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PMID:18460334

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Citation

Wang, B, Goode, J, Best, J, Meltzer, J, Schilman, PE, Chen, J, Garza, D, Thomas, JB and Montminy, M (2008) The insulin-regulated CREB coactivator TORC promotes stress resistance in Drosophila. Cell Metab. 7:434-44

Abstract

In fasted mammals, glucose homeostasis is maintained through induction of the cAMP response element-binding protein (CREB) coactivator transducer of regulated CREB activity 2 (TORC2), which stimulates the gluconeogenic program in concert with the forkhead factor FOXO1. Here we show that starvation also triggers TORC activation in Drosophila, where it maintains energy balance through induction of CREB target genes in the brain. TORC mutant flies have reduced glycogen and lipid stores and are sensitive to starvation and oxidative stress. Neuronal TORC expression rescued stress sensitivity as well as CREB target gene expression in TORC mutants. During refeeding, increases in insulin signaling inhibited TORC activity through the salt-inducible kinase 2 (SIK2)-mediated phosphorylation and subsequent degradation of TORC. Depletion of neuronal SIK2 increased TORC activity and enhanced stress resistance. As disruption of insulin signaling also augmented TORC activity in adult flies, our results illustrate the importance of an insulin-regulated pathway that functions in the brain to maintain energy balance.

Links

PubMed Online version:10.1016/j.cmet.2008.02.010

Keywords

Animals; Animals, Genetically Modified; Blotting, Western; Brain/metabolism; Cyclic AMP Response Element-Binding Protein/metabolism; Drosophila Proteins/metabolism; Drosophila melanogaster; Female; Glycogen/metabolism; Hypoglycemic Agents/pharmacology; Insulin/pharmacology; Lipids; Male; Neurons/metabolism; Oxidative Stress; Peptide Fragments/immunology; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; Starvation; Transcription Factors/metabolism

Significance

Annotations

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

DROME:M9PFU2

involved_in

GO:0042594: response to starvation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:M9PFU2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:M9PFU2

involved_in

GO:0006979: response to oxidative stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:M9PFU2

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:M9PFU2

involved_in

GO:0032793: positive regulation of CREB transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:M9PFU2

involved_in

GO:0071320: cellular response to cAMP

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9W532

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:Q9W532

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9W532

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0010379

P

Seeded From UniProt

complete


See also

References

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