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https://www.readbyqxmd.com/read/27899403/meta-analysis-of-genome-wide-association-studies-for-abdominal-aortic-aneurysm-identifies-four-new-disease-specific-risk-loci
#1
Gregory T Jones, Gerard Tromp, Helena Kuivaniemi, Solveig Gretarsdottir, Annette F Baas, Betti Giusti, Ewa Strauss, Femke N van 't Hof, Thomas Webb, Robert Erdman, Marylyn D Ritchie, James R Elmore, Anurag Verma, Sarah Pendergrass, Iftikhar J Kullo, Zi Ye, Peggy L Peissig, Omri Gottesman, Shefali S Verma, Jennifer Malinowski, Laura J Rasmussen-Torvik, Kenneth Borthwick, Diane T Smelser, David R Crosslin, Mariza de Andrade, Evan J Ryer, Catherine A McCarty, Erwin P Bottinger, Jennifer A Pacheco, Dana C Crawford, David S Carrell, Glenn S Gerhard, David P Franklin, David J Carey, Victoria L Phillips, Michael J Williams, Wenhua Wei, Ross Blair, Andrew A Hill, Thodur M Vasudevan, David R Lewis, Ian A Thomson, Jo Krysa, Geraldine B Hill, Justin Roake, Tony R Merriman, Grzegorz Oszkinis, Silvia Galora, Claudia Saracini, Rosanna Abbate, Raffaele Pulli, Carlo Pratesi, Athanasios Saratzis, Anna Verissimo, Suzannah J Bumpstead, Stephen A Badger, Rachel E Clough, Gillian W Cockerill, Hany Hafez, D J Scott, T S Futers, Simon P Romaine, Katherine Bridge, Kathryn J Griffin, Marc A Bailey, Alberto Smith, Matt M Thompson, Frank van Bockxmeer, Stefan E Matthiasson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jan D Blankensteijn, Joep A Teijink, Cisca Wijmenga, Jacqueline de Graaf, Lambertus A Kiemeney, Jes S Lindholt, Anne E Hughes, Declan T Bradley, Kathleen Stirrups, Jonathan Golledge, Paul E Norman, Janet T Powell, Steve E Humphries, Stephen E Hamby, Alison H Goodall, Christopher P Nelson, Natzi Sakalihasan, Audrey Courtois, Robert E Ferrell, Per Eriksson, Lasse Folkersen, Anders Franco-Cereceda, John D Eicher, Andrew D Johnson, Christer Betsholtz, Arno Ruusalepp, Oscar Franzén, Eric Schadt, Johan L Björkegren, Leonard Lipovich, Anne M Drolet, Eric Verhoeven, Clark J Zeebregts, Robert H Geelkerken, Marc R van Sambeek, Steven M van Sterkenburg, Jean-Paul P de Vries, Kari Stefansson, John R Thompson, Paul I de Bakker, Panos Deloukas, Robert D Sayers, Seamus Harrison, Andre M van Rij, Nilesh J Samani, Matthew J Bown
RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS). METHODS AND RESULTS: Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32...
November 29, 2016: Circulation Research
https://www.readbyqxmd.com/read/27377701/smyd5-plays-pivotal-roles-in-both-primitive-and-definitive-hematopoiesis-during-zebrafish-embryogenesis
#2
Tomoaki Fujii, Shin-Ichiro Tsunesumi, Hiroshi Sagara, Miyo Munakata, Yoshihiro Hisaki, Takao Sekiya, Yoichi Furukawa, Kazuhiro Sakamoto, Sumiko Watanabe
Methylation of histone tails plays a pivotal role in the regulation of a wide range of biological processes. SET and MYND domain-containing protein (SMYD) is a methyltransferase, five family members of which have been identified in humans. SMYD1, SMYD2, SMYD3, and SMYD4 have been found to play critical roles in carcinogenesis and/or the development of heart and skeletal muscle. However, the physiological functions of SMYD5 remain unknown. To investigate the function of Smyd5 in vivo, zebrafish were utilised as a model system...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27216279/a-clickable-glutathione-approach-for-identification-of-protein-glutathionylation-in-response-to-glucose-metabolism
#3
Kusal T G Samarasinghe, Dhanushka N P Munkanatta Godage, Yani Zhou, Fidelis T Ndombera, Eranthie Weerapana, Young-Hoon Ahn
Glucose metabolism and mitochondrial function are closely interconnected with cellular redox-homeostasis. Although glucose starvation, which mimics ischemic conditions or insufficient vascularization, is known to perturb redox-homeostasis, global and individual protein glutathionylation in response to glucose metabolism or mitochondrial activity remains largely unknown. In this report, we use our clickable glutathione approach, which forms clickable glutathione (azido-glutathione) by using a mutant of glutathione synthetase (GS M4), for detection and identification of protein glutathionylation in response to glucose starvation...
July 19, 2016: Molecular BioSystems
https://www.readbyqxmd.com/read/27163177/an-integrative-proteomic-approach-identifies-novel-cellular-smyd2-substrates
#4
Hazem Ahmed, Shili Duan, Cheryl H Arrowsmith, Dalia Barsyte-Lovejoy, Matthieu Schapira
Protein methylation is a post-translational modification with important roles in transcriptional regulation and other biological processes, but the enzyme-substrate relationship between the 68 known human protein methyltransferases and the thousands of reported methylation sites is poorly understood. Here, we propose a bioinformatic approach that integrates structural, biochemical, cellular, and proteomic data to identify novel cellular substrates of the lysine methyltransferase SMYD2. Of the 14 novel putative SMYD2 substrates identified by our approach, six were confirmed in cells by immunoprecipitation: MAPT, CCAR2, EEF2, NCOA3, STUB1, and UTP14A...
June 3, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27075367/discovery-and-characterization-of-a-highly-potent-and-selective-aminopyrazoline-based-in-vivo-probe-bay-598-for-the-protein-lysine-methyltransferase-smyd2
#5
Erik Eggert, Roman C Hillig, Silke Koehr, Detlef Stöckigt, Jörg Weiske, Naomi Barak, Jeffrey Mowat, Thomas Brumby, Clara D Christ, Antonius Ter Laak, Tina Lang, Amaury E Fernandez-Montalvan, Volker Badock, Hilmar Weinmann, Ingo V Hartung, Dalia Barsyte-Lovejoy, Magdalena Szewczyk, Steven Kennedy, Fengling Li, Masoud Vedadi, Peter J Brown, Vijayaratnam Santhakumar, Cheryl H Arrowsmith, Timo Stellfeld, Carlo Stresemann
Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood...
May 26, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27040643/systems-biology-analysis-of-hepatitis-c-virus-infection-reveals-the-role-of-copy-number-increases-in-regions-of-chromosome-1q-in-hepatocellular-carcinoma-metabolism
#6
Ibrahim E Elsemman, Adil Mardinoglu, Saeed Shoaie, Taysir H Soliman, Jens Nielsen
Hepatitis C virus (HCV) infection is a worldwide healthcare problem; however, traditional treatment methods have failed to cure all patients, and HCV has developed resistance to new drugs. Systems biology-based analyses could play an important role in the holistic analysis of the impact of HCV on hepatocellular metabolism. Here, we integrated HCV assembly reactions with a genome-scale hepatocyte metabolic model to identify metabolic targets for HCV assembly and metabolic alterations that occur between different HCV progression states (cirrhosis, dysplastic nodule, and early and advanced hepatocellular carcinoma (HCC)) and healthy liver tissue...
April 26, 2016: Molecular BioSystems
https://www.readbyqxmd.com/read/26988419/coordination-of-stress-signals-by-the-lysine-methyltransferase-smyd2-promotes-pancreatic-cancer
#7
Nicolas Reynoird, Pawel K Mazur, Timo Stellfeld, Natasha M Flores, Shane M Lofgren, Scott M Carlson, Elisabeth Brambilla, Pierre Hainaut, Ewa B Kaznowska, Cheryl H Arrowsmith, Purvesh Khatri, Carlo Stresemann, Or Gozani, Julien Sage
Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors...
April 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/26790435/residual-expression-of-smyd2-and-smyd3-is-associated-with-the-acquisition-of-complex-karyotype-in-chronic-lymphocytic-leukemia
#8
Wilson Oliveira-Santos, Doralina Amaral Rabello, Antônio Roberto Lucena-Araujo, Fábio Morato de Oliveira, Eduardo Magalhaes Rego, Fábio Pittella Silva, Felipe Saldanha-Araujo
SET and MYND domain containing 2 (SMYD2) and the SET and MYND domain containing 3 (SMYD3) are the most studied and well-characterized members of SMYD family. It has been demonstrated that their altered expression is associated with the progression of several solid tumors. Nevertheless, whether these methyltransferases exert any impact in chronic lymphocytic leukemia (CLL) remains unknown. Here, we investigated the gene expression profile of SMYD2 and SMYD3 in 59 samples of CLL and 10 normal B cells. The obtained results were associated with white blood cells (WBC) and platelet counts, ZAP-70 protein expression, and cytogenetic analysis...
July 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/26585137/purification-of-histone-lysine-methyltransferase-smyd2-and-co-crystallization-with-a-target-peptide-from-estrogen-receptor-%C3%AE
#9
Yuanyuan Jiang, Joshua Holcomb, Nicholas Spellmon, Zhe Yang
Methylation of estrogen receptor α by the histone lysine methyltransferase SMYD2 regulates ERα chromatin recruitment and its target gene expression. This protocol describes SMYD2 purification and crystallization of SMYD2 in complex with an ERα peptide. Recombinant SMYD2 is overexpressed in Escherichia coli cells. After release from the cells by French Press, SMYD2 is purified to apparent homogeneity with multiple chromatography methods. Nickel affinity column purifies SMYD2 based on specific interaction of its 6×His tag with the bead-immobilized nickel ions...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/26488939/expression-of-histone-methyltransferases-as-novel-biomarkers-for-renal-cell-tumor-diagnosis-and-prognostication
#10
Ana Sílvia Pires-Luís, Márcia Vieira-Coimbra, Filipa Quintela Vieira, Pedro Costa-Pinheiro, Rui Silva-Santos, Paula C Dias, Luís Antunes, Francisco Lobo, Jorge Oliveira, Céline S Gonçalves, Bruno M Costa, Rui Henrique, Carmen Jerónimo
Renal cell tumors (RCTs) are the most lethal of the common urological cancers. The widespread use of imaging entailed an increased detection of small renal masses, emphasizing the need for accurate distinction between benign and malignant RCTs, which is critical for adequate therapeutic management. Histone methylation has been implicated in renal tumorigenesis, but its potential clinical value as RCT biomarker remains mostly unexplored. Hence, the main goal of this study was to identify differentially expressed histone methyltransferases (HMTs) and histone demethylases (HDMs) that might prove useful for RCT diagnosis and prognostication, emphasizing the discrimination between oncocytoma (a benign tumor) and renal cell carcinoma (RCC), especially the chromophobe subtype (chRCC)...
2015: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/26230726/evolutionary-history-of-the-smyd-gene-family-in-metazoans-a-framework-to-identify-the-orthologs-of-human-smyd-genes-in-drosophila-and-other-animal-species
#11
Eduardo Calpena, Francesc Palau, Carmen Espinós, Máximo Ibo Galindo
The Smyd gene family code for proteins containing a conserved core consisting of a SET domain interrupted by a MYND zinc finger. Smyd proteins are important in epigenetic control of development and carcinogenesis, through posttranslational modifications in histones and other proteins. Previous reports indicated that the Smyd family is quite variable in metazoans, so a rigorous phylogenetic reconstruction of this complex gene family is of central importance to understand its evolutionary history and functional diversification or conservation...
2015: PloS One
https://www.readbyqxmd.com/read/26191084/ball-snp-combining-genetic-and-structural-information-to-identify-candidate-non-synonymous-single-nucleotide-polymorphisms
#12
Sabine C Mueller, Christina Backes, Olga V Kalinina, Benjamin Meder, Daniel Stöckel, Hans-Peter Lenhof, Eckart Meese, Andreas Keller
BACKGROUND: High-throughput genetic testing is increasingly applied in clinics. Next-Generation Sequencing (NGS) data analysis however still remains a great challenge. The interpretation of pathogenicity of single variants or combinations of variants is crucial to provide accurate diagnostic information or guide therapies. METHODS: To facilitate the interpretation of variants and the selection of candidate non-synonymous polymorphisms (nsSNPs) for further clinical studies, we developed BALL-SNP...
2015: Genome Medicine
https://www.readbyqxmd.com/read/26101576/discovery-of-a-893-a-new-cell-active-benzoxazinone-inhibitor-of-lysine-methyltransferase-smyd2
#13
Ramzi F Sweis, Zhi Wang, Mikkel Algire, Cheryl H Arrowsmith, Peter J Brown, Gary G Chiang, Jun Guo, Clarissa G Jakob, Steven Kennedy, Fengling Li, David Maag, Bailin Shaw, Nirupama B Soni, Masoud Vedadi, William N Pappano
A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line...
June 11, 2015: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/25925379/dysregulation-of-akt-pathway-by-smyd2-mediated-lysine-methylation-on-pten
#14
Makoto Nakakido, Zhenzhong Deng, Takehiro Suzuki, Naoshi Dohmae, Yusuke Nakamura, Ryuji Hamamoto
Phosphatase and tensin homologue (PTEN), one of the well-characterized tumor suppressor proteins, counteracts the phosphatidylinositol 3-kinase-AKT pathway through its unique lipid phosphatase activity. The functions of PTEN are regulated by a variety of posttranslational modifications such as acetylation, oxidation, ubiquitylation, phosphorylation, and SUMOylation. However, methylation of PTEN has not been reported so far. In this study, we demonstrated that the oncogenic protein lysine methyltransferase SET and MYND domain containing 2 (SMYD2) methylates PTEN at lysine 313 in vitro and in vivo...
April 2015: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/25825497/lly-507-a-cell-active-potent-and-selective-inhibitor-of-protein-lysine-methyltransferase-smyd2
#15
Hannah Nguyen, Abdellah Allali-Hassani, Stephen Antonysamy, Shawn Chang, Lisa Hong Chen, Carmen Curtis, Spencer Emtage, Li Fan, Tarun Gheyi, Fengling Li, Shichong Liu, Joseph R Martin, David Mendel, Jonathan B Olsen, Laura Pelletier, Tatiana Shatseva, Song Wu, Feiyu Fred Zhang, Cheryl H Arrowsmith, Peter J Brown, Robert M Campbell, Benjamin A Garcia, Dalia Barsyte-Lovejoy, Mary Mader, Masoud Vedadi
SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary carcinomas, and that overexpression correlates with poor patient survival. However, the mechanism(s) by which SMYD2 promotes oncogenesis is not understood. A small molecule probe for SMYD2 would allow for the pharmacological dissection of this biology. In this report, we disclose LLY-507, a cell-active, potent small molecule inhibitor of SMYD2...
May 29, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/25583990/the-histone-methyltransferase-smyd2-is-a-negative-regulator-of-macrophage-activation-by-suppressing-interleukin-6-il-6-and-tumor-necrosis-factor-%C3%AE-tnf-%C3%AE-production
#16
Guiliang Xu, Guilin Liu, Sidong Xiong, Haiyan Liu, Xi Chen, Biao Zheng
SET and MYND domain-containing 2 (Smyd2), a histone 3 lysine 4- and histone 3 lysine 36 (H3K36)-specific methyltransferase, plays critical roles in cardiac development and tumorigenesis. However, the role of Smyd2 in immunity and inflammation remains poorly understood. In this study, we report that Smyd2 is a novel negative regulator for macrophage activation and M1 polarization. Elevated Smyd2 expression suppresses the production of proinflammatory cytokines, including IL-6 and TNF, and inhibits the expression of important cell surface molecules, including major MHC-II and costimulatory molecules...
February 27, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/25565104/a-new-test-of-computational-protein-design-predicting-posttranslational-modification-specificity-for-the-enzyme-smyd2
#17
COMMENT
Kimberly A Reynolds
In this issue of Structure, Lanouette and colleagues use a combination of computation and experiment to define a specificity motif for the lysine methyltransferase SMYD2. Using this motif, they predict and experimentally verify four new SMYD2 substrates.
January 6, 2015: Structure
https://www.readbyqxmd.com/read/25562686/the-selective-activation-of-p53-target-genes-regulated-by-smyd2-in-bix-01294-induced-autophagy-related-cell-death
#18
Jia-Dong Fan, Pin-Ji Lei, Jun-Yi Zheng, Xiang Wang, Shangze Li, Huan Liu, Yi-Lei He, Zhao-Ning Wang, Gang Wei, Xiaodong Zhang, Lian-Yun Li, Min Wu
Transcription regulation emerged to be one of the key mechanisms in regulating autophagy. Inhibitors of H3K9 methylation activates the expression of LC3B, as well as other autophagy-related genes, and promotes autophagy process. However, the detailed mechanisms of autophagy regulated by nuclear factors remain elusive. In this study, we performed a drug screen of SMYD2-/- cells and discovered that SMYD2 deficiency enhanced the cell death induced by BIX01294, an inhibitor of histone H3K9 methylation. BIX-01294 induces accumulation of LC3 II and autophagy-related cell death, but not caspase-dependent apoptosis...
2015: PloS One
https://www.readbyqxmd.com/read/25537518/genetic-alterations-of-histone-lysine-methyltransferases-and-their-significance-in-breast-cancer
#19
Lanxin Liu, Sarah Kimball, Hui Liu, Andreana Holowatyj, Zeng-Quan Yang
Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome...
February 10, 2015: Oncotarget
https://www.readbyqxmd.com/read/25533488/discovery-of-substrates-for-a-set-domain-lysine-methyltransferase-predicted-by-multistate-computational-protein-design
#20
Sylvain Lanouette, James A Davey, Fred Elisma, Zhibin Ning, Daniel Figeys, Roberto A Chica, Jean-François Couture
Characterization of lysine methylation has proven challenging despite its importance in biological processes such as gene transcription, protein turnover, and cytoskeletal organization. In contrast to other key posttranslational modifications, current proteomics techniques have thus far shown limited success at characterizing methyl-lysine residues across the cellular landscape. To complement current biochemical characterization methods, we developed a multistate computational protein design procedure to probe the substrate specificity of the protein lysine methyltransferase SMYD2...
January 6, 2015: Structure
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