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A new DAF-16 isoform regulates longevity.

Authors
  • Kwon, Eun-Soo
  • Narasimhan, Sri Devi
  • Yen, Kelvin
  • Tissenbaum, Heidi A
Type
Published Article
Journal
Nature
Publisher
Springer Nature
Publication Date
Jul 22, 2010
Volume
466
Issue
7305
Pages
498–502
Identifiers
DOI: 10.1038/nature09184
PMID: 20613724
Source
Medline
License
Unknown

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.

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