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Life Span Extension and Neuronal Cell Protection by Drosophila Nicotinamidase
- Source :
- Journal of Biological Chemistry. 283:27810-27819
- Publication Year :
- 2008
- Publisher :
- Elsevier BV, 2008.
-
Abstract
- The life span of model organisms can be modulated by environmental conditions that influence cellular metabolism, oxidation, or DNA integrity. The yeast nicotinamidase gene pnc1 was identified as a key transcriptional target and mediator of calorie restriction and stress-induced life span extension. PNC1 is thought to exert its effect on yeast life span by modulating cellular nicotinamide and NAD levels, resulting in increased activity of Sir2 family class III histone deacetylases. In Caenorhabditis elegans, knockdown of a pnc1 homolog was shown recently to shorten the worm life span, whereas its overexpression increased survival under conditions of oxidative stress. The function and regulation of nicotinamidases in higher organisms has not been determined. Here, we report the identification and biochemical characterization of the Drosophila nicotinamidase, D-NAAM, and demonstrate that its overexpression significantly increases median and maximal fly life span. The life span extension was reversed in Sir2 mutant flies, suggesting Sir2 dependence. Testing for physiological effectors of D-NAAM in Drosophila S2 cells, we identified oxidative stress as a primary regulator, both at the transcription level and protein activity. In contrast to the yeast model, stress factors such as high osmolarity and heat shock, calorie restriction, or inhibitors of TOR and phosphatidylinositol 3-kinase pathways do not appear to regulate D-NAAM in S2 cells. Interestingly, the expression of D-NAAM in human neuronal cells conferred protection from oxidative stress-induced cell death in a sirtuin-dependent manner. Together, our findings establish a life span extending the ability of nicotinamidase in flies and offer a role for nicotinamide-modulating genes in oxidative stress regulated pathways influencing longevity and neuronal cell survival.
- Subjects :
- Transcription, Genetic
Cell Survival
Longevity
Saccharomyces cerevisiae
Cell
Calorie restriction
Models, Biological
Biochemistry
Histone Deacetylases
Phosphatidylinositol 3-Kinases
Molecular Basis of Cell and Developmental Biology
Osmotic Pressure
Chlorocebus aethiops
medicine
Animals
Drosophila Proteins
Humans
Sirtuins
Heat shock
Molecular Biology
Caloric Restriction
Neurons
biology
Schneider 2 cells
Cell Biology
biology.organism_classification
Nicotinamidase
Oxidative Stress
Drosophila melanogaster
medicine.anatomical_structure
COS Cells
Mutation
Heat-Shock Response
Drosophila Protein
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 283
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....9d858e14f3b5cb8af1601be5473ea2b0