The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans

Nature. 1997 Oct 30;389(6654):994-9. doi: 10.1038/40194.

Abstract

In mammals, insulin signalling regulates glucose transport together with the expression and activity of various metabolic enzymes. In the nematode Caenorhabditis elegans, a related pathway regulates metabolism, development and longevity. Wild-type animals enter the developmentally arrested dauer stage in response to high levels of a secreted pheromone, accumulating large amounts of fat in their intestines and hypodermis. Mutants in DAF-2 (a homologue of the mammalian insulin receptor) and AGE-1 (a homologue of the catalytic subunit of mammalian phosphatidylinositol 3-OH kinase) arrest development at the dauer stage. Moreover, animals bearing weak or temperature-sensitive mutations in daf-2 and age-1 can develop reproductively, but nevertheless show increased energy storage and longevity. Here we show that null mutations in daf-16 suppress the effects of mutations in daf-2 or age-1; lack of daf-16 bypasses the need for this insulin receptor-like signalling pathway. The principal role of DAF-2/AGE-1 signalling is thus to antagonize DAF-16. daf-16 is widely expressed and encodes three members of the Fork head family of transcription factors. The DAF-2 pathway acts synergistically with the pathway activated by a nematode TGF-beta-type signal, DAF-7, suggesting that DAF-16 cooperates with nematode SMAD proteins in regulating the transcription of key metabolic and developmental control genes. The probable human orthologues of DAF-16, FKHR and AFX, may also act downstream of insulin signalling and cooperate with TGF-beta effectors in mediating metabolic regulation. These genes may be dysregulated in diabetes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Blood Proteins / chemistry
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins*
  • DNA-Binding Proteins / chemistry
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Helminth Proteins / genetics
  • Helminth Proteins / metabolism*
  • Humans
  • Insulin / metabolism*
  • Longevity*
  • Molecular Sequence Data
  • Mutation
  • Phosphatidylinositol 3-Kinases*
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Signal Transduction*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transduction, Genetic
  • Transforming Growth Factor beta / metabolism

Substances

  • Blood Proteins
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • FOXO1 protein, human
  • FOXO4 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Helminth Proteins
  • Insulin
  • Transcription Factors
  • Transforming Growth Factor beta
  • daf-16 protein, C elegans
  • Phosphatidylinositol 3-Kinases
  • AGE-1 protein, C elegans
  • DAF-2 protein, C elegans
  • Receptor, Insulin

Associated data

  • GENBANK/AF020342
  • GENBANK/AF020343
  • GENBANK/AF020344