Cell-nonautonomous signaling of FOXO/DAF-16 to the stem cells of Caenorhabditis elegans.
In Caenorhabditis elegans (C. elegans), the promotion of longevity by the transcription factor DAF-16 requires reduced insulin/IGF receptor (IIR) signaling or the ablation of the germline, although the reason for the negative impact of germ cells is unknown. FOXO/DAF-16 activity inhibits germline proliferation in both daf-2 mutants and gld-1 tumors. In contrast to its function as a germline tumor suppressor, we now provide evidence that somatic DAF-16 in the presence of IIR signaling can also result in tumorigenic activity, which counteracts robust lifespan extension. In contrast to the cell-autonomous IIR signaling, which is required for larval germline proliferation, activation of DAF-16 in the hypodermis results in hyperplasia of the germline and disruption of the surrounding basement membrane. SHC-1 adaptor protein and AKT-1 kinase antagonize, whereas AKT-2 and SGK-1 kinases promote, this cell-nonautonomous DAF-16 function. Our data suggest that a functional balance of DAF-16 activities in different tissues determines longevity and reveals a novel, cell-nonautonomous role of FOXO/DAF-16 to affect stem cells.
Faculty of Biology, Bioinformatics, and Molecular Genetics, Center for Biochemistry and Molecular Cell Research, Freiburg, Germany.
Wenjing
W
Qi
Xu
X
Huang
Elke
E
Neumann-Haefelin
Ekkehard
E
Schulze
Ralf
R
Baumeister
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008136:Longevity / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D017451:Receptors, Somatomedin; D055765:Shc Signaling Adaptor Proteins; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C540745:Sgk-1 protein, C elegans; C494915:akt-1 protein, C elegans; C494916:akt-2 protein, C elegans