title: 14-3-3 Epsilon antagonizes FoxO to control growth, apoptosis and longevity in Drosophila.
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.
authors.affiliation: Department of Biology, University of Rochester, Rochester, NY 14627, USA.
authors.forename: Mette Damgaard
authors.initials: MD
authors.lastname: Nielsen
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.forename: Benoît
authors.initials: B
authors.lastname: Biteau
authors.forename: Keith
authors.initials: K
authors.lastname: Syverson
authors.forename: Heinrich
authors.initials: H
authors.lastname: Jasper
mesh_terms: D048948:14-3-3 Proteins / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics / Q000254:growth & development*; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008297:Male; D018384:Oxidative Stress / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D012160:Retina / Q000254:growth & development / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D048948:14-3-3 Proteins; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms