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Updated: Jul 3, 2026
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Published on: October 19, 2006
14-3-3 Epsilon antagonizes FoxO to control growth, apoptosis and longevity in Drosophila
Mette Damgaard Nielsen1, Xi Luo, Benoît Biteau
1Department of Biology, University of Rochester, Rochester, NY 14627, USA.
Abstract:
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 14-3-3epsilon antagonizes FoxO function in Drosophila. We find that dFoxO and 14-3-3epsilon proteins interact in vivo and that this interaction is lost in response to oxidative stress. Loss of 14-3-3epsilon 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 14-3-3epsilon reverts FoxO-induced growth defects. 14-3-3epsilon thus serves as a central modulator of FoxO activity in the regulation of growth, cell death and longevity in vivo.
Insights
14-3-3epsilon antagonizes the transcription factor FoxO in fruit flies, impacting growth, cell death, and lifespan. This interaction is lost during oxidative stress, leading to extended longevity and increased stress resistance.
Area of Science:
- Molecular biology
- Genetics
- Aging research
Background:
- Growth and stress signaling pathways are crucial for maintaining tissue homeostasis and longevity.
- The transcription factor FoxO plays a central role in regulating cell proliferation, stress responses, apoptosis, and lifespan.
- Insulin/IGF signaling phosphorylates FoxO, leading to its interaction with 14-3-3 proteins, but the consequences for biological processes and lifespan are not fully understood.
Purpose of the Study:
- To investigate the role of 14-3-3epsilon in antagonizing FoxO function in Drosophila.
- To elucidate the in vivo interaction between dFoxO and 14-3-3epsilon and its regulation by oxidative stress.
- To determine the impact of 14-3-3epsilon on FoxO-mediated regulation of growth, cell death, and longevity.
Main Methods:
- Genetic studies in Drosophila melanogaster.
- Biochemical interaction studies.
- Analysis of stress-induced apoptosis, growth repression, and lifespan.
Main Results:
- 14-3-3epsilon directly interacts with dFoxO in vivo.
- This interaction is disrupted by oxidative stress.
- Loss of 14-3-3epsilon leads to increased stress-induced apoptosis, growth repression, and extended lifespan.
- Overexpression of 14-3-3epsilon rescues FoxO-induced growth defects.
Conclusions:
- 14-3-3epsilon acts as a key antagonist of FoxO activity in Drosophila.
- The interaction between 14-3-3epsilon and dFoxO modulates growth, cell death, and longevity.
- 14-3-3epsilon is a central regulator of FoxO-dependent processes in vivo.
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