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Title: Impaired autophagy due to constitutive mTOR activation sensitizes TSC2-null cells to cell death under stress
Authors: Ng, S.
Wu, Y.-T.
Chen, B. 
Zhou, J. 
Shen, H.-M. 
Keywords: Apoptosis
Issue Date: Oct-2011
Citation: Ng, S., Wu, Y.-T., Chen, B., Zhou, J., Shen, H.-M. (2011-10). Impaired autophagy due to constitutive mTOR activation sensitizes TSC2-null cells to cell death under stress. Autophagy 7 (10) : 1173-1186. ScholarBank@NUS Repository.
Abstract: It has been well documented that cells deficient in either TSC1 or TSC2 are highly sensitive to various cell death stimuli. In this study, we utilized the TSC2 -/- mouse embryonic fibroblasts (MEFs) to study the involvement of autophagy in the enhanced susceptibility of TSC2-null cells to cell death. We first confirmed that both TSC1-null and TSC2-null MEFs are more sensitive to apoptosis in response to amino acid starvation (EBSS ) and hypoxia. Second, we found that both the basal and inducible autophagy in TSC2 -/- MEFs is impaired, mainly due to constitutive activation of mTORC1. Third, suppression of autophagy by chloroquine and Atg7 knockdown sensitizes TSC2 +/+ cells, but not TSC2 -/- cells, to EBSS-induced cell death. Conversely, the inhibition of mTORC1 by raptor knockdown and rapamycin activates autophagy and subsequently rescues TSC2 -/- cells. Finally, in starved cells, nutrient supplementations (insulin-like growth factor-1 (IGF-1) and leucine) enhanced cell death in TSC2 -/- cells, but reduced cell death in TSC2 +/+ cells. Taken together, these data indicate that constitutive activation of mTORC1 in TSC2 -/- cells leads to suppression of autophagy and enhanced susceptibility to stress-mediated cell death. Our findings thus provide new insights into the complex relationships among mTOR, autophagy and cell death, and support the possible autophagy-targeted intervention strategies for the treatment of TSC-related pathologies. © 2011 Landes Bioscience.
Source Title: Autophagy
ISSN: 15548627
DOI: 10.4161/auto.7.10.16681
Appears in Collections:Staff Publications

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