| Project/Area Number |
10680609
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Functional biochemistry
|
|---|
| Research Institution | Kobe University |
|---|
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)
|
|---|
| 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)
|
|---|
| Project Period (FY) |
1998 – 1999
|
| Project Status |
Completed (Fiscal Year 1999)
|
| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1999: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
|
|---|
| Keywords | amino acid / leucine / mitogen / rapamycin / mTOR / protein synthesis / p70 S6 kinase / eIF4E binding protein / インスリン / mTORキナーゼ / 細胞増殖 / eIF-4E BP-1 |
|---|
| 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.
|
