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PMID:20203043

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Citation

Lee, JH, Budanov, AV, Park, EJ, Birse, R, Kim, TE, Perkins, GA, Ocorr, K, Ellisman, MH, Bodmer, R, Bier, E and Karin, M (2010) Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327:1223-8

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.

Links

PubMed PMC2866632 Online version:10.1126/science.1182228

Keywords

AMP-Activated Protein Kinases/metabolism; Aging; Amino Acid Sequence; Animals; Autophagy; Cell Size; Drosophila Proteins/antagonists & inhibitors; Drosophila Proteins/chemistry; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila Proteins/physiology; Drosophila melanogaster/cytology; Drosophila melanogaster/growth & development; Drosophila melanogaster/metabolism; Drosophila melanogaster/physiology; Fat Body/metabolism; Feedback, Physiological; Forkhead Transcription Factors/metabolism; Gene Expression Regulation; Heart/physiology; Heat-Shock Proteins/chemistry; Heat-Shock Proteins/genetics; Heat-Shock Proteins/physiology; JNK Mitogen-Activated Protein Kinases/metabolism; Mitochondria, Muscle/physiology; Mitochondria, Muscle/ultrastructure; Models, Animal; Molecular Sequence Data; Muscles/physiology; Oxidative Stress; Protein Kinases/metabolism; Reactive Oxygen Species/metabolism; Signal Transduction; Transcription, Genetic; Triglycerides/metabolism; Wing/cytology; Wing/growth & development; Wing/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:INSR

involved_in

GO:2000377: regulation of reactive oxygen species metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SESN1

involved_in

GO:0030308: negative regulation of cell growth

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9U9A9

involved_in

GO:2000377: regulation of reactive oxygen species metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9VCC9

involved_in

GO:2000377: regulation of reactive oxygen species metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:TOR

involved_in

GO:2000377: regulation of reactive oxygen species metabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0283499

P

Seeded From UniProt

complete

DROME:RHEB

involved_in

GO:2000377: regulation of reactive oxygen species metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:SESN

involved_in

GO:0030308: negative regulation of cell growth

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:SESN

involved_in

GO:0000422: autophagy of mitochondrion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:SESN

involved_in

GO:0010259: multicellular organism aging

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:SESN

involved_in

GO:2000377: regulation of reactive oxygen species metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SESN2

involved_in

GO:0030308: negative regulation of cell growth

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:P91634

involved_in

GO:2000377: regulation of reactive oxygen species metabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0283499

P

Seeded From UniProt

complete


See also

References

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