugation system. Biochem Biophys Res Commun 306:32–38Google Scholar
  68. 68.
    Tsan MF, Gao B (2004) Cytokine function of heat shock proteins. Am J Physiol Cell Physiol 286:C739–C744Google Scholar
  69. 69.
    Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858CrossRefPubMedGoogle Scholar
  70. 70.
    Srivastava P (2002) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 20:395–425CrossRefPubMedGoogle Scholar
  71. 71.
    Larsen PM, Fey SJ, Larsen MR et al (2001) Proteome analysis of interleukin-1beta-induced changes in protein expression in rat islets of Langerhans. Diabetes 50:1056–1063PubMedGoogle Scholar
  72. 72.
    John NE, Andersen HU, Fey SJ et al (2000) Cytokine- or chemically derived nitric oxide alters the expression of proteins detected by two-dimensional gel electrophoresis in neonatal rat islets of Langerhans. Diabetes 49:1819–1829Google Scholar
  73. 73.
    Cardozo AK, Heimberg H, Heremans Y et al (2001) A comprehensive analysis of cytokine-induced and nuclear factor-kappa B-dependent genes in primary rat pancreatic beta-cells. J Biol Chem 276:48879–48886CrossRefPubMedGoogle Scholar
  74. 74.
    Asea A, Kraeft SK, Kurt-Jones EA et al (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442CrossRefPubMedGoogle Scholar
  75. 75.
    Ohashi K, Burkart V, Flohe S, Kolb H (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 164:558–561PubMedGoogle Scholar
  76. 76.
    Moroi Y, Mayhew M, Trcka J et al (2000) Induction of cellular immunity by immunization with novel hybrid peptides complexed to heat shock protein 70. Proc Natl Acad Sci USA 97:3485–3490Google Scholar
  77. 77.
    Cho BK, Palliser D, Guillen E et al (2000) A proposed mechanism for the induction of cytotoxic T lymphocyte production by heat shock fusion proteins. Immunity 12:263–272Google Scholar
  78. 78.
    Binder RJ, Anderson KM, Basu S, Srivastava PK (2000) Cutting edge: heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo. J Immunol 165:6029–6035Google Scholar
  79. 79.
    Wang Y, Kelly CG, Karttunen JT et al (2001) CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 15:971–983Google Scholar
  80. 80.
    Wallin RP, Lundqvist A, More SH, von Bonin A, Kiessling R, Ljunggren HG (2002) Heat-shock proteins as activators of the innate immune system. Trends Immunol 23:130–135Google Scholar
  81. 81.
    Bausinger H, Lipsker D, Ziylan U et al (2002) Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur J Immunol 32:3708–3713Google Scholar
  82. 82.
    Millar DG, Garza KM, Odermatt B et al (2003) Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med 9:1469–1476Google Scholar
  83. 83.
    Liu B, Dai J, Zheng H, Stoilova D, Sun S, Li Z (2003) Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proc Natl Acad Sci USA 100:15824–15829Google Scholar
  84. 84.
    Fink AL (1999) Chaperone-mediated protein folding. Physiol Rev 79:425–449PubMedGoogle Scholar
  85. 85.
    Le Goff P, Le Drean Y, Le Peron C, Jossic-Corcos C, Ainouche A, Michel D (2004) Intracellular trafficking of heat shock factor 2. Exp Cell Res 294:480–493Google Scholar
  86. 86.
    He H, Soncin F, Grammatikakis N et al (2003) Elevated expression of heat shock factor (HSF) 2A stimulates HSF1-induced transcription during stress. J Biol Chem 278:35465–35475Google Scholar
  87. 87.
    Alastalo TP, Hellesuo M, Sandqvist A, Hietakangas V, Kallio M, Sistonen L (2003) Formation of nuclear stress granules involves HSF2 and coincides with the nucleolar localization of Hsp70. J Cell Sci 116:3557–3570Google Scholar
  88. 88.
    Hilgarth RS, Hong Y, Park-Sarge OK, Sarge KD (2003) Insights into the regulation of heat shock transcription factor 1 SUMO-1 modification. Biochem Biophys Res Commun 303:196–200Google Scholar
  89. 89.
    Hietakangas V, Ahlskog JK, Jakobsson AM et al (2003) Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol Cell Biol 23:2953–2968CrossRefPubMedGoogle Scholar
  90. 90.
    Hilgarth RS, Hong Y, Park-Sarge OK, Sarge KD (2003) Insights into the regulation of heat shock transcription factor 1 SUMO-1 modification. Biochem Biophys Res Commun 303:196–200Google Scholar
  91. 91.
    Hietakangas V, Ahlskog JK, Jakobsson AM et al (2003) Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol Cell Biol 23:2953–2968CrossRefPubMedGoogle Scholar
  92. 92.
    De Bosscher K, Vanden Berghe W, Haegeman G (2003) The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. Endocr Rev 24:488–522Google Scholar
  93. 93.
    Smith DF, Whitesell L, Katsanis E (1998) Molecular chaperones: biology and prospects for pharmacological intervention. Pharmacol Rev 50:493–514Google Scholar
  94. 94.
    Pratt WB, Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev 18:306–360Google Scholar
  95. 95.
    Tian S, Poukka H, Palvimo JJ, Janne OA (2002) Small ubiquitin-related modifier-1 (SUMO-1) modification of the glucocorticoid receptor. Biochem J 367:907–911Google Scholar
  96. 96.
    Le Drean Y, Mincheneau N, Le Goff P, Michel D (2002) Potentiation of glucocorticoid receptor transcriptional activity by sumoylation. Endocrinology 143:3482–3489Google Scholar
  97. 97.
    Mathis D, Vence L, Benoist C (2001) Beta-cell death during progression to diabetes. Nature 414:792–798CrossRefPubMedGoogle Scholar
  98. 98.
    Onengut-Gumuscu S, Concannon P (2002) Mapping genes for autoimmunity in humans: type 1 diabetes as a model. Immunol Rev 190:182–194Google Scholar
  99. 99.
    Owerbach D, Pina L, Gabbay KH (2004) A 212-kb region on chromosome 6q25 containing the TAB2 gene is associated with susceptibility to type 1 diabetes. Diabetes 53:1890–1893Google Scholar
  100. 100.
    Rasschaert J, Liu D, Kutlu B et al (2003) Global profiling of double stranded RNA- and IFN-gamma-induced genes in rat pancreatic beta cells. Diabetologia 46:1641–1657CrossRefPubMedGoogle Scholar
  101. 101.
    Gylvin T, Bergholdt R, Nerup J, Pociot F (2002) Characterization of a nuclear-factor-kappa B (NFkappaB) genetic marker in type 1 diabetes (T1DM) families. Genes Immun 3:430–432Google Scholar
  102. 102.
    Hegazy DM, O’Reilly DA, Yang BM, Hodgkinson AD, Millward BA, Demaine AG (2001) NFkappaB polymorphisms and susceptibility to type 1 diabetes. Genes Immun 2:304–308Google Scholar
  103. 103.
    Mabley JG, Hasko G, Liaudet L et al (2002) NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes. J Endocrinol 173:457–464Google Scholar
  104. 104.
    Lamhamedi-Cherradi SE, Zheng S, Hilliard BA et al (2003) Transcriptional regulation of type I diabetes by NF-kappa B. J Immunol 171:4886–4892Google Scholar
  105. 105.
    Smyth D, Lowe CE, Howon JMM et al (2005) Lack of support for a genetic association of the SUMO4 Met55Val polymorphism with type 1 diabetes. Nat Genet (in press)Google Scholar
  106. 106.
    Qu H, Bharaj B, Liu X-Q et al (2005) Is the association of SUMO4 with type 1 diabetes dependent on ethnic background? Nat Genet (in press)Google Scholar
  107. 107.
    Park Y, Park S, Kang J et al (2005) Additional support for a genetic association between SUMO4 and type 1 diabetes in the Korean population. Nat Genet (in press)Google Scholar
  108. 108.
    Wang C-Y, Yang P, She J-X (2005) Genetic heterogeneity of the IDDM5 (SUMO4) locus. Nat Genet (in press)Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Manyu Li
    • 1
  • Dehuang Guo
    • 1
  • Carlos M. Isales
    • 2
  • Decio L. Eizirik
    • 3
  • Mark Atkinson
    • 4
  • Jin-Xiong She
    • 1
  • Cong-Yi Wang
    • 1
  1. 1.Center for Biotechnology and Genomic MedicineMedical College of GeorgiaAugustaUSA
  2. 2.Department of MedicineMedical College of GeorgiaAugustaUSA
  3. 3.Laboratory of Experimental MedicineUniversite Libre de BruxellesBrusselsBelgium
  4. 4.Department of Pathology, Immunology and Laboratory Medicine, College of MedicineUniversity of FloridaGainesvilleUSA

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