Submitted to: Keystone Symposia
Publication Type: Abstract Only
Publication Acceptance Date: 3/1/2006
Publication Date: 4/2/2006
Citation: Wang, F., Tong, Q. 2006. SIRT2 deacetylates adn regulates FOXO3 function in response to nutrient deprivation and oxidative stress [abstract]. Keystone Symposia, Metabolomics: From Bioenergetics to Apoptosis, April 2-7, 2006, Snowbird, Utah. Abstract #329, p. 77. Interpretive Summary:
Technical Abstract: The sirtuin family of NAD-dependant deacetylases plays an important role in aging and metabolic regulation. Yeast Sir2 and Hst2, mediate the action of caloric restriction on life span extension in yeast. The mammalian Sir2 homolog, SIRT1, is up-regulated by caloric restriction and can deacetylate a variety of substrates, including histones, p53, NF'B and the O subfamily of Forkhead transcription factors (FOXO). Herein, we report that caloric restriction and oxidative stress elevate the protein level of the mammalian ortholog of Hst2, SIRT2, mainly in adipose tissue. We have demonstrated that SIRT2 binds to FOXO3a and reduces its acetylation level, leading to an increased binding of FOXO3a to its target gene promoter. Forced expression of SIRT2 increases FOXO transactivation, resulting in elevated expression of p27[Kip1], MnSOD and Bim; whereas, RNAi knockdown of SIRT2 decreases expression of these FOXO target genes. Consequently, SIRT2 overexpressing cells exhibit lower levels of reactive oxygen species (ROS) when treated with hydrogen peroxide. Furthermore, SIRT2 promotes cell death when cells are under stress. These results link SIRT2 to caloric restriction, the insulin signaling pathway and oxidative stress response, all key players of longevity determination, suggesting SIRT2 might play an important role in the regulation of longevity in mammals.