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T Jayasena, A Poljak, N Braidy, L Zhong, B Rowlands, J Muenchhoff, R Grant, G Smythe, C Teo, M Raftery, P Sachdev
Sirtuin proteins have a variety of intracellular targets, thereby regulating multiple biological pathways including neurodegeneration. However, relatively little is currently known about the role or expression of the 7 mammalian sirtuins in the central nervous system. Western blotting, PCR and ELISA are the main techniques currently used to measure sirtuin levels. To achieve sufficient sensitivity and selectivity in a multiplex-format, a targeted mass spectrometric assay was developed and validated for the quantification of all seven mammalian sirtuins (SIRT1-7)...
October 20, 2016: Scientific Reports
Asad Ali Shah, Akihiro Ito, Akiko Nakata, Minoru Yoshida
SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro...
2016: Biological & Pharmaceutical Bulletin
Hongxing Ye, Hongguang Huang, Fei Cao, Mantao Chen, Xiujue Zheng, Renya Zhan
Heat shock proteins belong to a conserved protein family and are involved in multiple cellular processes. Heat shock protein 27 (Hsp27), also known as heat HSPB1, participates in cellular responses to not only heat shock, but also oxidative or chemical stresses. However, the contribution of HSPB1 to anti-oxidative response remains unclear. Here, we show that HSPB1 activates G6PD in response to oxidative stress or DNA damage. HSPB1 enhances the binding between G6PD and SIRT2, leading to deacetylation and activation of G6PD...
2016: PloS One
Seong-Hui Eo, Soo Young Choi, Song Ja Kim
Matrix metalloproteinases (MMPs) are critical for the degradation of the extracellular matrix (ECM), which includes cartilage-specific collagen types I, II and XI. We previously found that PEP-1-sirtuin (SIRT)2 could induce dedifferentiation of articular chondrocytes; however, the underlying mechanisms remains unclear. We addressed this in the present study by examining the association between PEP-1-SIRT2 and the expression of MMP-1 and MMP-13 and type II collagen in rabbit articular chondrocytes. We found that PEP-1-SIRT2 increased MMP-1 and -13 expression in a dose- and time-dependent manner, as determined by western blotting...
September 30, 2016: Experimental Cell Research
Ivan Dimauro, Mattia Scalabrin, Cristina Fantini, Elisa Grazioli, Maria Reyes Beltran Valls, Neri Mercatelli, Attilio Parisi, Stefania Sabatini, Luigi Di Luigi, Daniela Caporossi
Regular physical activity is effective as prevention and treatment for different chronic conditions related to the ageing processes. In fact, a sedentary lifestyle has been linked to a worsening of cellular ageing biomarkers such as telomere length (TL) and/or specific epigenetic changes (e.g. DNA methylation), with increase of the propensity to aging-related diseases and premature death. Extending our previous findings, we aimed to test the hypothesis that 12 weeks of low frequency, moderate intensity, explosive-type resistance training (EMRT) may attenuate age-associated genomic changes...
September 21, 2016: Redox Biology
Ha Yong Song, Marco Biancucci, Hong-Jun Kang, Carol O'Callaghan, Seong-Hoon Park, Daniel R Principe, Haiyan Jiang, Yufan Yan, Karla Fullner Satchell, Kirtee Raparia, David Gius, Athanassios Vassilopoulos
The observation that cellular transformation depends on breaching a crucial KRAS activity threshold, along with the finding that only a small percentage of cellsharboring KRAS mutations are transformed, support the idea that additional, not fully uncovered, regulatory mechanisms may contribute to KRAS activation. Here we report that KrasG12D mice lacking Sirt2 show an aggressive tumorigenic phenotype as compared to KrasG12D mice. This phenotype includes increased proliferation, KRAS acetylation, and activation of RAS downstream signaling markers...
September 13, 2016: Oncotarget
Ratana Lim, Gillian Barker, Ramkumar Menon, Martha Lappas
Preterm birth remains the major cause of neonatal mortality and morbidity, mediated largely by an inflammatory process. The sirtuin (SIRT) family of cellular regulators have been implicated as key inhibitors of inflammation. We have previously reported a role for SIRT1, SIRT2 and SIRT6 in regulating inflammation-induced pro-labor mediators. In this study, we determined the effect of term labor and pro-inflammatory cytokines on SIRT3, SIRT4, SIRT5 and SIRT7 expression in human myometrium. Functional studies were also employed to investigate the effect of siRNA knockdown of SIRTs in regulating inflammation-induced pro-labor mediators...
September 14, 2016: Biology of Reproduction
Jing Jin, Bin He, Xiaoyu Zhang, Hening Lin, Yi Wang
Post-translational modifications (PTMs) regulate numerous proteins and are important for many biological processes. Lysine 4-oxononanoylation (4-ONylation) is a newly discovered histone PTM that prevents nucleosome assembly under oxidative stress. Whether there are cellular enzymes that remove 4-ONyl from histones remains unknown, which hampers the further investigation of the cellular function of this PTM. Here, we report that mammalian SIRT2 can remove 4-ONyl from histones and other proteins in live cells...
September 28, 2016: Journal of the American Chemical Society
Shuang-Nian Xu, Tian-Shi Wang, Xi Li, Yi-Ping Wang
Like most other types of cancer cells, leukaemia cells undergo metabolic reprogramming to support rapid proliferation through enhancing biosynthetic processes. Pentose phosphate pathway (PPP) plays a pivotal role in meeting the anabolic demands for cancer cells. However, the molecular mechanism by which PPP contributes to leukaemia remains elusive. Here, we report that leukaemia cell proliferation is dependent on the oxidative branch of PPP, in particular the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD)...
2016: Scientific Reports
Mitsuyasu Kawaguchi, Shohei Ikegawa, Naoya Ieda, Hidehiko Nakagawa
Sirtuins (SIRTs) are a family of NAD+-dependent histone deacetylases. In mammals, dysfunction of SIRTs is associated with age-related metabolic diseases and cancers, so SIRT modulators are considered attractive therapeutic targets. However, current screening methodologies are problematic, and no tools are available for imaging endogenous SIRT activity in living cells. In this work, we present a series of simple and highly sensitive novel SIRT activity probes. Fluorescence of these probes is activated by SIRT-mediated hydrolytic release of a 4-(4-dimethylaminophenylazo)benzoyl (Dabcyl)-based FRET quencher moiety from the -amino group of lysine in a histone H3K9-derived nonapeptide bearing a C-terminal fluorophore...
August 19, 2016: Chembiochem: a European Journal of Chemical Biology
Patrícia S Guerreiro, Joana E Coelho, Inês Sousa-Lima, Paula Macedo, Luísa V Lopes, Tiago F Outeiro, Teresa F Pais
The protein α-synuclein (α-Syn) interferes with glucose and lipid uptake and also activates innate immune cells. However, it remains unclear whether α-Syn or its familial mutant forms contribute to metabolic alterations and inflammation in synucleinopathies, such as Parkinson's disease (PD). Here, we address this issue in transgenic mice for the mutant A53T human α-Syn (α-SynA53T), a mouse model of synucleinopathies. At 9.5 months of age, mice overexpressing α-SynA53T (homozygous) had a significant reduction in weight, exhibited improved locomotion and did not show major motor deficits compared with control transgenic mice (heterozygous)...
August 17, 2016: Neuromolecular Medicine
Jie Wang, Hyoung-Won Koh, Lu Zhou, Ui-Jin Bae, Hwa-Suk Lee, In Hyuk Bang, Sun-O Ka, Seon-Hee Oh, Eun Ju Bae, Byung-Hyun Park
: Sirtuin 2 (Sirt2) is known to negatively regulate anoxia-reoxygenation injury in myoblasts. Because we observed increased protein levels of Sirt2 in ischemia-reperfusion (I/R)-injured liver tissues, we here examined whether Sirt2 is protective or detrimental against hepatic I/R injury. We overexpressed Sirt2 in the liver of C57BL/6 mice using a Sirt2 adenovirus. Wild-type and Sirt2 knockout mice were subjected to a partial (70%) hepatic ischemia for 45 minutes, followed by various periods of reperfusion...
August 17, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Jin-Kwan Lee, Janet Lee, Heounjeong Go, Chang Geun Lee, Suhyeon Kim, Hyun-Soo Kim, Hyeseong Cho, Kyeong Sook Choi, Geun-Hyoung Ha, Chang-Woo Lee
Five brain-expressed X-linked (BEX) gene members (BEX1-5) are arranged in tandem on chromosome X, and are highly conserved across diverse species. However, little is known about the function and role of BEX. This study represents a first attempt to demonstrate the molecular details of a novel oncogene BEX4. Among BEX proteins, BEX4 localizes to microtubules and spindle poles, and interacts with α-tubulin (α-TUB) and sirtuin 2 (SIRT2). The overexpression of BEX4 leads to the hyperacetylation of α-TUB by inhibiting SIRT2-mediated deacetylation...
2016: Cell Death & Disease
Warren Fiskus, Veena Coothankandaswamy, Jianguang Chen, Hongwei Ma, Kyungsoo Ha, Dyana T Saenz, Stephanie S Krieger, Christopher P Mill, Baohua Sun, Peng Huang, Jeffrey S Mumm, Ari M Melnick, Kapil N Bhalla
SIRT2 is a protein deacetylase with tumor suppressor activity in breast and liver tumors where it is mutated; however, the critical substrates mediating its antitumor activity are not fully defined. Here we demonstrate that SIRT2 binds, deacetylates, and inhibits the peroxidase activity of the antioxidant protein peroxiredoxin (Prdx-1) in breast cancer cells. Ectopic overexpression of SIRT2, but not its catalytically dead mutant, increased intracellular levels of reactive oxygen species (ROS) induced by hydrogen peroxide, which led to increased levels of an overoxidized and multimeric form of Prdx-1 with activity as a molecular chaperone...
September 15, 2016: Cancer Research
Hanna G Budayeva, Ileana M Cristea
Human sirtuin 2 (SIRT2) is an NAD(+)-dependent deacetylase that primarily functions in the cytoplasm, where it can regulate α-tubulin acetylation levels. SIRT2 is linked to cancer progression, neurodegeneration, and infection with bacteria or viruses. However, the current knowledge about its interactions and the means through which it exerts its functions has remained limited. Here, we aimed to gain a better understanding of its cellular functions by characterizing SIRT2 subcellular localization, the identity and relative stability of its protein interactions, and its impact on the proteome of primary human fibroblasts...
October 2016: Molecular & Cellular Proteomics: MCP
Xianfeng Wang, Nancy L Buechler, Ayana Martin, Jonathan Wells, Barbara Yoza, Charles E McCall, Vidula Vachharajani
OBJECTIVE: Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis...
2016: PloS One
Guoxiang Liu, Seong-Hoon Park, Xianghui Zou, Yueming Zhu, Haiyan Jiang, Loukia Parisiadou, David Gius
Sirtuins connect energy generation and metabolic stress to the cellular acetylome. Currently, only the mitochondrial sirtuins (SIRT3-5) and SIRT1 have been shown to direct mitochondrial function, however SIRT2, the primary cytoplasmic sirtuin, is not yet reported to associate with mitochondria. This study revealed a novel physiological function of SIRT2: the regulation of mitochondrial function. First, the acetylation of several metabolic mitochondrial proteins was found to be altered in Sirt2-deficient mice, which was subsequently validated by immunoprecipitation experiments in which the acetylated mitochondrial proteins directly interacted with SIRT2...
July 26, 2016: Antioxidants & Redox Signaling
Paula Simó-Mirabet, Azucena Bermejo-Nogales, Josep Alvar Calduch-Giner, Jaume Pérez-Sánchez
The seven sirtuin (SIRT) counterparts of higher vertebrates were identified and molecularly characterized in a farmed fish of the Sparidae family, order Perciformes. These proteins are NAD(+)-dependent deacetylases that couple protein deacetylation with the energy status of the cell via the cellular NAD(+)/NADH ratio with a strict conservation of the characteristic catalytic domain surrounded by divergent N- and C- terminal regions. Phylogenetic analysis showed three major clades corresponding to SIRT1-3, SIRT4-5, and SIRT6-7 that reflected the present hierarchy of vertebrates and the accepted classification of SIRTs...
July 18, 2016: Journal of Comparative Physiology. B, Biochemical, Systemic, and Environmental Physiology
Luisa Quinti, Malcolm Casale, Sébastien Moniot, Teresa F Pais, Michael J Van Kanegan, Linda S Kaltenbach, Judit Pallos, Ryan G Lim, Sharadha Dayalan Naidu, Heike Runne, Lisa Meisel, Nazifa Abdul Rauf, Dmitriy Leyfer, Michele M Maxwell, Eddine Saiah, John E Landers, Ruth Luthi-Carter, Ruben Abagyan, Albena T Dinkova-Kostova, Clemens Steegborn, J Lawrence Marsh, Donald C Lo, Leslie M Thompson, Aleksey G Kazantsev
There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity...
July 21, 2016: Cell Chemical Biology
Gloria Biella, Federica Fusco, Emanuele Nardo, Ottavia Bernocchi, Alessio Colombo, Stefan F Lichtenthaler, Gianluigi Forloni, Diego Albani
The neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23)...
June 30, 2016: Journal of Alzheimer's Disease: JAD
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