JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling.
Aging of a eukaryotic organism is affected by its nutrition state and by its ability to prevent or repair oxidative damage. Consequently, signal transduction systems that control metabolism and oxidative stress responses influence life span. When nutrients are abundant, the insulin/IGF signaling (IIS) pathway promotes growth and energy storage but shortens life span. The transcription factor Foxo, which is inhibited by IIS, extends life span in conditions of low IIS activity. Life span can also be increased by activating the stress-responsive Jun-N-terminal kinase (JNK) pathway. Here we show that JNK requires Foxo to extend life span in Drosophila. JNK antagonizes IIS, causing nuclear localization of Foxo and inducing its targets, including growth control and stress defense genes. JNK and Foxo also restrict IIS activity systemically by repressing IIS ligand expression in neuroendocrine cells. The convergence of JNK signaling and IIS on Foxo provides a model to explain the effects of stress and nutrition on longevity.
Wang
Meng C
MC
Department of Biomedical Genetics, The Aab Institute of Biomedical Sciences, University of Rochester Medical Center, 601 Elmwood Avenue, Box 633, Rochester, New York 14642, USA.
Bohmann
Dirk
D
Jasper
Heinrich
H
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D005123:Eye / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D051858:Forkhead Transcription Factors; D007328:Insulin / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D007328:Insulin; D013002:Somatomedins; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases