SMK-1, an essential regulator of DAF-16/FOXO3a mediated longevity
Hui Ma, Suzanne Wolff, Denise Burch, Gustavo Maciel, Pamela J. Woodring, Tony Hunter and Andrew Dillin
The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA
Insulin/IGF-1 signaling (IIS) regulates the aging process in worms,
flies and mice. In the nematode Caenorhabditis elegans, IIS regulates
processes in addition to aging such as early developmental decisions
and the reproductive status of the animal. We present evidence for the
placement of the uncharacterized gene, smk-1, within the insulin/IGF-1
pathway. Genetic analysis indicates that loss of smk-1 specifically
influences the aging related function of the DAF-2 (IIS) signaling
pathway. Localization analysis of DAF-16 places SMK-1 downstream of
DAF-16's phosphorylation-dependent relocation to the nucleus,
transcriptional assays indicate that SMK-1 is required for maximal
DAF-16/FOXO3a transcription, and physiological evidence suggests that
DAF-16 and SMK-1 are capable of functional interaction in the nuclei of
intestinal cells and neurons. Taken together, our data indicate that
SMK-1 is a new component of the IIS longevity pathway, and the first
that plays a role in longevity without affecting other processes
regulated by IIS, presumably by modulating DAF-16 transcriptional
specificity.
Key words:
insulin/IGF-1, C. elegans, longevity, FOXO3a, DAF-16
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