| Project/Area Number |
16390094
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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 |
Pathological medical chemistry
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| Research Institution | Kobe University |
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Principal Investigator |
YOSHINO Ken-ichi (2005-2006) Kobe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (90280792)
米澤 一仁 (2004) 神戸大学, バイオシグナル研究センター, 教授 (70283900)
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| Co-Investigator(Kenkyū-buntansha) |
OSHIRO Noriko Kobe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (70372662)
KIKKAWA Ushio Kobe University, Biosignal Research Center, Professor, バイオシグナル研究センター, 教授 (40150354)
吉野 健一 神戸大学, バイオシグナル研究センター, 助手 (90280792)
徳永 千春 神戸大学, バイオシグナル研究センター, 助手 (70335462)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2006: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2005: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2004: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | immunosuppressant / rapamycin / mTOR / cell growth / PRAS40 / restenosis prevention / side effect / amino acids / ラパマイシン / リン酸化 / raptor / mTOR複合体 / 4EBP1 / 血小板減少 / 創傷治癒 / タンパク質リン酸化 / Rapamycin / 創傷治癒遅延 / 中性脂肪上昇 / 血小板現象 |
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| Research Abstract |
The mammalian target of rapamycin (mTOR) is a Ser/Thr protein kinase that plays a crucial role in a nutrient-sensitive signalling pathway that regulates cell growth. TOR signalling is potently inhibited by rapamycin, through the direct binding of a FK506-binding protein 12 (FKBP12)/rapamycin complex to the TOR FRB domain, a segment amino terminal to the kinase catalytic domain. Raptor (regulatory associated protein of mTOR) is a recently identified mTOR binding partner that is essential for mTOR signalling in vivo, and whose binding to mTOR is critical for mTOR-catalyzed substrate phosphorylation in vitro.
Here we investigated the stability of endogenous mTOR/raptor complex in response to rapamycin in vivo, and to the direct addition of a FKBP12/rapamycin complex in vitro. We demonstrated that rapamycin inhibits mTOR function, at least in part, by inhibiting the interaction of raptor with mTOR; this action uncouples mTOR from its substrates, and inhibits mTOR signalling without altering
… More
mTOR's intrinsic catalytic activity.
We showed that heat shock protein 90 (Hsp90) is involved in the regulation of protein translation by facilitating the phosphorylation reaction of eukaryotic initiation factor-4E (eIF4E) binding protein 1 (4E-BP1) and p70 S6 kinase (S6K) catalyzed by the mTOR/raptor complex through the association with raptor, and that the mTOR signaling pathway is a novel target of geldanamycin.
We found that the TOS motif has an essential function whereas the RAIP motif has an accessory role in the association with raptor and mTOR-mediated phosphorylation of 4E-BP1 to dissociate it from raptor and release eIF4E in response to amino acid stimulation leading to the control of cell size.
The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor binding protein that is phosphorylated directly by mTOR complex (mTORC) 1 but not mTORC 2 in vitro, predominantly at PRAS40 (Serl 83). We establish PRAS40 as a physiological mTORCl substrate that contains a variant TOS motif Moreover, they indicate that the capacity or ability of raptor to bind endogenous substrates is limiting for the activity of mTORCl in vivo, and is therefore a potential locus of regulation, as suggested by others. Less
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