Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Caenorhabditis elegans / genetics
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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 Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Forkhead Transcription Factors
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Gene Expression Regulation, Developmental
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Germ Cells / cytology
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Germ Cells / metabolism
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Humans
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Longevity / genetics*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / 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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Receptors, Somatomedin / genetics
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Receptors, Somatomedin / metabolism
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Shc Signaling Adaptor Proteins / genetics
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Shc Signaling Adaptor Proteins / metabolism
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Signal Transduction / genetics*
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Stem Cells / cytology
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Stem Cells / 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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Forkhead Transcription Factors
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Receptors, Somatomedin
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Shc Signaling Adaptor Proteins
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Transcription Factors
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daf-16 protein, C elegans
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Sgk-1 protein, C elegans
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akt-1 protein, C elegans
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akt-2 protein, C elegans