Inhibition of mTORC1 by Astrin and Stress Granules Prevents Apoptosis in Cancer Cells

被引：255

作者：

Thedieck, Kathrin ^{[1
,2
,3
,7
]}

Holzwarth, Birgit ^{[1
]}

Prentzell, Mirja Tamara ^{[1
,4
]}

Boehlke, Christopher ^{[7
]}

Klaesener, Kathrin ^{[1
,2
,8
]}

Ruf, Stefanie ^{[1
,2
,5
]}

Sonntag, Annika Gwendolin ^{[1
]}

Maerz, Lars ^{[1
]}

Grellscheid, Sushma-Nagaraja ^{[9
]}

Kremmer, Elisabeth ^{[10
]}

Nitschke, Roland ^{[1
,2
,3
]}

Kuehn, E. Wolfgang ^{[2
,7
]}

Jonker, Johan W. ^{[12
]}

Groen, Albert K. ^{[12
]}

Reth, Michael ^{[1
,2
,8
]}

Hall, Michael N. ^{[11
]}

Baumeister, Ralf ^{[1
,2
,3
,6
]}

机构：

[1] Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany

[2] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79104 Freiburg, Germany

[3] Univ Freiburg, Ctr Syst Biol ZBSA, D-79104 Freiburg, Germany

[4] Univ Freiburg, Spemann Grad Sch Biol & Med SGBM, D-79104 Freiburg, Germany

[5] Univ Freiburg, Res Training Grp RTG 1104, D-79104 Freiburg, Germany

[6] Univ Freiburg, Fac Med, ZBMZ Ctr Biochem & Mol Cell Res, D-79104 Freiburg, Germany

[7] Univ Hosp Freiburg, Div Renal, D-79106 Freiburg, Germany

[8] Max Planck Inst Immunobiol & Epigenet, D-79108 Freiburg, Germany

[9] Univ Durham, Sch Biol & Biomed Sci, Durham DH1 3LE, England

[10] Inst Mol Immunol, Helmholtz Zentrum Munchen, D-81377 Munich, Germany

[11] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland

[12] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Ctr Liver Digest & Metab Dis, NL-9713 GZ Groningen, Netherlands

来源：

CELL | 2013年 / 154卷 / 04期

基金：

欧洲研究理事会;

关键词：

MESSENGER-RNA TRANSLATION; MAMMALIAN TARGET; HYDROGEN-PEROXIDE; COMPLEX; SIGNALING PATHWAY; RAPAMYCIN; PROTEIN; ACTIVATION; INITIATION; KINASE;

D O I：

10.1016/j.cell.2013.07.031

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：859 / 874

页数：16

共 66 条

[1] ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS [J].