Nutrient Availability Regulates SIRT1 Through a Forkhead-Dependent Pathway

Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD 20892, USA.
Science (Impact Factor: 33.61). 01/2005; 306(5704):2105-8. DOI: 10.1126/science.1101731
Source: PubMed


Nutrient availability regulates life-span in a wide range of organisms. We demonstrate that in mammalian cells, acute nutrient
withdrawal simultaneously augments expression of the SIRT1 deacetylase and activates the Forkhead transcription factor Foxo3a.
Knockdown of Foxo3a expression inhibited the starvation-induced increase in SIRT1 expression. Stimulation of SIRT1 transcription
by Foxo3a was mediated through two p53 binding sites present in the SIRT1 promoter, and a nutrient-sensitive physical interaction
was observed between Foxo3a and p53. SIRT1 expression was not induced in starved p53-deficient mice. Thus, in mammalian cells,
p53, Foxo3a, and SIRT1, three proteins separately implicated in aging, constitute a nutrient-sensing pathway.

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    • "SIRT1 is the mammalian homolog of yeast silent information regulator-2 (Sir2), which is the most widely studied of the sirtuins [25] [26] [27]. SIRT1 expression increases under various physiological conditions, including nutrient starvation, aging, and cell stress such as oxidative stress [28] [29] [30]. "
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    ABSTRACT: Fluoride is an effective caries prophylactic, but at high doses can also be an environmental health hazard. Acute or chronic exposure to high fluoride doses can result in dental enamel and skeletal and soft tissue fluorosis. Dental fluorosis is manifested as mottled, discolored, porous enamel that is susceptible to dental caries. Fluoride induces cell stress, including endoplasmic reticulum stress and oxidative stress, which leads to impairment of ameloblasts responsible for dental enamel formation. Recently we reported that fluoride activates SIRT1 and autophagy as an adaptive response to protect cells from stress. However, it still remains unclear how SIRT1/autophagy is regulated in dental fluorosis. In this study, we demonstrate that fluoride exposure generates reactive oxygen species (ROS) and the resulting oxidative damage is counteracted by SIRT1/autophagy induction through JUN-terminal kinase (JNK) signaling in ameloblasts. In the mouse-ameloblast-derived cell line LS8, fluoride induced ROS, mitochondrial damage including cytochrome-c release, up-regulation of UCP2, attenuation of ATP synthesis, and H2AX phosphorylation (γH2AX), which is a marker of DNA damage. We evaluated the effects of the ROS inhibitor N-acetylcysteine (NAC) and the JNK inhibitor SP600125 on fluoride-induced SIRT1/autophagy activation. NAC decreased fluoride-induced ROS generation and attenuated JNK and c-Jun phosphorylation. NAC decreased SIRT1 phosphorylation and formation of the autophagy marker LC3II, which resulted in an increase in the apoptosis mediators γH2AX and cleaved/activated caspase-3. SP600125 attenuated fluoride-induced SIRT1 phosphorylation, indicating that fluoride activates SIRT1/autophagy via the ROS-mediated JNK pathway. In enamel organs from rats or mice treated with 50, 100, or 125ppm fluoride for 6 weeks, cytochrome-c release and the DNA damage markers 8-oxoguanine, p-ATM, and γH2AX were increased compared to those in controls (0ppm fluoride). These results suggest that fluoride-induced ROS generation causes mitochondrial damage and DNA damage, which may lead to impairment of ameloblast function. To counteract this impairment, SIRT1/autophagy is induced via JNK signaling to protect cells/ameloblasts from fluoride-induced oxidative damage that may cause dental fluorosis.
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    • "Silent mating type information regulation 2 homolog 1 (SIRT1) belongs to the class III histone deacetylase (HDAC) family. Best known as a regulator in stress signaling, [1] [2] SIRT1 also exerts control on tumor suppressor genes, [3] [4] and influences lifespan in many organism [5] [6] [7]. In both cell lines and tumor specimens from diverse malignancies, SIRT1 is highly expressed [8] and evidence for epigenetic modification of SIRT1 suggests it may contribute to emergence of drug resistance in cancer [9] [10]. "
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    Biochimica et Biophysica Acta (BBA) - General Subjects 11/2014; 1850(2):401-410. DOI:10.1016/j.bbagen.2014.11.007 · 4.38 Impact Factor
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    • "Sirt1 was reported to deacetylate various nonhistone protein targets, including p53, NF-κB, β-catenin, and FoxO3a [32–34]. Because H1299 cells do not express the tumor suppressor p53 protein, we used Western blot to analyze the protein level of β-catenin, NF-κB p65, and FoxO3a after sirtinol treatment (Figure 5). "
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    ABSTRACT: Sirtuins, NAD(+)-dependent deacetylases, could target both histones and nonhistone proteins in mammalian cells. Sirt1 is the major sirtuin and has been shown to involve various cellular processes, including antiapoptosis, cellular senescence. Sirt1 was reported to be overexpressed in many cancers, including lung cancer. Sirtinol, a specific inhibitor of Sirt1, has been shown to induce apoptosis of cancer cells by elevating endogenous level of reactive oxygen species. In the study, we investigated the effect of sirtinol on the proliferation and apoptosis of nonsmall cell lung cancer (NSCLC) H1299 cells. The results of proliferation assay and colony formation assay showed the antigrowth effect of sirtinol. The annexin-V staining further confirmed the apoptosis induction by sirtinol treatment. Interestingly, the levels of phosphorylated Akt and β-catenin were significantly downregulated with treating the apoptotic inducing doses. On the contrary, sirtinol treatment causes the significantly increased level of FoxO3a, a proapoptotic transcription factor targeted by Sirt1. These above results suggested that sirtinol may inhibit cell proliferation of H1299 cells by regulating the axis of Akt-β-catenin-FoxO3a. Overall, this study demonstrates that sirtinol attenuates the proliferation and induces apoptosis of NSCLC cells, indicating the potential treatment against NSCLC cells by inhibiting Sirt1 in future applications.
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