| Project/Area Number |
15590335
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
INOUE Hirokazu School of Medicine, Department of Microbiology, Associate Professor, 医学部, 助教授 (30176440)
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| Co-Investigator(Kenkyū-buntansha) |
HARAGUCHI Seiki School of Medicine, Department of Microbiology, Research Associate, 医学部, 助手 (10324576)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Tumor suppressor gene / Apoptosis / Knockout mouse / Drs |
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| Research Abstract |
The drs gene was originally isolated as a suppressor against v-src transformation.
Drs protein has one transmembrane domain and three consensus repeat called Sushi motif. Expression of drs mRNA was markedly downregulated in a variety of human cancer cell lines and tissues, suggesting that the drs gene acts as a tumor suppressor. In this study, we investigated the function of Drs and the mechanism of tumor suppression by this gene and obtained the following results.
(1)Drs induces apoptosis by a novel pathway mediated by ASY/Nogo-B/RTN-xS, caspase-12, caspase-9 and caspase-3 in human cancer cells.
(2)We investigated the tumor suppressor function in vivo of drs and its physiological roles in apoptosis by generating a gene-knockout mouse. Malignant tumors including lymphomas, lung adenocarcinomas, hepatomas, and sarcoma were generated in about 25% of 46 drs-knockout(KO)mice. No tumors were detected in all (23) wild-type mice examined at the same age.
(3)Re-introduction of drs by retrovirus vector into a lung cancer cell line derived from a lung adenocarcinoma of a drs KO mouse caused suppression of tumorigenicity in nude mouse and elevation of apoptosis mediated by activation of caspase-3.
(4)Drs KO MEF cells showed resistance to certain apoptosis-inducing reagent such as rapamycine and dexamethazone.
(5)Apoptosis was induced in glucose-depleted Drs KO MEF cells, suggesting the closstalk between Drs-induced apoptosis pathway and mTOR signal pathway.
These results idicate that the drs gene acts as a tumor suppressor in genesis of malignant tumors and that drs play a role in certain apoptotic pathways in physiological conditions.
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