A new DAF-16 isoform regulates longevity
Program in Gene Function and Expression
Medical Subject Headings
Active Transport, Cell Nucleus; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Gene Expression Regulation; Insulin; Insulin-Like Growth Factor I; Longevity; Mutation; Organ Specificity; Phosphatidylinositol 3-Kinases; Promoter Regions, Genetic; Protein Isoforms; Proto-Oncogene Proteins c-akt; Signal Transduction; Superoxide Dismutase; Transcription Factors; Transgenes
Genetics and Genomics
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.
Rights and Permissions
Citation: Nature. 2010 Jul 22;466(7305):498-502. Epub 2010 Jul 7. Link to article on publisher's site