Publication Date:
2010-03-06
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866632/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866632/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jun Hee -- Budanov, Andrei V -- Park, Eek Joong -- Birse, Ryan -- Kim, Teddy E -- Perkins, Guy A -- Ocorr, Karen -- Ellisman, Mark H -- Bodmer, Rolf -- Bier, Ethan -- Karin, Michael -- AI070654/AI/NIAID NIH HHS/ -- CA118165/CA/NCI NIH HHS/ -- DK082080/DK/NIDDK NIH HHS/ -- ES006376/ES/NIEHS NIH HHS/ -- NS29870/NS/NINDS NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- P30-CA23100/CA/NCI NIH HHS/ -- P41-RR004050/RR/NCRR NIH HHS/ -- P42 ES010337/ES/NIEHS NIH HHS/ -- P42 ES010337-10S20010/ES/NIEHS NIH HHS/ -- P42-ES010337/ES/NIEHS NIH HHS/ -- R01 CA118165/CA/NCI NIH HHS/ -- R01 CA118165-04/CA/NCI NIH HHS/ -- R01 ES006376/ES/NIEHS NIH HHS/ -- R01 ES006376-17/ES/NIEHS NIH HHS/ -- New York, N.Y. -- Science. 2010 Mar 5;327(5970):1223-8. doi: 10.1126/science.1182228.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093-0723, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20203043" target="_blank"〉PubMed〈/a〉
Keywords:
AMP-Activated Protein Kinases/metabolism
;
*Aging
;
Amino Acid Sequence
;
Animals
;
Autophagy
;
Cell Size
;
Drosophila Proteins/antagonists &
;
inhibitors/chemistry/genetics/metabolism/*physiology
;
Drosophila melanogaster/cytology/growth & development/metabolism/*physiology
;
Fat Body/metabolism
;
Feedback, Physiological
;
Forkhead Transcription Factors/metabolism
;
Gene Expression Regulation
;
Heart/physiology
;
Heat-Shock Proteins/chemistry/genetics/*physiology
;
JNK Mitogen-Activated Protein Kinases/metabolism
;
Mitochondria, Muscle/physiology/ultrastructure
;
Models, Animal
;
Molecular Sequence Data
;
Muscles/physiology
;
Oxidative Stress
;
Protein Kinases/*metabolism
;
Reactive Oxygen Species/metabolism
;
Signal Transduction
;
TOR Serine-Threonine Kinases
;
Transcription, Genetic
;
Triglycerides/metabolism
;
Wings, Animal/cytology/growth & development/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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