期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 46, 期 11, 页码 1500-1509出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2009.03.001
关键词
Mammalian target of rapamycin; mTOR; Raptor; Hydrogen peroxide; Tuberous sclerosis complex; PRAS40; Proline-rich Akt substrate; 4E-BP1; Insulin; Free radicals
资金
- National Institutes of Health [K08-HL071905]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [K08HL071905] Funding Source: NIH RePORTER
Oxidants are well recognized for their capacity to reduce the phosphorylation of the mammalian target of rapamycin (mTOR) substrates, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and p70 S6 kinase 1 (S6K1), thereby hindering mRNA translation at the level of initiation. mTOR functions to regulate mRNA translation by forming the signaling complex mTORC1 (mTOR, raptor, G beta L). Insulin signaling to mTORC1 is dependent upon phosphorylation of Akt/PKB and the inhibition of the tuberous sclerosis complex (TSC1/2), thereby enhancing the phosphorylation of 4E-BP1 and S6K1. In this study we report the effect of H2O2 on insulin-stimulated mTORC1 activity and assembly using A549 and bovine aortic smooth muscle cells. We show that insulin stimulated the phosphorylation of TSC2 leading to a reduction in raptor-mTOR binding and in the quantity of proline-rich Akt substrate 40 (PRAS40) precipitating with mTOR. Insulin also increased 4E-BP1 coprecipitating with mTOR and the phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1. H2O2, on the other hand, opposed the effects of insulin by increasing raptor-mTOR binding and the ratio of PRAS40/raptor derived from the mTOR immunoprecipitates in both cell types. These effects occurred in conjunction with a reduction in 4E-BP1 phosphorylation and the 4E-BP1/raptor ratio. siRNA-mediated knockdown of PRAS40 in A549 cells partially reversed the effect of H2O2 on 4E-BP1 phosphorylation but not on S6K1. These findings are consistent with PRAS40 functioning as a negative regulator of insulin-stimulated mTORC1 activity during oxidant stress. (C) 2009 Elsevier Inc. All rights reserved.
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