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Structural diversity of mucins : Significance in infection and immunity

Research Project

Project/Area Number 12307054
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

IRIMURA Tatsuro  The University of Tokyo, Graduate school of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (80092146)

Co-Investigator(Kenkyū-buntansha) NAGAI-DENDA Kaori  The University of Tokyo, Graduate school of Pharmaceutical Sciences, Research Associate, 大学院・薬学系研究科, 助手 (00313122)
TSUIJI Makoto  The University of Tokyo, Graduate school of Pharmaceutical Sciences, Research Associate, 大学院・薬学系研究科, 助手 (90302611)
HIGASHI Nubuaki  The University of Tokyo, Graduate school of Pharmaceutical Sciences, Lecturer, 大学院・薬学系研究科, 講師 (40302616)
Project Period (FY) 2000 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥43,090,000 (Direct Cost: ¥36,700,000、Indirect Cost: ¥6,390,000)
Fiscal Year 2003: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
Fiscal Year 2002: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2001: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2000: ¥15,400,000 (Direct Cost: ¥15,400,000)
KeywordsMucin / MUC2 / UDP-GalNAc-polypeptide / O-glycosylation / Lectin / Ebola virus / amoeba infection / macrophage / 腸管上皮細胞 / グラム陰性菌 / 生体防御
Research Abstract

The specific aim of this proposal was to prove or disprove a hypothesis whether mucins, epithelial surface glycoproteins with a high degree of O-glycosylation, played roles as specific defense molecules against parasites, such as protozoa, bacteria, and viruses. The following conclusions were obtained.
(1)Epithelial mucins were highly diverse in their glycosylation profiles.
(2)The specific glycosylation of mucins were regulated in a high degree of fidelity by concerted actions of multiple UDP-GalNAc-polypeptide N-acetylgalactosaminyltransferases (ppGalNAc Ts).
(3)A Th2 cytokine, IL-4, drastically enhance the expression of a few ppGalNAc Ts (ppGalNAc T1, 4, and 7), which resulted in an alteration of glycosylation profiles of mucin 2.
(4)After such alterations, the secreted mucins changed its reactivity with lectins, carbohydrate-binding proteins.
(5)Various oligosaccharide-polypeptide complexes were prepared by the use of recombinant ppGalNAc Ts and other glycosyltransferases in vitro. They were tested to determine the specificity of lectins toward mucin motifs.
(6)Variations in mucin motifs on pathogens, such as the surface coat glycoproteins of Ebola virus, were also shown to play important roles in the regulation of infective processes.
(7)In these processes, C-type/galactose-type lectins on macrophages and dendritic cells were shown to be significantly involved.

Report

(5 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (65 results)

All Other

All Publications (65 results)

  • [Publications] Miyahara N, et al.: "Expression of UDP-N-acetyl-alpha-D-galactosamine-potypeptide N-acetylgalactosaminyltransferase isozyme 3 in the subserosal layer correlates with postsurgical survival of pathological tumor stage 2 carcinoma of the gallbladder."Clinical Can Res. 10. 2090-2099 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tamada Y, et al.: "Model for paraaortic lymph node metastasis produced by orthotopic implantation of ovarian carcinoma cells in athymic nude mice."Euro J.of Can.. 40. 158-163 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horinouchi M, et al.: "Expression of Different Glycoforms of Membrane Mucin (MUC1) and Secretory Mucin (MUC2, MUC5AC and MUC6) in Pancreatic Neoplasms."Acta Histochem.Cytochem.. 36(5). 443-453 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsuiji H, et al.: "Aberrant O-glycosylation inhibits stable expression of dysadherin, a carcinoma-associated antigen, and facilitates cell-cell adhesion."Glycobiology. 13. 521-527 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kanoh A, et al.: "Expression levels of FUT6 gene transfected into human colon carcinoma cells switch two sialyl-Lewis X-related carbohydrate antigens with distinct properties in cell adhesion."Biochem biophi res com.. 303. 896-901 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyahara N, Shoda J, Kawamoto T, Furukawa M, Ueda T, Todoroki T, Tanaka N, Matsuo K, Yamada Y, Kohno K, Irimura T.: "Expression of UDP-N Acetylgalactosaminyl transferase isozyme 3 in the subserosal layer correlates with postsurgical survival of pathological tumor stage 2 carcinoma of the gallbladder."Clinical Can Res. 10. 2090-2099 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tamada Y, Aoki D, Nozawa S, Irimura T: "Model for paraaortic lymph node metastasis produced by orthotopic implantation of ovarian carcinoma cells in athymic nude mice."Eur J Can. 40. 158-163 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horinouchi M, Nagata K, Nakamura A, Goto M, Takao S, Sakamoto M, Fukushima N, Miwa A, Irimura T, Imai K, Sato E, Yonezawa S.: "Expression of Different Glycoforms of Membrane Mucin (MUC1) and Secretory Mucin (MUC2, MUCSAC and MUC6) in Pancreatic Neoplasms."Acta Histochem.Cytochem.. 36(5). 443-453 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tsuiji H, Takasaki, Sakamoto M, Irimura T, Hirohashi S: "Aberrant O-glycosylation inhibits stable expression of dysadherin, a carcinoma-associated antigen, and facilitates cell-cell adhesion."Glycobiology. 13. 521-527 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kanoh A, Ota M, Narimatsu H, Irimura T.: "Expression levels of fut6 gene transfected into human colon carcinoma cells swich two sialyl-lewis x-related carbohydrate antigens with distinct properties in cell adhesion."Biochem biophi res com.. 303. 896-901 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyahara N, et al.: "Expression of UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase isozyme 3 in the subserosal layer correlates with postsurgical survival of pathological tumor stage 2 carcinoma of the gallbladder."Clinical Can Res. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hamada T, et al.: "Mucin Expression in Pleomorphic Adenoma of Salivary Gland : A Potential Role of MUC1 as a Marker to Predict a Recurrence."J.Clinical pathology. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tamada Y, et al.: "Model for paraaortic lymph node metastasis produced by orthotopic implantation of ovarian carcinoma cells in athymic nude mice."Euro J. of Can.. 40. 158-163 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Horinouchi M, et al.: "Expression of Different Glycoforms of Membrane Mucin (MUC1) and Secretory Mucin (MUC2,MUC5AC and MUC6) in Pancreatic Neoplasms."Acta Histochem.Cytochem.. 36(5). 443-453 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tsuiji H, et al.: "Aberrant O-glycosylation inhibits stable expression of dysadherin, a carcinoma-associated antigen, and facilitates cell-cell adhesion."Glycobiology. 13. 521-527 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanoh A, et al.: "Expression levels of FUT6 gene transfected into human colon carcinoma cells switch two sialyl-Lewis X-related carbohydrate antigens with distinct properties in cell adhesion."Biochem biophi res com.. 303. 896-901 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Higashi N: "The macrophage C-type lectin specific for galactose/N-acetylgalactosamine is an endocytic receptor expressed on monocyte-derived immature dendritic cells"J Biol Chem.. 277. 20686-20693 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Bando T: "Basic studies on a labeled anti-mucin antibody detectable by infrared-fluorescence endoscopy"J Gastroenterol.. 37. 260-269 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Onami TM: "The generation of mice deficient for the macrophage galactose and N-acetylgalactosamine specific lectin : limited role in lymphoid and erythroid homeostasis, and evidence for multiple lectins"Mol Cell Biol.. 22. 5173-5181 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsuji T: "Regulation of melanoma cell migration and invasion by laminin-5 and α3β1 integrin(VLA-3)"Clin Exp Metastasis. 19. 127-134 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Denda-Nagai K: "Macrophage C-type lectin(MGL)on bone marrow-derived immature dendritic cells is involved in the recognition and internalization of glycosylated antigens"Glycobiology. 12. 443-450 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Higashi N: "Human macrophage lectin specific for galactose/N-acetylgalactosamine is a marker for cells at an intermediate stage in their differentiation from monocytes into macrophages"Int Immunol. 14. 545-554 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsuiji M: "Molecular cloning and characterization of a novel mouse macrophage C-type lectin, mMGL2, which has a distinct carbohydrate specificity from mMGL1"J Biol Chem.. 277. 28892-28901 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kato T: "Characterization of the primoter for the mouse a3 integrin gene involvement of the ets-family of transcription factors in the promoter actlvity"Eur J Biochem.. 269. 4524-4532 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takeuchi H: "The epitope recognized by the unique anti-MUC1 monoclonal antibody MY.1E12 involves sialyl α2-3galactosyl β1-3N-acetylgalactosaminide linked to a distinct threonine residue in the MUC1 tandem repeat"J Immunol Methods. 270. 199-209 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Higashi N: "Redistribution of fibroblasts and macrophages as micrometastases develop into established liver metastases"Cline Exp Metastasis. 19. 631-638 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sugahara D: "Fluorescence Labeling of Oligosaccharides Useful in the Determination of Molecular Interactions"Analytical Sci.. 19. 167-169 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takeuchi H: "O-GalNAc incorporation into a cluster acceptor site of three consecutive threonines, Distinct specificity of GalNAc-transferase isoforms"Eur.J.Biochem.. 269. 6173-6183 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Taki C: "MUC1 mucin expression in follocular dendritic cells and lymphoepithelial lesions of gastric mucosa-associated lymphoid tissue lymphoma"Pathology Int.. 52. 691-701 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kamata M: "Vaccination of mice with MUC1 cDNA suppresses the development of lung metastases"Clin Exp metastasis. 19. 689-696 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kato K. et al.: "Distinct Orders of GalNAc Incorporation into a Peptide with Consecutive Threonines"Biochem Biohys Res Commun.. 287. 110-115 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato K. et al.: "N-acetylgalactosamine in corporation into a Peptide containing consecutive threonine residues by UDP-N-acetyl-D-galactosaminide : polypetide N-acetylgalactosaminyltransferases"Glycobiology. 11. 812-829 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Togayachi A. et al.: "Molecular cloning and characterization of UDP-GlcNAc : Lactosylceramide B1, 3-N-Acetylgalucosaminyltransferase (B3Gn-T5), an essential enzyme for the expression of HNK-1 and Lewix X epitopes on glycolipids"J Biol Chem.. 276. 22032-22040 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yim M. et al.: "Mutated plant lectin library useful to identify different cells"Proc Nat Acad Sci USA. 98. 2222-2225 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shirota K. et al.: "Anti-metastatic effect of the sialyl lewis-x analog GSC-150 on the human colon carcinoma derived cell line KM12-HX in the mouse"Biol Pharm Bull. 24. 316-319 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kawamoto T, et al.: "Expression of MUC1 mucins with sialylated carbohydrates at the deepest invasding sites correlates with post-surgical prognosis of pT2 carcinoma of the galbladder"Clin Cancer Res. 7. 1333-1342 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Amano J. et al.: "Intestinal epithelial cells express and secrete the CD43 glycoform that contains core 2 O-glycans"Microbes and Infect. 3. 723-728 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Uwatoku R, . et al.: "Kupffer cell-mediated recruitment of rat dendritic cells to the liver : roles of N-acetylgaractosamine-specific sger receptors"Gasteroenterology. 121. 1460-1472 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Morimoto M. et al.: "Fibroblast migratory factor derived from mouse colon carcinoma cells : potential roles of fibronectin in tumor stroma formation"J Cell Biochem. 80. 635-646 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Denda-Nagai K. et al.: "MUC1 in carcinoma-host Interactions"Giycoconjugate J. 17. 649-658 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Denda-Nagai K. et al.: "Absence of correlation of MUC1 expression to mallgnant behavior of renal cell carcinoma in experimental systems"Clin Exp Metastasis. 18. 71-81 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kusaka Y. et al.: "Vital immunostaining of human gastric and colorectal cancer grafted into nude mice ; a preclinical assessment of a potential adjunct to videoendoscopy"J Gastroenterol. 35. 748-752 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Chun K-H, et al.: "Involvement of cytokines in the skin-to-lymph node trafficking of cells of the monocyte-macrophage lineage expressing a C-type lectin"Int Immunol. 12. 1695-1703 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ichii S, et al.: "Initlal steps in lymph node metastasis formation in an experimental system : possible involvement of recognition by macrophage C-type lectins"Cancer Immunol Immunother.. 49. 1-9 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Chun K-H, et al.: "Migration of dermal cells expressing a macrophage C-type lectin during the sensitization phase of delayed-type hypersensitivity"J Leukocyte Biol. 68. 471-478 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ota M, et al.: "Involvement of cell surface glycans in adhesion of human colon carcinoma cells to liver tissue in a frozen section assay : role of endo-b-galactosidase-sensitive structures"Cancer Res.. 60. 5261-5268 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Koike J, et al.: "Density-dependent induction of TNF-a release from human monocytes by immobilized P-selectin"FEBS Lett. 477. 84-88 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Iida S, et al.: "Order and maximum incorporation of N-acetyl-D-galactosamine into threonine residues of MUC2 core peptide with microsome fraction of human-colon-carcinoma-LS174T-cells"Biochem J. 347. 535-542 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kang Y, et al.: "Increased expression after X-irradiation of NUC1 in cultured human colon carcinoma HT-29 cells"Jpn J Cancer Res. 91. 324-330 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Vestergaard C. et al.: "Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopi dermatitis-like lesions"J Clin Invest. 104. 1097-1105 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nagata K. et al.: "Redistribution of selectin counter-ligands induced by cytokines"Int Immunol. 12. 487-492 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kimura T. et al.: "Epitope mapping of monoclonal antibodies specific for a macrophage lectin : a calcium-dependent epitope is in the carbohydrate recognition domain"Mol Immunol. 37. 151-160 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nagata,K.: "Redistribution of selectin counter-ligands〜."Int.Immunol.. 12. 487-492 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Vestergaard,C.: "Overproduction of Th2-specific chemokines〜."J.Clinic.Invest.. 104. 1097-1105 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kang,Y.: "Increased expression after X-irradiator〜."Jpn.J.Cancer Res.. 91. 324-330 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Iida,S.: "Order and maximum incorporation of〜."Biochem.J.. 347. 535-542 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Koike,J.: "Density-dependent induction of TNF-a〜."FEBS Lett.. 477. 84-88 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ota,M.: "Involvement of cell surface glycans in〜."Cancer Res.. 60. 5261-5268 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chun,K.: "Migration of dermal cells expressing〜."J.Leukocyte Biol.. 68. 471-478 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ichii,S.: "Initial steps in lymph node metastasis〜."Cancer Immunol.. 49. 1-9 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chun,K.: "Involvement of cytokines in the skin-to〜."Int.Immunol.. 12. 1695-1703 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kusaka,Y.: "Vital immunostaining of human gastic〜."J.Gastroenterol.. 35. 748-752 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Denda-Nagai,K.: "Absence of correlation of Mull〜."Clin.Exp.Metastasis.. 18. 71-81 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yim,M.: "Mutated plant lectin library useful〜."PNAS. 98. 2222-2225 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Morimoto,M.: "Fibroblast migratory factor derived from〜."J.Cell.Biochem.. 80. 635-646 (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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