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Nature. 2010 Jul 22;466(7305):498-502. doi: 10.1038/nature09184. Epub 2010 Jul 7.

A new DAF-16 isoform regulates longevity.

Author information

  • 1Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

Abstract

The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway. One of two isoforms, DAF-16a, is known to regulate longevity, stress response and dauer diapause. However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.

PMID:
20613724
[PubMed - indexed for MEDLINE]
PMCID:
PMC3109862
Free PMC Article

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