An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1

Title
An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1
Authors
Thoreen, Carson C.Kang, Seong A.Chang, Jae WonLiu, QingsongZhang, JianmingGao, YiReichling, Laurie J.심태보Sabatini, David M.Gray, Nathanael S.
Keywords
mTor; kinase; cancer; Rapamycin; inhibitor
Issue Date
2009-03
Publisher
The Journal of biological chemistry
Citation
VOL 284, NO 12, 8023-8032
Abstract
The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1inhibitor with clinical applications as an immunosuppressant and anti-cancer agent. Here we find that Torin1, a highly potent and selective ATP-competitive mTOR inhibitor that directly inhibits both complexes, impairs cell growth and proliferation to a far greater degree than rapamycin. Surprisingly, these effects are independent of mTORC2 inhibition and are instead because of suppression of rapamycin-resistant functions of mTORC1 that are necessary for cap-dependent translation and suppression of autophagy. These effects are at least partly mediated by mTORC1-dependent and rapamycin-resistant phosphorylation of 4E-BP1. Our findings challenge the assumption that rapamycin completely inhibits mTORC1 and indicate that direct inhibitors of mTORC1 kinase activity may be more successful than rapamycin at inhibiting tumors that depend on mTORC1.
URI
http://pubs.kist.re.kr/handle/201004/35405
ISSN
0021-9258
Appears in Collections:
KIST Publication > Article
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