Cell-nonautonomous signaling of FOXO/DAF-16 to the stem cells of Caenorhabditis elegans

PLoS Genet. 2012;8(8):e1002836. doi: 10.1371/journal.pgen.1002836. Epub 2012 Aug 16.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Developmental
  • Germ Cells / cytology
  • Germ Cells / metabolism
  • Humans
  • Longevity / genetics*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Somatomedin / genetics
  • Receptors, Somatomedin / metabolism
  • Shc Signaling Adaptor Proteins / genetics
  • Shc Signaling Adaptor Proteins / metabolism
  • Signal Transduction / genetics*
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Receptors, Somatomedin
  • Shc Signaling Adaptor Proteins
  • Transcription Factors
  • daf-16 protein, C elegans
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Sgk-1 protein, C elegans
  • akt-1 protein, C elegans
  • akt-2 protein, C elegans