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

Authors: Ogg, S; Paradis, S; Gottlieb, S; Patterson, G I; Lee, L; Tissenbaum, H A; Ruvkun, G

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.

Keywords: Alternative Splicing; Amino Acid Sequence; Animals; Blood Proteins/chemistry; Caenorhabditis elegans/genetics/*metabolism; *Caenorhabditis elegans Proteins; DNA-Binding Proteins/chemistry; Forkhead Transcription Factors; Helminth Proteins/genetics/*metabolism; Humans; Insulin/*metabolism; *Longevity; Molecular Sequence Data; Mutation; *Phosphatidylinositol 3-Kinases; Receptor, Insulin/genetics/metabolism; *Signal Transduction; Transcription Factors/chemistry/genetics/*metabolism; Transduction, Genetic; Transforming Growth Factor beta/metabolism
Journal: Nature
Volume: 389
Issue: 6654
Pages: 994-9
Date: Nov. 14, 1997
PMID: 9353126
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Citation:

Ogg, S, Paradis, S, Gottlieb, S, Patterson, G I, Lee, L, Tissenbaum, H A, Ruvkun, G (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389: 994-9.


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