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 Posted: Tue Nov 04, 2008 4:23 am Post subject: The Target of Rapamycin pathway antagonizes pha-4/FoxA to co |
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Curr Biol. 2008 Sep 23;18(18):1355-64.
The Target of Rapamycin pathway antagonizes pha-4/FoxA to control
development and aging.
Sheaffer KL, Updike DL, Mango SE.
Department of Oncological Sciences, Huntsman Cancer Institute,
University of Utah, Salt Lake City, UT 84112, USA.
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.
PMID: 18804378 [PubMed - in process] |
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