Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 327 (5970): 1223-1228

Copyright © 2010 by the American Association for the Advancement of Science

Sestrin as a Feedback Inhibitor of TOR That Prevents Age-Related Pathologies

Jun Hee Lee,1 Andrei V. Budanov,1 Eek Joong Park,1 Ryan Birse,2 Teddy E. Kim,3 Guy A. Perkins,4 Karen Ocorr,2 Mark H. Ellisman,4 Rolf Bodmer,2 Ethan Bier,3,* Michael Karin1,*

Abstract: Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate–activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.

1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093–0723, USA.
2 Development and Aging Program, Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
3 Section of Cell and Developmental Biology, UCSD, La Jolla, CA 92093–0349, USA.
4 National Center for Microscopy and Imaging Research and Department of Neurosciences, UCSD, La Jolla, CA 92093–0608, USA.

* To whom correspondence should be addressed. E-mail: ebier{at}ucsd.edu (E.B.); karinoffice{at}ucsd.edu (M.K.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Cross Talk between Cellular Redox Status, Metabolism, and p53 in Neural Stem Cell Biology.
K. Forsberg and S. Di Giovanni (2014)
Neuroscientist
   Abstract »    Full Text »    PDF »
A Reactive Oxygen Species-Mediated, Self-Perpetuating Loop Persistently Activates Platelet-Derived Growth Factor Receptor {alpha}.
H. Lei and A. Kazlauskas (2014)
Mol. Cell. Biol. 34, 110-122
   Abstract »    Full Text »    PDF »
Sestrin 3 regulation in type 2 diabetic patients and its influence on metabolism and differentiation in skeletal muscle.
E. B. Nascimento, M. E. Osler, and J. R. Zierath (2013)
Am J Physiol Endocrinol Metab 305, E1408-E1414
   Abstract »    Full Text »    PDF »
Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models.
F. Demontis, R. Piccirillo, A. L. Goldberg, and N. Perrimon (2013)
Dis. Model. Mech. 6, 1339-1352
   Abstract »    Full Text »    PDF »
Molecular Pathways: Reactive Oxygen Species Homeostasis in Cancer Cells and Implications for Cancer Therapy.
V. Nogueira and N. Hay (2013)
Clin. Cancer Res. 19, 4309-4314
   Abstract »    Full Text »    PDF »
Miniature curved artificial compound eyes.
D. Floreano, R. Pericet-Camara, S. Viollet, F. Ruffier, A. Bruckner, R. Leitel, W. Buss, M. Menouni, F. Expert, R. Juston, et al. (2013)
PNAS 110, 9267-9272
   Abstract »    Full Text »    PDF »
Cellular and molecular mechanisms of muscle atrophy.
P. Bonaldo and M. Sandri (2013)
Dis. Model. Mech. 6, 25-39
   Abstract »    Full Text »    PDF »
Gene expression changes governing extreme dehydration tolerance in an Antarctic insect.
N. M. Teets, J. T. Peyton, H. Colinet, D. Renault, J. L. Kelley, Y. Kawarasaki, R. E. Lee Jr, and D. L. Denlinger (2012)
PNAS 109, 20744-20749
   Abstract »    Full Text »    PDF »
Contribution of Impaired Mitochondrial Autophagy to Cardiac Aging: Mechanisms and Therapeutic Opportunities.
D. Dutta, R. Calvani, R. Bernabei, C. Leeuwenburgh, and E. Marzetti (2012)
Circ. Res. 110, 1125-1138
   Abstract »    Full Text »    PDF »
Mapping Autophagy on to Your Metabolic Radar.
E. Yamada and R. Singh (2012)
Diabetes 61, 272-280
   Full Text »    PDF »
Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks.
S. Alers, A. S. Loffler, S. Wesselborg, and B. Stork (2012)
Mol. Cell. Biol. 32, 2-11
   Abstract »    Full Text »    PDF »
Developmental trajectories of gene expression reveal candidates for diapause termination: a key life-history transition in the apple maggot fly Rhagoletis pomonella.
G. J. Ragland, S. P. Egan, J. L. Feder, S. H. Berlocher, and D. A. Hahn (2011)
J. Exp. Biol. 214, 3948-3960
   Abstract »    Full Text »    PDF »
Activation of hypoxia-inducible factor-1 protects airway epithelium against oxidant-induced barrier dysfunction.
N. Olson, M. Hristova, N. H. Heintz, K. M. Lounsbury, and A. van der Vliet (2011)
Am J Physiol Lung Cell Mol Physiol 301, L993-L1002
   Abstract »    Full Text »    PDF »
Drosophila, Genetic Screens, and Cardiac Function.
M. J. Wolf and H. A. Rockman (2011)
Circ. Res. 109, 794-806
   Abstract »    Full Text »    PDF »
FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model.
T. G. Schips, A. Wietelmann, K. Hohn, S. Schimanski, P. Walther, T. Braun, T. Wirth, and H. J. Maier (2011)
Cardiovasc Res 91, 587-597
   Abstract »    Full Text »    PDF »
Cellular stress response pathways and ageing: intricate molecular relationships.
N. Kourtis and N. Tavernarakis (2011)
EMBO J. 30, 2520-2531
   Abstract »    Full Text »    PDF »
Potential upstream regulators and downstream targets of AMP-activated kinase signaling during oocyte maturation in a marine worm.
S. A. Stricker (2011)
Reproduction 142, 29-39
   Abstract »    Full Text »    PDF »
mTor Signaling in Skeletal Muscle During Sepsis and Inflammation: Where Does It All Go Wrong?.
R. A. Frost and C. H. Lang (2011)
Physiology 26, 83-96
   Abstract »    Full Text »    PDF »
TOR and ageing: a complex pathway for a complex process.
M. A. McCormick, S.-y. Tsai, and B. K. Kennedy (2011)
Phil Trans R Soc B 366, 17-27
   Abstract »    Full Text »    PDF »
p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation.
R. Scherz-Shouval, H. Weidberg, C. Gonen, S. Wilder, Z. Elazar, and M. Oren (2010)
PNAS 107, 18511-18516
   Abstract »    Full Text »    PDF »
Stressin' Sestrins take an aging fight.
A. V. Budanov, J. H. Lee, and M. Karin (2010)
EMBO Mol Med. 2, 388-400
   Abstract »    Full Text »    PDF »
Paradoxical suppression of cellular senescence by p53.
Z. N. Demidenko, L. G. Korotchkina, A. V. Gudkov, and M. V. Blagosklonny (2010)
PNAS 107, 9660-9664
   Abstract »    Full Text »    PDF »
Burn Out or Fade Away?.
I. Topisirovic and N. Sonenberg (2010)
Science 327, 1210-1211
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882