| Project/Area Number |
13470022
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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 | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Kobe University |
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Principal Investigator |
KATAOKA Tohru Kobe Univ. Grad. Sch. Med., Dept. Mol. Cell. Biol., Professor, 大学院・医学系研究科, 教授 (40144472)
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| Co-Investigator(Kenkyū-buntansha) |
EDAMATSU Hironori Kobe Univ. Grad. Sch. Med., Dept. Mol. Cell. Biol., Instructor, 大学院・医学系研究科, 助手 (70335438)
SHIMA Fumi Kobe Univ. Grad. Sch. Med., Dept. Mol. Cell. Biol., Instructor, 大学院・医学系研究科, 助手 (60335445)
SATOH Takaya Kobe Univ. Grad. Sch. Med., Dept. Mol. Cell. Biol., Associate Professor, 大学院・医学系研究科, 助教授 (20251655)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2002: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2001: ¥10,100,000 (Direct Cost: ¥10,100,000)
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| Keywords | Phospholipase C / Inositol Signaling / Small G Proteins / Intracellular Signal Transduction / Ras Protein / Rap1 Protein / Knockout Mice / Caenorhabditis elegans / 低分子量GTP結合蛋白質 / Ras / Rap1 / グアニンヌクレオチド交換促進因子 / RAドメイン / 神経系幹細胞 / ゴルジ装置 |
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| Research Abstract |
We have clarified the regulation mechanism of a novel class of phospholipase C, PLCε, and established PLDε as an effector of small GTPases Ras and Pap1. Also, a physiological function of PlCε has been elucidated.
1. The CDC25 homology domain of PLCε acts as a guanine nucleotide exchange factor for Rap1, thereby amplifying Rap1-dependent signaling. Stimulation of cells by platelet-derived growth factor (PDGF), induces two phase activation of PLCε through activation of Ras and Rap1. The rapid and initial phase of this activation is mediated by Ras at the plasma membrane, whereas Rap1 is responsible for the prolonged activation at the Golgi apparatus. The CDC25 homology domain is crucial for the prolonged activation of PCLε by Rap1. The Ras/Rap1-dependent activation of PLCε prevents BaF3 cells from undergoing apoptosis and sustains their proliferation.
2. Analysis of the spatial and temporal expression patterns of PLCε indicates that in mouse embryos a specific induction of PLCε expression is observed during the course of differentiation of the neural stem cells into the neuronal lineage. In adult, PLCε is expressed abundantly in the heart. The PLCε gene-knockout mice, created by gene targeting, are found to exhibit a phenotype characterized by a market cardiomegaly as well as by overexpression of the heart failure markers as early as 4 weeks of age. Thus, PLCε may play a crucial function in intracellular signaling of the cardiomyocytes by linking the Ras pathway with the Ca^<2+>-calcineurin-NFAT pathway.
3. We have isolated a Caenorhabditis elegans mutant worm lacking the PLCε gene. It exhibits a sterile phenotype due to a disorder in transporting the eggs to the uterus, which is presumably caused by defective relaxation of the sphincters of the spermatheca. It is interesting that both the mammals and the nematodes exhibit a similar phenotype carrying a defect in rhythmic muscular contraction.
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