REGURATORY MECHANISM OF CELL GROWTH AND SURVIVAL BY SPHINGOLIPID METABOLISM
| Project/Area Number |
17510175
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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 |
Living organism molecular science
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| Research Institution | Gifu University |
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Principal Investigator |
BANNO Yoshiko GIFU UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 大学院医学系研究科, 助教授 (50116852)
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| Co-Investigator(Kenkyū-buntansha) |
MURATE Takashi NAGOYA UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (30239537)
NOZAWA Yoshinori GIFU INTERNATIONAL INSTITUTE, CHIEF, 所長 (10021362)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | SPHINGOLIPIDS / CELL GROWTH / APOPTOSIS REGULATION / スフィンゴ脂質 / スフインゴ脂質 |
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| Research Abstract |
It has been known that sphingomyelin metabolites are important for regulation of cell death and survival. Ceramide generated by sphingomyelinase (SMase) induces cell death and sphingosine 1-phosphate (SIP), produced by sphingosine kinase (SPHK), acts both by intracellular and extracellular modes. 1)We have found that a human prostate cancer cell line PC3 is resistant to anticancer drug, camptothecin (CPT). To elucidate the mechanism of this resistance, we have examined the involvement of SPHK and SIP receptor in CPT-resistant PC3 and-sensitive LNCaP cells. PC3 cells exhibited higher activity accompanied with higher expression levels of protein and mRNA of SPHK1, as compared with those of LNCaP cells. The knockdown of SPHK1 by small interfering RNA in PC3 cells induced significant inhibition of cell growth, suggesting implication of SPHK1 and S1P receptors in cell proliferation in PC3 cells. Furthermore, the treatment of PC3 cells with CPT was found to induce up-regulation of the SPHK1/
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S1P signaling by induction of both SPHK1 enzyme. 2) We have demonstrated the oncogenic role of SPHK1 in MEN2A type tumor. Promoter analysis showed that AP-2 and Sp1 binding motif of the 5' promoter region of SPHK1 gene is important for its induction by glial cell line-derived neurotrophic factor (GDNF) and that ERK1/2 and PI3 kinase are involved in GDNF-induced SPHK1 transcription in NIH 3T3 cells. 3) We have examined tole of SPHK1 in cell differentiation. We evaluated the role of SPHK1 in granurocytic differentiation of HL60 cells and in osteoclastogenesis using bone marrow-derived macro-phage (BMM) single and BMM/osteoblast coculture systems. SPHK1 played a role in granurocytic differentition via ERK activation, and in BMM single cultures, SPHK1 siRNA enhanced and SPHK1 overexpression attenuated osteoclastogenesis via modulation of p38 and ERK activities, and NFATc1 and c-Fos levels. These results suggested that SPHK1/S1P play a important role in cell survival, growth and differentiation. Less
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Report
(3 results)
Research Products
(35 results)
