title: The Target of Rapamycin pathway antagonizes pha-4/FoxA to control development and aging.
abstract: BACKGROUND
  FoxA factors are critical regulators of embryonic development and postembryonic life, but little is know about the upstream pathways that modulate their activity. C. elegans pha-4 encodes a FoxA transcription factor that is required to establish the foregut in embryos and to control growth and longevity after birth. We previously identified the AAA+ ATPase homolog ruvb-1 as a potent suppressor of pha-4 mutations.
  
  
  RESULTS
  Here we show that ruvb-1 is a component of the Target of Rapamycin (TOR) pathway in C. elegans (CeTOR). Both ruvb-1 and let-363/TOR control nucleolar size and promote localization of box C/D snoRNPs to nucleoli, suggesting a role in rRNA maturation. Inactivation of let-363/TOR or ruvb-1 suppresses the lethality associated with reduced pha-4 activity. The CeTOR pathway controls protein homeostasis and also contributes to adult longevity. We find that pha-4 is required to extend adult lifespan in response to reduced CeTOR signaling. Mutations in the predicted CeTOR target rsks-1/S6 kinase or in ife-2/eIF4E also reduce protein biosynthesis and extend lifespan, but only rsks-1 mutations require pha-4 for adult longevity. In addition, rsks-1, but not ife-2, can suppress the larval lethality associated with pha-4 loss-of-function mutations.
  
  
  CONCLUSIONS
  The data suggest that pha-4 and the CeTOR pathway antagonize one another to regulate postembryonic development and adult longevity. We suggest a model in which nutrients promote TOR and S6 kinase signaling, which represses pha-4/FoxA, leading to a shorter lifespan. A similar regulatory hierarchy may function in other animals to modulate metabolism, longevity, or disease.
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Karyn L
authors.initials: KL
authors.lastname: Sheaffer
authors.forename: Dustin L
authors.initials: DL
authors.lastname: Updike
authors.forename: Susan E
authors.initials: SE
authors.lastname: Mango
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D007814:Larva / Q000502:physiology; D008136:Longevity; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000235:genetics; D034622:RNA Interference; D012261:Ribonucleoproteins / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D009687:Nuclear Proteins; C113277:Pha-4 protein, C elegans; D012261:Ribonucleoproteins; D015534:Trans-Activators; D012313:RNA; D017853:Phosphotransferases (Alcohol Group Acceptor); C472494:let-363 protein, C elegans