Disease relevance of Sirt1

• These results suggest that endogenous Sir2alpha plays an essential role in mediating cell survival, whereas Sir2alpha overexpression protects myocytes from apoptosis and causes modest hypertrophy [1].
• In short, the results suggest that H2A.z is required for cardiac hypertrophy, where its stability and the extent of cell growth and apoptosis are moderated by Sir2alpha [2].

High impact information on Sirt1

• We review Sir2, a factor linking genomic stability, metabolism, and aging [3].
• We report that Sir2 activation through increased sir-2.1 dosage or treatment with the sirtuin activator resveratrol specifically rescued early neuronal dysfunction phenotypes induced by mutant polyglutamines in transgenic Caenorhabditis elegans [4].
• Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response [5].
• The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast [5].
• Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo [5].

Biological context of Sirt1

• Gene expression profiling with oligonucleotide microarrays also demonstrated a significant correlation between the expression profiles of Nampt- and Sir2alpha-overexpressing cells [6].
• Increased dosage of Nampt, but not Nmnat, increased the total cellular NAD level and enhanced the transcriptional regulatory activity of the catalytic domain of Sir2alpha recruited onto a reporter gene in mouse fibroblasts [6].
• Negative control of p53 by Sir2alpha promotes cell survival under stress [5].
• We found that the level of Sir2alpha expression during embryogenesis was high [7].
• 5. Quantitative reverse transcription polymerase chain reaction showed a 60% reduction in Sir2alpha mRNA content in the heart between E12.5 and E14 [7].

Anatomical context of Sirt1

• We show that Sirt1 positively regulates insulin secretion in pancreatic beta cells [8].
• Microarray analyses of beta cell lines reveal that Sirt1 regulates genes involved in insulin secretion, including uncoupling protein 2 (Ucp2) [9].
• In embryos, Sir2alpha was expressed at high levels in the heart, brain, spinal cord, and dorsal root ganglia [7].
• Cardiac myocytes express Sir2alpha predominantly in the nucleus [1].
• Activation of Sirt1 has recently been shown to decrease adipocyte development from preadipocytes through inhibition of PPARgamma2 [10].

Associations of Sirt1 with chemical compounds

• Pancreatic perfusion experiments further demonstrate that Sirt1 enhances insulin secretion in response to glucose and KCl [9].
• Treatment with the plant polyphenol resveratrol as well as isonicotinamide, both of which activate Sirt1, blocked adipocyte development and increased the expression of osteoblast markers [10].
• Furthermore, activation of Sirt1 prevented the increase in adipocytes caused by the PPARgamma-agonist troglitazone [10].
• Sir2 family deacetylases, which regulate acetyl-coenzyme A synthesis, have recently been shown to impart longevity in a variety of organisms through a pathway related to calorie restriction [11].
• This type of cell death was blocked by repletion of cellular NAD levels as well as by activation of the longevity factor Sir2alpha deacetylase, indicating that PARP induction and subsequent depletion of NAD levels are the sequence of events causing angiotensin II-mediated cardiomyocyte cell death [12].

Physical interactions of Sirt1

• Here, we show that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions [5].

Other interactions of Sirt1

• These findings suggest that NAD biosynthesis mediated by Nampt regulates the function of Sir2alpha and thereby plays an important role in controlling various biological events in mammals [6].
• Our findings establish Foxo1 as a direct and functional target for Sir2 in mammalian systems [13].
• Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha [5].
• Predominant expression of Sir2alpha, an NAD-dependent histone deacetylase, in the embryonic mouse heart and brain [7].
• Sir2 is recruited to insulin response sequence-containing promoter and increases the expression of manganese superoxide dismutase and p27(kip1) in a deacetylase-activity-dependent manner [13].

References