Journal
AGING CELL
Volume 7, Issue 5, Pages 688-699Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1474-9726.2008.00420.x
Keywords
14-3-3; aging; apoptosis; FoxO; insulin signaling; oxidative stress
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Funding
- Lundbeck Foundation
- National Institutes of Health [R01 AG026691, R01 AG028127]
- Lundbeck Foundation [R7-2006-665] Funding Source: researchfish
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Antagonism between growth-promoting and stress-responsive signaling influences tissue homeostasis and longevity in metazoans. The transcription factor FoxO is central to this regulation, affecting cell proliferation, stress responses, apoptosis, and longevity. Insulin/IGF signaling promotes FoxO phosphorylation, causing its interaction with 14-3-3 molecules. The consequences of this interaction for FoxO-induced biological processes and for the regulation of lifespan in higher organisms remain unclear. Significant complexities in the effects of 14-3-3 proteins on lifespan have been uncovered in Caenorhabditis elegans, suggesting both positive and negative roles for 14-3-3 proteins in the control of aging. Using genetic and biochemical studies, we show here that 14-3-3 epsilon antagonizes FoxO function in Drosophila. We find that dFoxO and 14-3-3 epsilon proteins interact in vivo and that this interaction is lost in response to oxidative stress. Loss of 14-3-3 epsilon results in increased stress-induced apoptosis, growth repression and extended lifespan of flies, phenotypes associated with elevated FoxO function. Our results further show that increased expression of 14-3-3 epsilon reverts FoxO-induced growth defects. 14-3-3 epsilon thus serves as a central modulator of FoxO activity in the regulation of growth, cell death and longevity in vivo.
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