Abstract
Insulin regulates development, metabolism, and lifespan via a conserved PI3K/Akt pathway that promotes cytoplasmic sequestration of FoxO transcription factors. The regulation of nuclear FoxO is poorly understood. In the nematode Caenorhabditis elegans, insulin-like signaling functions in larvae to inhibit dauer arrest and acts during adulthood to regulate lifespan. In a screen for genes that modulate C. elegans insulin-like signaling, we identified eak-3, which encodes a novel protein that is specifically expressed in the two endocrine XXX cells. The dauer arrest phenotype of eak-3 mutants is fully suppressed by mutations in daf-16/FoxO, which encodes the major target of C. elegans insulin-like signaling, and daf-12, which encodes a nuclear receptor regulated by steroid hormones known as dafachronic acids. eak-3 mutation does not affect DAF-16/FoxO subcellular localization but enhances expression of the direct DAF-16/FoxO target sod-3 in a daf-16/FoxO- and daf-12-dependent manner. eak-3 mutants have normal lifespans, suggesting that EAK-3 decouples insulin-like regulation of development and longevity. We propose that EAK-3 activity in the XXX cells promotes the synthesis and/or secretion of a hormone that acts in parallel to AKT-1 to inhibit the expression of DAF-16/FoxO target genes. Similar hormonal pathways may regulate FoxO target gene expression in mammals.
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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Alleles
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Animals
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Animals, Genetically Modified
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Base Sequence
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / growth & development*
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Caenorhabditis elegans / metabolism*
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism*
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Cell Nucleus / metabolism
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Cloning, Molecular
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism
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DNA Primers / genetics
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DNA, Helminth / genetics
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Gene Expression Regulation, Developmental
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Genes, Helminth
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Longevity / genetics
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Longevity / physiology
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Models, Biological
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Mutation
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Polymerase Chain Reaction
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Polymorphism, Single Nucleotide
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Receptor, Insulin / genetics
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Receptor, Insulin / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Caenorhabditis elegans Proteins
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DNA Primers
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DNA, Helminth
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Forkhead Transcription Factors
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Recombinant Fusion Proteins
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Transcription Factors
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daf-16 protein, C elegans
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Green Fluorescent Proteins
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Cytochrome P-450 Enzyme System
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DAF-9 protein, C elegans
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DAF-2 protein, C elegans
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Receptor, Insulin