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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Animals, Genetically Modified
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Caenorhabditis elegans / enzymology
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans / physiology*
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Caenorhabditis elegans Proteins / chemistry
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism*
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Forkhead Transcription Factors
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Gene Expression Regulation
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Insulin / metabolism
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Insulin-Like Growth Factor I / metabolism
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Longevity / genetics
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Longevity / physiology*
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Mutation
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Organ Specificity
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Phosphatidylinositol 3-Kinases / metabolism
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Promoter Regions, Genetic
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
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Superoxide Dismutase / genetics
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transgenes
Substances
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Caenorhabditis elegans Proteins
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Forkhead Transcription Factors
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Insulin
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Protein Isoforms
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Transcription Factors
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daf-16 protein, C elegans
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Insulin-Like Growth Factor I
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Sod-3 protein, C elegans
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Superoxide Dismutase
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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akt-1 protein, C elegans
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akt-2 protein, C elegans