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CYCLONET—An Integrated Database on Cell Cycle Regulation And D550–D556 Nucleic Acids Research, 2007, Vol. 35, Database issue doi:10.1093/nar/gkl912 CYCLONET—an integrated database on cell cycle regulation and carcinogenesis Fedor Kolpakov1,2, Vladimir Poroikov3, Ruslan Sharipov1,2,4,*, Yury Kondrakhin1,2, Alexey Zakharov3, Alexey Lagunin3, Luciano Milanesi5 and Alexander Kel6 1Institute of Systems Biology, 15, Detskiy proezd, Novosibirsk 630090, Russia, 2Design Technological Institute of Digital Techniques, Siberian Branch of Russian Academy of Sciences, 6, Institutskaya, Novosibirsk 630090, Russia, 3Institute of Biomedical Chemistry of Russian Academy of Medical Sciences, 10, 4 Pogodinskaya Street, Moscow 119121, Russia, Institute of Cytology and Genetics, Siberian Branch of Downloaded from Russian Academy of Sciences, 10, Lavrentyev Avenue, Novosibirsk 630090, Russia, 5CNR-Institute of Biomedical Technologies, 93, Via Fratelli Cervi, Segrate (MI) 20090, Italy and 6BIOBASE GmbH, 33, Halchtersche Strasse, Wolfenbuettel 38304, Germany Received August 16, 2006; Revised October 12, 2006; Accepted October 13, 2006 http://nar.oxfordjournals.org/ ABSTRACT INTRODUCTION Computational modelling of mammalian cell cycle The main goal of the Cyclonet database is to integrate information from genomics, proteomics, chemoinformatics regulation is a challenging task, which requires at McGill University Libraries on December 28, 2012 comprehensive knowledge on many interrelated and systems biology on mammalian cell cycle regulation in processes in the cell. We have developed a web- normal and pathological states. This will help molecular biologists working in the field of anticancer drug develop- based integrated database on cell cycle regulation ment to analyze systematically all these data and generate in mammals in normal and pathological states experimentally testable hypotheses (Figure 1). (Cyclonet database). It integrates data obtained by Cyclonet incorporates data on various carcinogenesis related ‘omics’ sciences and chemoinformatics on the topics, such as: cell cycle control in mammals (Figure 2), basis of systems biology approach. Cyclonet is a cell survival programs (e.g. NF-kB pathway), regulation of specialized resource, which enables researchers covalent histone modifications and chromatin remodelling in working in the field of anticancer drug discovery cell cycle, DNA methylation and other epigenetic mechanisms to analyze the wealth of currently available informa- of cell growth and differentiation. Biological pathways, tion in a systematic way. Cyclonet contains informa- computer models of cell cycle, microarray data coming from tion on relevant genes and molecules; diagrams studies of cell cycle and analysis of cancer-related materials and models of cell cycle regulation and results of are also systematically collected in this database (1) (http:// www.impb.ru/~rcdl2004/cgi/get_paper_pdf.cgi?pid=30). their simulation; microarray data on cell cycle and Cyclonet supports discovery of novel drug targets and on various types of cancer, information on drug development of effective anticancer therapies by collecting targets and their ligands, as well as extensive biblio- all available data related to the control of cell cycle in graphy on modelling of cell cycle and cancer-related normal and pathological states and providing a system bio- gene expression data. The Cyclonet database is also logy platform for knowledge-based anticancer drug accessible through the BioUML workbench, which discovery. allows flexible querying, analyzing and editing the Novel software technologies were used for the database data by means of visual modelling. Cyclonet aims development: to predict promising anticancer targets and their (i) the BioUML workbench [http://www.biouml.org, (2,3)] agents by application of Prediction of Activity was used for formal description and visual modelling of Spectra for Substances. The Cyclonet database is biological pathways and processes related to the cell available at http://cyclonet.biouml.org. cycle regulation and cancer (Figure 2). It also allows to *To whom correspondence should be addressed. Tel/Fax: +7 383 3303070; Email: [email protected] Ó 2006 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Nucleic Acids Research, 2007, Vol. 35, Database issue D551 simulate the behaviour of the described systems using THE CYCLONET DATABASE STRUCTURE Java or MATLAB simulation engines; AND CONTENT (ii) BeanExplorer Enterprise Edition (http://www. The Cyclonet database consists of three main components beanexplorer.com) was used to develop web interface (see Table 1): for the Cyclonet database (Figure 3). (i) diagrams and models of biological pathways (metabolic pathways, signal transduction pathways and gene networks) involved in cell cycle regulation and carcinogenesis; (ii) microarray original data and results of their statistical analysis; (iii) chemoinformatics data—drug targets, ligands and phar- macological activities for cancer treatment. Downloaded from The Cyclonet database is organized as a relational database (MySQL DBMS). All sections contain a number of tables that are highly interconnected through crossreferences. Such elaborated relational schema enables complex queries com- bining various types of information. http://nar.oxfordjournals.org/ Data in Cyclonet are compiled mainly by manual literature annotation. Links to the public databases, such as, Gene- Ontology (4), RefSeq (5) and Ensembl (6) are provided from genes, proteins and other respective entries. Cyclonet Figure 1. Diagrams and models of carcinogenesis related processes as the also contains a vast body of literature references that are basis for information integration in the Cyclonet database. arranged by categories. at McGill University Libraries on December 28, 2012 Figure 2. An example of cell cycle model visualization and simulation by the BioUML workbench (the diagram DGR0068a of the Cyclonet database). D552 Nucleic Acids Research, 2007, Vol. 35, Database issue Downloaded from http://nar.oxfordjournals.org/ at McGill University Libraries on December 28, 2012 Figure 3. Web interface of the Cyclonet database generated by BeanExplorer technology. Top screen displays fragment of microarray series classification in the Cyclonet database, bottom left screen demonstrates a fragment of the list of pharmacological activities for anticancer therapy, bottom right—examples of chemical structure of two tubulin antagonists. Biological pathways Models We use BioUML for formal description of signal transduction The BioUML technology was also used for visual modelling pathways and gene networks involved in cell cycle regu- of cell cycle regulation. Known cell cycle models were lation and carcinogenesis (2,3,7). Cyclonet pathways section imported from SBML (8) and CellML (9) model repositories. allows to store the detailed description of biological pathways, We added into Cyclonet several new recent models by their components, models as well as the results of simulation. manual annotation of respective literature sources. We also We are using several diagram types of BioUML to describe created our own novel model of regulation of G1/S transition cell cycle regulation and carcinogenesis: of cell cycle. Currently, Cyclonet contains 37 models of cell cycle regu- (i) semantic networks describing relationships between the lation. All models can be classified into two groups: main concepts (for example, G1 phase, G1/S transition, (i) general models that simulate behaviour of rather small sys- mitotic checkpoints) and components of cell cycle tems including abstract objects that reflect real biological com- regulation; ponents in the cell; (ii) ‘portrait’ models that try to simulate (ii) pathways describing structure of cell cycle regulatory different sub-processes in cell cycle and include real genes, networks as compartmentalized graphs. We have classi- proteins and other cellular components. We validated each fied the annotated networks into a number of categories model by using the BioUML simulation engine and comparing that describe different parts of cell cycle regulatory the results with the published results. The results of such networks in details (for example, a network that provides simulations were then stored in the Cyclonet database. These G1/S transition, NF-kB signal transduction pathway and data can be displayed as graphs by the BioUML workbench its influence on apoptosis and others). (Figure 2) or web isnterface generated by BeanExplorer EE. Nucleic Acids Research, 2007, Vol. 35, Database issue D553 Table 1. Number of entries for the main blocks (tables, sections) of the were loaded into the Cyclonet database and analysed. We did Cyclonet database a statistical analysis as well as meta-analysis of the data (see Supplementary Data) and obtained 33 gene lists (IDs Sections of the Cyclonet database Number of Entries GL0001–GL0033 in ‘Microarray data and results’ of Cyclonet) that belong to several categories: Biological pathways Compartments: cellular and organism compartments, 120 (i) lists of genes periodically expressed during cell cycle for example, cytoplasm, liver, blood (GL0007, GL0020 and GL0021) (15,16); Concepts: biological processes, states, functions etc. 987 (ii) lists of genes whose expression is changing mono- For example, G1
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