期刊
CELLULAR SIGNALLING
卷 22, 期 10, 页码 1469-1476出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2010.05.015
关键词
Reactive oxygen species; mTOR complex 1; Protein phospholipase 2A; AMP-activated kinase
类别
资金
- National Natural Sciences Foundation of China [30771027, 30870955]
- Program for New Century Excellent Talents in University [NCET-08-0646]
The mammalian target of rapamycin complex 1(mTORC1) integrates diverse signals to control cell growth, proliferation, survival, and metabolism. Role of reactive oxygen species (ROS) on mTORC1 signaling remains obscure and mechanisms through which ROS modulate mTORC1 are not known. We demonstrate that low doses ROS exposure stimulate mTORC1 while high concentrations or long-term ROS treatment decrease mTORC1 activity in vivo and in a variety of cell lines. The dose/time needed for inhibition or activation are cell type-dependent. In HEK293 cells hydrogen peroxide (H2O2) stimulates phosphorylation of AMP-activated kinase (AMPK) (T172) and Raptor (S792), enhances association of activated AMPK with Raptor. Furthermore, AMPK inhibitor compound c inhibits H2O2-induced Raptor (5792) phosphorylation and reverses H2O2-induced dephosphorylation of mTORC1 downstream targets p70-S6K1 (T389), S6 (S235/236) and 4E-BP1 (T37/46). H2O2 also stimulates association of endogenous protein phosphatase 2A catalytic subunit (PP2Ac) with p70-S6K1. Like compound c, inhibitor of PP2A, okadaic acid partially reverses inactivation of mTORC1 substrates induced by H2O2. Moreover, inhibition of PP2A and AMPK partially rescued cells from H2O2-induced cell death. High doses of H2O2 inhibit while low doses of H2O2 activate mTORC1 both in TSC2(-/-)P53(-/-) and TSC2(+/+)P53(-/-) MEFs. These data suggest that PP2A and AMPK-mediated phosphorylation of Raptor mediate H2O2-induced inhibition of mTORC1 signaling. (C) 2010 Elsevier Inc. All rights reserved.
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