Authors: Zhang Y; Xu J; Puscau C; Kim Y; Wang X; Alam H; Hu PJ
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.
Keywords: Alleles; Animals; Animals, Genetically Modified; Base Sequence; Caenorhabditis elegans/genetics/*growth & development/*metabolism; Caenorhabditis elegans Proteins/genetics/*metabolism; Cell Nucleus/metabolism; Cloning, Molecular; Cytochrome P-450 Enzyme System/genetics/metabolism; DNA Primers/genetics; DNA, Helminth/genetics; Forkhead Transcription Factors/genetics/*metabolism; Gene Expression Regulation, Developmental; Genes, Helminth; Green Fluorescent Proteins/genetics/metabolism; Longevity/genetics/physiology; Models, Biological; Mutation; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Receptor, Insulin/genetics/metabolism; Recombinant Fusion Proteins/genetics/metabolism; Transcription Factors/genetics/*metabolism|
Journal: Developmental biology Volume: 315 Issue: 2 Pages: 290-302 Date: Feb. 5, 2008 PMID: 18241854 |
Zhang Y, Xu J, Puscau C, Kim Y, Wang X, Alam H, Hu PJ (2008) Caenorhabditis elegans EAK-3 inhibits dauer arrest via nonautonomous regulation of nuclear DAF-16/FoxO activity. Developmental biology 315: 290-302.
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