| Co-Investigator(Kenkyū-buntansha) |
KONTANI Kenji The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor (30302615)
FUKUYAMA Masamitsu The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor (20422389)
KAJIHO Hiroaki The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor (70401221)
KOBAYASHI Tetsuo The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor (80433994)
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| Budget Amount *help |
¥49,790,000 (Direct Cost: ¥38,300,000、Indirect Cost: ¥11,490,000)
Fiscal Year 2007: ¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000)
Fiscal Year 2006: ¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000)
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| Research Abstract |
G proteins, which cycle between the two different conformations of GTP- and GDP-bound states, play important roles as a "molecular switch" in many intracellular signaling pathways. The G protein families include 1) translation factors involved in protein synthesis and mRNA degradation, 2) trimeric G proteins, and 3) small GTPases. The small GTPases, such as Ras, Rab, Arf, and Rho/Rac family, are involved in the regulation of cell growth and differentiation, intracellular vesicle trafficking, and cell shape and adhesion. However, there are still many other small GTPases, of which functions are unknown. In this study, we have identified and characterized novel small GTPases exhibiting unique biochemical properties or tissue expression.
1. The Arl8 GTPase was essential for lysosome biogenesis in the macrophage-like coelomocytes of C. elegans: ARL-8 localized primarily to lysosomes, and a deletion mutant of arl-8 displayed an increase in number of lysosomes that were small in size and non-a
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cidic. Extracellular macromolecules were endocytosed and transported through endosomes in arl-8 mutant coelomocytes, but its degradation was markedly reduced. Thus, Arl8 appeared to function as an important regulator of lysosome biogenesis/function.
2. Rab45 is an atypical GTPase that contains a coiled-coil motif at the mid region and a distinct N-terminal EF-hand domain with C-terminal Rab-homology domain. Rab45 was capable of self-interacting, and the self-interaction required the mid region containing the coiled-coil motif. Rab45 expressed in HeLa cells was localized in a small patch in the perinuclear area of the cell, and the localization was regulated by the guanine nucleotide-bound states of Rab45. The mid region, together with Rab domain, appeared to be essential for the characteristic perinuclear localization of Rab45.
3. Di-Ras, which belongs to a distinct branch of the Ras family, existed predominantly as a GTP-bound form in living cells. The expression of Di-Ras was rather specific in neuronal cells, and its over-expression induced apoptotic cell death with DNA fragmentation in neuronal cells. A deletion mutant of arl-8 in C. elegans displayed a phenotype that acetylcholine release from nerve cells might be impaired. Less
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