The primary objective of this proposal is to determine the roles of core 2 branched O-glycans in cell adhesion, development, and cancer progression. In the past few years, we have made critical progress in this field. First, we have shown that core 2 branched O-glycans play a major role in lymphocyte adhesion and tumor metastasis. Second, we have cloned cDNAs encoding two novel core 2 branching beta1,6-N-acetylglucosaminyltransferases (Core2GlcNAcT-2 and Core2GlcNAcT-3), which have different substrate specificity and tissue distribution from Core 2GlcNAcT-1 originally cloned. Third, we have demonstrated that alpha 1,4-GlcNAc on core 2 O-glycans inhibits Helicobacter pylori colonization while 6-sulfosialyl Lewis X on core 2 O-glycans facilitates H. pylori-induced inflammation. Based on these findings, three major studies are proposed as follows: 1) Identifying core 2 beta1,6-N -acetylglucosaminyltransferases that play major roles in the biosynthesis of mucin-type O-glycans in the stomach. We will determine which Core2GlcNAcTs play a major role in providing backbone structures for alpha 1,4-GlcNAc-capping structure and Lewis b blood group antigen. 2) Determining the roles of Core2GlcNAcTs in cell adhesion. We will determine the roles of Core2GlcNAcT-2 and Core2GlcNAcT-3 in selectin-mediated adhesion by utilizing mice deficient in Core2GlcNAcT-2 and Core2GlcNAcT-3. 3) Determining the roles of core 2 branched O-glycans in inflammation and tumor formation initiated by H. pylori infection. We will determine if inactivation of one of Core2GlcNAcTs leads to increased H. pylori colonization, thus early onset of gastric cancer and if inactivation of another Core2GlcNAcTs leads to attenuated lymphocyte recruitment, thus impairing inflammation and delaying the onset of gastric cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA033000-27
Application #
7229455
Study Section
Special Emphasis Panel (ZRG1-ICI (01))
Program Officer
Sathyamoorthy, Neeraja
Project Start
1982-01-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
27
Fiscal Year
2007
Total Cost
$362,205
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Lee, Seung Ho; Fukuda, Minoru (2013) Study of the biological functions of mucin type core 3 O-glycans. Methods Mol Biol 1022:41-50
Tsuboi, Shigeru; Hatakeyama, Shingo; Ohyama, Chikara et al. (2012) Two opposing roles of O-glycans in tumor metastasis. Trends Mol Med 18:224-32
Kobayashi, Motohiro; Hoshino, Hitomi; Suzawa, Kenichi et al. (2012) Two distinct lymphocyte homing systems involved in the pathogenesis of chronic inflammatory gastrointestinal diseases. Semin Immunopathol 34:401-13
Kobayashi, Motohiro; Mitoma, Junya; Hoshino, Hitomi et al. (2011) Prominent expression of sialyl Lewis X-capped core 2-branched O-glycans on high endothelial venule-like vessels in gastric MALT lymphoma. J Pathol 224:67-77
Arata-Kawai, Hanayo; Singer, Mark S; Bistrup, Annette et al. (2011) Functional contributions of N- and O-glycans to L-selectin ligands in murine and human lymphoid organs. Am J Pathol 178:423-33
Hoshino, Hitomi; Tsuchida, Akiko; Kametani, Kiyokazu et al. (2011) Membrane-associated activation of cholesterol ?-glucosyltransferase, an enzyme responsible for biosynthesis of cholesteryl-?-D-glucopyranoside in Helicobacter pylori critical for its survival. J Histochem Cytochem 59:98-105
Hatakeyama, Shingo; Kyan, Atsushi; Yamamoto, Hayato et al. (2010) Core 2 N-acetylglucosaminyltransferase-1 expression induces aggressive potential of testicular germ cell tumor. Int J Cancer 127:1052-9
Lee, Seung Ho; Yu, Shin-Yi; Nakayama, Jun et al. (2010) Core2 O-glycan structure is essential for the cell surface expression of sucrase isomaltase and dipeptidyl peptidase-IV during intestinal cell differentiation. J Biol Chem 285:37683-92
Mitoma, Junya; Fukuda, Minoru (2010) Core O-glycans required for lymphocyte homing gene knockout mice of core 1 beta1,3-N-acetylglucosaminyltransferase and core 2 N-acetylglucosaminyltransferase. Methods Enzymol 479:257-70
Piao, Shunfu; Jin, Xiao Ling; Yun, Bo-Young et al. (2010) Crystal structure and functional insight of HP0420-homolog from Helicobacter felis. Biochem Biophys Res Commun 394:940-6

Showing the most recent 10 out of 92 publications