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Thedieck, K.* ; Holzwarth, B.* ; Prentzell, M.T.* ; Boehlke, C.* ; Klasener, K.* ; Ruf, S.* ; Sonntag, A.G.* ; Maerz, L.* ; Grellscheid, S.N.* ; Kremmer, E. ; Nitschke, R.* ; Kuehn, E.W.* ; Jonker, J.W.* ; Groen, A.K.* ; Reth, M.* ; Hall, M.N.* ; Baumeister, R.*

Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells.

Cell 154, 859-874 (2013)
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Mammalian target of rapamycin complex 1 (mTORC1) controls growth and survival in response to metabolic cues. Oxidative stress affects mTORC1 via inhibitory and stimulatory inputs. Whereas downregulation of TSC1-TSC2 activates mTORC1 upon oxidative stress, the molecular mechanism of mTORC1 inhibition remains unknown. Here, we identify astrin as an essential negative mTORC1 regulator in the cellular stress response. Upon stress, astrin inhibits mTORC1 association and recruits the mTORC1 component raptor to stress granules (SGs), thereby preventing mTORC1-hyperactivation-induced apoptosis. In turn, balanced mTORC1 activity enables expression of stress factors. By identifying astrin as a direct molecular link between mTORC1, SG assembly, and the stress response, we establish a unifying model of mTORC1 inhibition and activation upon stress. Importantly, we show that in cancer cells, apoptosis suppression during stress depends on astrin. Being frequently upregulated in tumors, astrin is a potential clinically relevant target to sensitize tumors to apoptosis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Messenger-rna Translation ; Spindle-associated Protein ; Mammalian Target ; Signaling Pathway ; Hydrogen-peroxide ; Complex 1 ; Gene-expression ; Rapamycin ; Kinase ; Raptor
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 154, Issue: 4, Pages: 859-874 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-501793-001
PubMed ID 23953116
DOI 10.1016/j.cell.2013.07.031
WOS ID WOS:000323202500016
Scopus ID 84882800242
Erfassungsdatum 2013-09-13
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