1999 Fiscal Year Final Research Report Summary
Control of cell cycle checkpoint mediated by mammalian target of rapamycin
| Project/Area Number |
10680609
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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 |
Functional biochemistry
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| Research Institution | Kobe University |
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Principal Investigator |
YONEZAWA Kazuyoshi Kobe University, Biosignal Research Center, Professor, バイオシグナル研究センター, 教授 (70283900)
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| Co-Investigator(Kenkyū-buntansha) |
TSUJISHITA Yosuke Kobe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (80263408)
HARA Kenta Kobe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (70294254)
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| Project Period (FY) |
1998 – 1999
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| Keywords | amino acid / leucine / mitogen / rapamycin / mTOR / protein synthesis / p70 S6 kinase / eIF4E binding protein |
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| Research Abstract |
Rapamycin is a lipophilic macrolide compound and binds to FKBP12 in mammalian cells. The mTOR (mammalian target of rapamycin) protein was identified as a target of FKBP12-rapamycin complex. This protein has a calculated molecular weight of 289 kDa and contains a kinase-like domain at its carboxyl-terminus. In this study, we obtained following findings.
(1)mTOR participates in nutrient-sensing, especially amino acid-sensing, in mammalian cells and regulates translational effectors, such as p70S6 kinase α (p70α) and eIF4E binding protein (4EBP).
(2)Activation of amino acid-mTOR signaling pathway is indispensable for mitogen-induced protein synthesis. In other words, amino acid-mTOR signaling is a priming signal for mitogen-induced protein synthesis.
(3)Among amino acids, leucine has the most potent ability to activate phosphorylation of p70α.
(4)p70α, extracted in inactive forms from rapamycin-treated cells, can be directly phosphorylated by the mTOR kinase at the rapamycin-sensitive site Thr-412. mTOR-catalyzed p70α phosphorylation in vitro is accompanied by a substantial restoration in p70α kinase activity.
(5)Sequential phosphorylation of p70α by mTOR and 3-phosphoinositide-dependent protein kinase 1 in vitro results in a synergistic stimulation of p70α activity to levels similar to that attained by serum stimulation in vivo.
(6)Several candidates of binding partners of mTOR were identified using conventional biochemical methods and yeast-two hybrid system and detailed analyses are now in progress.
(7)Some of leucine derivatives were found to have the ability to inhibit p70α activation and T cell proliferation. This analysis is also now in progress.
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Research Products
(18 results)
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[Publications] Hara,K., Yonezawa,K., Weng,Q.P., Kozlowski,M.T., Belham,C., and Avruch,J.: "Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF4E BP1 through a common effector mechanism"J. Biol. Chem.. 273-23. 14484-14494 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Nanahoshi,M., Nishiuma,T., Tsujishita,Y., Hara,K., Inui,S., Sakaguchi,N., and Yonezawa,K.: "Regulation of protein phosphatase 2A catalytic activity by alpha4 protein and its yeast homolog Trap42"Biochem. Biophys. Res. Commun.. 251-2. 520-526 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Gout,I., Minami,T., Hara,K., Tsujishita,Y., Filonenko,V., Waterfield,M.D., and Yonezawa,K.: "Molecular cloning and characterization of a novel p70 S6 kinase, p70 S6 kinase β containing a proline-rich region"J. Biol. Chem.. 273-46. 30061-30064 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Nishiuma,T., Hara,K., Tsujishita,Y., Kaneko,K., Shii,K., and Yonezawa,K.: "Characterization of the phosphoproteins and protein kinase activity in mTOR immunoprecipitates"Biochem. Biophys. Res. Commun.. 252-2. 440-444 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Shigemitu,K., Tsujishita,Y., Hara,K., Nanahoshi,M., Avruch,J., and Yonezawa,K.: "Regulation of translational effecters by amino acid and mammalian target of rapamycin signaling pathways : Possible involvement of autophagy in cultured hepatoma cells"J. Biol. Chem.. 274-2. 1058-1065 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Nanahoshi,M., Tsujishita,Y., Tokunaga,C., Inui,S., Sakaguchi,N., Hara,K., and Yonezawa,K.: "Alpha4 protein as a common regulator of type 2A-related serine/threonine protein phosphatases"FEBS Let.. 446-1. 108-112 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Shigemitsu,K., Tsujishita,Y., Miyake,H., Hidayat,S., Tanaka,N., Hara,K., and Yonezawa,K.: "Structural requirement of leucine for activation of p70 S6 kinase"FEBS Let.. 447-2・3. 303-306 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Isotani,S., Hara,K., Tokunaga,C., Inoue,H., Avruch,J., and Yonezawa,K.: "Immunopurified mammalian target of rapamycin (mTOR) phosphorylates and activates p70 S6 kinase α in vitro"J. Biol. Chem.. 274-48. 34493-34498 (1999)
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「研究成果報告書概要(欧文)」より
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