2004 Fiscal Year Final Research Report Summary
Molecular Mining and Functional Analysis of Cell Growth Control System
| Project/Area Number |
15570116
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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 |
YOSHINO Ken-ichi Kobe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (90280792)
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| Co-Investigator(Kenkyū-buntansha) |
YONEZAWA Kazuyoshi Kobe University, Biosignal Research Center, Professor, バイオシグナル研究センター, 教授 (70283900)
TOKUNAGA Chiharu Kobe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (70335462)
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| Project Period (FY) |
2003 – 2004
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| Keywords | mTOR / rapter / cell growth / mass spectrometry / amino acid / tuberous sclerosis / pyrimidine biosynthesi / heat shock protein 90 |
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| Research Abstract |
The mammalian target of rapamycin (mTOR) controls cell growth (increase in cell mass or size) in response to availability of nutrient such as amino acids. The mTOR has been known to function as an integrator of larger signaling pathways for cell growth, however, little has been known about members of mTOR signaling.
We found the mammalian homolog protein of LST8, which was registered as Similar to G beta-like protein "Gable" in mammalian, is one of components mTOR complex. The mLST8 is a highly conserved 36 kDa protein that consists almost entirely seven WD40 repeats with high sequence similarity to those found in the beta subunit of heterotorimeric G proteins.
We identified an enzyme which takes part in pyrimidine biosynthesis as an interacting protein of mLST8 or WD40 domain of raptor. The pyrimidine ring is derived from Gln and Asp, and bicarbonate. This finding suggests that mTOR controls pyrimidine biosynthesis as well as protein synthesis,
The TSC1-TSC2 heterodimer (tuberous sclerosis gene products complex) and the small GTPase Rheb (Ras-homolog enriched in brain) have been known as upstream regulator of mTOR. The TSC2 acts as a GTPase activating protein against Rheb. We found another novel GTPase activating protein which interacts to TSC1,as well as TSC2. The molecular size of the novel GTPase activating protein was found to be 32 kDa, and it was shown that the protein interacts to the C-terminal coiled-coil (881-996) of TSC1.
We showed that the heat shock protein 90 (Hsp90) was co-purified with raptor. Geldanamycin, a potent inhibitor of Hsp90, disrupted the in vivo binding of Hsp90 to raptor without affecting the association of raptor and mTOR, and suppressed the phosphorylation by mTOR of the downstream translational regulators. It is suggested that the mTOR signaling pathway is a novel target of geldanamycin.
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