Expression of dominant-negative Dmp53 in the adult fly brain inhibits insulin signaling

In Drosophila melanogaster, p53 (Dmp53) is an important mediator of longevity. Expression of dominant-negative (DN) forms of Dmp53 in adult neurons, but not in muscle or fat body cells, extends lifespan. The lifespan of calorie-restricted flies is not further extended by simultaneously expressing DN-Dmp53 in the nervous system, indicating that a decrease in Dmp53 activity may be a part of the CR lifespan-extending pathway in flies. In this report, we show that selective expression of DN-Dmp53 in only the 14 insulin-producing cells (IPCs) in the brain extends lifespan to the same extent as expression in all neurons and this lifespan extension is not additive with CR. DN-Dmp53-dependent lifespan extension is accompanied by reduction of Drosophila insulin-like peptide 2 (dILP2) mRNA levels and reduced insulin signaling (IIS) in the fat body, which suggests that Dmp53 may affect lifespan by modulating insulin signaling in the fly.

[1]  S. W. Oh,et al.  C. elegans 14-3-3 proteins regulate life span and interact with SIR-2.1 and DAF-16/FOXO , 2006, Mechanisms of Ageing and Development.

[2]  S. Helfand,et al.  Neuronal Expression of p53 Dominant-Negative Proteins in Adult Drosophila melanogaster Extends Life Span , 2005, Current Biology.

[3]  P. Shen,et al.  Regulation of aversion to noxious food by Drosophila neuropeptide Y– and insulin-like systems , 2005, Nature Neuroscience.

[4]  T. Obsil,et al.  14-3-3 Protein interacts with nuclear localization sequence of forkhead transcription factor FoxO4. , 2005, Biochemistry.

[5]  E. Hafen,et al.  Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  E. Hafen,et al.  Cancer, type 2 diabetes, and ageing: news from flies and worms. , 2004, Swiss medical weekly.

[7]  B. Rogina,et al.  Sir2 mediates longevity in the fly through a pathway related to calorie restriction. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  L. Donehower,et al.  Diet-gene interactions in p53-deficient mice: insulin-like growth factor-1 as a mechanistic target. , 2004, The Journal of nutrition.

[9]  E. Hafen,et al.  Long-Lived Drosophila with Overexpressed dFOXO in Adult Fat Body , 2004, Science.

[10]  M. Tatar,et al.  Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body , 2004, Nature.

[11]  Marten P Smidt,et al.  The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. , 2004, The Biochemical journal.

[12]  S. Benzer,et al.  Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway , 2004, Current Biology.

[13]  K. Mohammad,et al.  Modulation of mammalian life span by the short isoform of p53. , 2004, Genes & development.

[14]  D. E. Anderson,et al.  Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. , 2003, Biochemistry.

[15]  D. Goberdhan,et al.  The functions of insulin signaling: size isn't everything, even in Drosophila. , 2003, Differentiation; research in biological diversity.

[16]  M. Tatar,et al.  The Endocrine Regulation of Aging by Insulin-like Signals , 2003, Science.

[17]  P. Auluck,et al.  Pharmacological prevention of Parkinson disease in Drosophila , 2002, Nature Medicine.

[18]  U. Heberlein,et al.  Functional Dissection of Neuroanatomical Loci Regulating Ethanol Sensitivity in Drosophila , 2002, The Journal of Neuroscience.

[19]  K. Nairz,et al.  Nutrient-Dependent Expression of Insulin-like Peptides from Neuroendocrine Cells in the CNS Contributes to Growth Regulation in Drosophila , 2002, Current Biology.

[20]  R. Nusse,et al.  Ablation of Insulin-Producing Neurons in Flies: Growth and Diabetic Phenotypes , 2002, Science.

[21]  J. S. Britton,et al.  Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. , 2002, Developmental cell.

[22]  J. Schulte,et al.  Peripheral glia direct axon guidance across the CNS/PNS transition zone. , 2001, Developmental biology.

[23]  M. Tatar,et al.  A Mutant Drosophila Insulin Receptor Homolog That Extends Life-Span and Impairs Neuroendocrine Function , 2001, Science.

[24]  E. Hafen,et al.  Extension of Life-Span by Loss of CHICO, a Drosophila Insulin Receptor Substrate Protein , 2001, Science.

[25]  G. Rubin,et al.  Drosophila p53 Binds a Damage Response Element at the reaper Locus , 2000, Cell.

[26]  L. Partridge,et al.  Female fitness in Drosophila melanogaster: an interaction between the effect of nutrition and of encounter rate with males , 1996, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[27]  T. Kitamoto,et al.  Analysis of cis-regulatory elements in the 5' flanking region of the Drosophila melanogaster choline acetyltransferase gene , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.