Authors: Lin, K; Hsin, H; Libina, N; Kenyon, C
Abstract: The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long. This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor. DAF-16 is thought to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is thought to lead to phosphorylation of DAF-16 by AKT activity, which in turn shortens lifespan. Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei. Disrupting Akt-consensus phosphorylation sites in DAF-16 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outputs. Lifespan in C. elegans can be extended by perturbing sensory neurons or germ cells. In both cases, lifespan extension requires DAF-16. We find that both sensory neurons and germline activity regulate DAF-16 accumulation in nuclei, but the nuclear localization patterns are different. Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging.
Keywords: Animals; Caenorhabditis elegans/*physiology; *Caenorhabditis elegans Proteins; Cell Nucleus/metabolism; Gene Expression Regulation; Germ Cells/metabolism; Helminth Proteins/genetics/*metabolism; Insulin/metabolism; Insulin-Like Growth Factor I/*metabolism; Longevity/genetics; Mutation; Neurons, Afferent/pathology/physiology; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; Receptor, Insulin/genetics/metabolism; *Signal Transduction; Stress, Physiological; Transcription Factors/genetics/*metabolism; Transcription, Genetic|
Journal: Nat Genet Volume: 28 Issue: 2 Pages: 139-45 Date: May 31, 2001 PMID: 11381260 |
Lin, K, Hsin, H, Libina, N, Kenyon, C (2001) Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28: 139-45.
Comment on This Data Unit