| Project/Area Number |
12557213
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | Showa University |
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Principal Investigator |
KUDO Ichiro School of Pharmaceutical Sciences, Showa University, Professor, 薬学部, 教授 (30134612)
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| Co-Investigator(Kenkyū-buntansha) |
UENO Akinoiri Kitasato University, School of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助教授 (00112657)
NAKATANI Yoshihito School of Pharmaceutical Sciences, Showa University,, 薬学部, 講師 (80266163)
MURAKAMI Makoto School of Pharmaceutical Sciences, Showa University, Assistant Professor, 薬学部, 助教授 (60276607)
SUGIMOTO Masamichi Chugai Pharmaceutical Co. Ltd, 研究所, 主任研究員
NARABA Hiroaki National Cardiovascular Center, 薬理部, 研究員 (90296517)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥12,600,000 (Direct Cost: ¥12,600,000)
Fiscal Year 2001: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 2000: ¥6,900,000 (Direct Cost: ¥6,900,000)
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| Keywords | PGE_2 / PGE_2 synthase / Cyclooxygenase / Hsp90 / Colon tumors / Arachidonic acid / Inflamamtory |
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| Research Abstract |
The aims of this study are to perform biochemical characterization of two prostaglandin E2 synthases (PGESs) and to clarify their physilogical and pathological functions.
Cytosolic PGES (cPGES) is a cytosolic 23-kDa protein that is expressed ubiuitously and constitutively in a wide variety of cells and tissues. This enzyme is identical to p23, which is associated with the molecular chaperone Hsp9O. cPGES is functionally coupled with cyclooxygenase (COX)-1 to promote immediate PGE2 production. The Hsp9O-bound cPGES is an active form, and the formation of this complex is facilitated immediately after cell activation with A23187. Hsp9O inhibitors, such as geldanamycin, as well as glucocorticoid prevents the formation of the Hsp9O/cPGES complex, thereby attenuating the PGE2biosynthetic response. After cell activation, cPGES translocates from the cytosol to the endoplasmic reticulum, where it is colocalized with COX-1. cPGES undergoes phosphorylation, although its biological significance rem
… More
ains elusive. Finally, there are at least four alternative spliced variants of cPGES, each of which exhibited distinct tissue distribution and showed different kinetic parameters (Km and Vmax) for the substrate PGH2.
Microsomal PGES (mPGES) is a perinuclear 18-kDa protein that is strongly induced in various cells and tissues following proinflamamtory stimuli. This enzyme belongs to the class microsomal glutathione-Stransferase family. mPGES is functionally coupled with COX-2 in marked preference to COX-1 to promote delayed PGE2 production and primed immediate PGE2 production. Cotransfection of COX-2 and mPGES into HEK293 cells results in aggressive growth and morphological change in culture. Furthermore, the cotransfectants grow in soft agar to form large colonies and are tumorigenic in nude mice. A colon carcinoma cell line (HCA-7), the growth of which depends on COX-2, also expresses mPGES, where both enzymes are colocalized in the perinuclear reagion. Immunohistochemical staining of human tissues reveal that both COX-2 and mPGES are expressed in colon tumors, rheumatoid arthritis, ischemic hearts, C-type hepatitis, and brain endothelial cells. Less
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