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  • PROTEIN  (9)
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  • 1
    Keywords: MODEL ; PROTEIN ; FAMILY ; PROTEIN FAMILIES ; PROTEIN FAMILY ; DOMAIN ; PAIRS ; recombination
    Abstract: There is a limited repertoire of domain families in nature that are duplicated and combined in different ways to form the set of proteins in a genome. Most proteins in both prokaryote and eukaryote genomes consist of two or more domains, and we show that the family size distribution of multi-domain protein families follows a power law like that of individual families. Most domain pairs occur in four to six different domain architectures: in isolation and in combinations with different partners. We showed previously that within the set of all pairwise domain combinations, most small and medium-sized families are observed in combination with one or two other families, while a few large families are very versatile and combine with many different partners. Though this may appear to be a stochastic pattern, in which large families have more combination partners by virtue of their size, we establish here that all the domain families with more than three members in genomes are duplicated more frequently than would be expected by chance considering their number of neighbouring domains. This duplication of domain pairs is statistically significant for between one and three quarters of all families with seven or more members. For the majority of pairwise domain combinations, there is no known three-dimensional structure of the two domains together, and we term these novel combinations. Novel domain combinations are interesting and important targets for structural elucidation, as the geometry and interaction between the domains will help understand the function and evolution of multi-domain proteins. Of particular interest are those combinations that occur in the largest number of multi-domain proteins, and several of these frequent novel combinations contain DNA-binding domains.
    Type of Publication: Journal article published
    PubMed ID: 14649290
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  • 2
    Keywords: EXPRESSION ; Germany ; human ; MODEL ; THERAPY ; DIAGNOSIS ; INFORMATION ; NETWORK ; TOOL ; DISEASE ; GENE ; GENES ; GENOME ; PROTEIN ; PROTEINS ; COMPLEX ; COMPLEXES ; BIOLOGY ; SEQUENCE ; FORM ; IDENTIFICATION ; HEALTH ; DATABASE ; PRODUCT ; bioinformatics ; LOCALIZATION ; WEB ; HUMAN GENES ; FUNCTIONAL GENOMICS ; PROTEOMICS ; PRODUCTS ; databases ; ANNOTATION ; RESOURCE ; PROTEIN-ANALYSIS ; FULL-LENGTH HUMAN ; HUMAN CDNAS
    Abstract: As several model genomes have been sequenced, the elucidation of protein function is the next challenge toward the understanding of biological processes in health and disease. We have generated a human ORFeome resource and established a functional genomics and proteomics analysis pipeline to address the major topics in the post-genome-sequencing era: the identification of human genes and splice forms, and the determination of protein localization, activity, and interaction. Combined with the understanding of when and where gene products are expressed in normal and diseased conditions, we create information that is essential for understanding the interplay of genes and proteins in the complex biological network. We have implemented bioinformatics tools and databases that are suitable to store, analyze, and integrate the different types of data from high-throughput experiments and to include further annotation that is based on external information. All information is presented in a Web database (http://www.dkfz.de/LIFEdb). It is exploited for the identification of disease-relevant genes and proteins for diagnosis and therapy
    Type of Publication: Journal article published
    PubMed ID: 15489336
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  • 3
    Keywords: EXPRESSION ; proliferation ; CELL-PROLIFERATION ; Germany ; INFORMATION ; screening ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; PROTEIN ; PROTEINS ; gene expression ; ASSAY ; DATABASE ; bioinformatics ; INTERFACE ; PROJECT ; INTEGRATION ; FEATURES ; RE ; cell proliferation ; FULL-LENGTH HUMAN ; HUMAN CDNAS ; ASSAYS ; genomic ; NORTHERN
    Abstract: LIFEdb (http://www.LIFEdb.de) integrates data from large-scale functional genomics assays and manual cDNA annotation with bioinformatics gene expression and protein analysis. New features of LIFEdb include (i) an updated user interface with enhanced query capabilities, (ii) a configurable output table and the option to download search results in XML, (iii) the integration of data from cell-based screening assays addressing the influence of protein-overexpression on cell proliferation and (iv) the display of the relative expression ('Electronic Northern') of the genes under investigation using curated gene expression ontology information. LIFEdb enables researchers to systematically select and characterize genes and proteins of interest, and presents data and information via its user-friendly web-based interface
    Type of Publication: Journal article published
    PubMed ID: 16381901
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  • 4
    Keywords: CANCER ; GROWTH ; INHIBITOR ; proliferation ; SURVIVAL ; tumor ; CELL-PROLIFERATION ; Germany ; KINASE ; INFORMATION ; TOOL ; DISEASE ; GENE ; GENES ; GENOME ; microarray ; PROTEIN ; PROTEINS ; transcription ; TUMORS ; RESOLUTION ; ACTIVATION ; DNA ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CYCLE ; ASSOCIATION ; MOUSE ; IDENTIFICATION ; PROGRESSION ; ASSAY ; microarrays ; PROSTATE-CANCER ; STRATEGIES ; DNA-REPLICATION ; REPLICATION ; signaling ; RE ; TUMORIGENICITY ; genomics ; TRANSITION ; DNA replication ; C-ELEGANS ; cell proliferation ; PROTEIN-ANALYSIS ; development ; ASSAYS ; DIFFERENTIALLY EXPRESSED GENES ; high throughput ; HIGH-THROUGHPUT ; LONG ; PRIME ; PRINCIPLES ; REPRESSOR ; ROLES
    Abstract: Cancer transcription microarray studies commonly deliver long lists of "candidate" genes that are putatively associated with the respective disease. For many of these genes, no functional information, even less their relevance in pathologic conditions, is established as they were identified in large-scale genomics approaches. Strategies and tools are thus needed to distinguish genes and proteins with mere tumor association from those causally related to cancer. Here, we describe a functional profiling approach, where we analyzed 103 previously uncharacterized genes in cancer relevant assays that probed their effects on DNA replication (cell proliferation). The genes had previously been identified as differentially expressed in genome-wide microarray studies of tumors. Using an automated high-throughput assay with single-cell resolution, we discovered seven activators and nine repressors of DNA replication. These were further characterized for effects on extracellular signal-regulated kinase 1/2 (ERK1/2) signaling (G(1)-S transition) and anchorage-independent growth (tumorigenicity). One activator and one inhibitor protein of ERK1/2 activation and three repressors of anchorage-independent growth were identified. Data from tumor and functional profiling make these proteins novel prime candidates for further in-depth study of their roles in cancer development and progression. We have established a novel functional profiling strategy that links genomics to cell biology and showed its potential for discerning cancer relevant modulators of the cell cycle in the candidate lists from microarray studies
    Type of Publication: Journal article published
    PubMed ID: 16140941
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  • 5
    Keywords: COMBINATION ; Germany ; GENERATION ; GENOME ; microarray ; PROTEIN ; PROTEINS ; MONOCLONAL-ANTIBODY ; BIOLOGY ; MOLECULAR-BIOLOGY ; antibodies ; antibody ; microarrays ; ARRAYS ; NUMBER ; REPRODUCIBILITY ; FUSION ; FUSION PROTEINS ; SURFACE ; MONOCLONAL-ANTIBODIES ; IMMOBILIZATION ; PROTEOMICS ; protein microarray ; PROTEIN MICROARRAYS ; FUSION PROTEIN ; SERUM ; molecular biology ; molecular ; RECOMBINANT ; ARRAY ; RESOURCE ; ANTIBODY MICROARRAYS ; CHIP ; 3D ; monoclonal antibodies ; monoclonal antibody ; ALLERGEN-SPECIFIC IGE ; DYES ; FLUORESCENT DYES
    Abstract: To process large numbers of samples in parallel is one potential of protein microarrays for research and diagnostics. However, the application of protein arrays is currently hampered by the lack of comprehensive technological knowledge about the suitability of 2-D and 3-D slide surface coatings. We have performed a systematic study to analyze how both surface types perform in combination with different fluorescent dyes to generate significant and reproducible data. In total, we analyzed more than 100 slides containing 1152 spots each. Slides were probed against different monoclonal antibodies (mAbs) and recombinant fusion proteins. We found two surface coatings to be most suitable for protein and antibody (Ab) immobilization. These were further subjected to quantitative analyses by evaluating intraslide and slide-to-slide reproducibilities, and the linear range of target detection. in summary, we demonstrate that only suitable combinations of surface and fluorescent dyes allow the generation of highly reproducible data
    Type of Publication: Journal article published
    PubMed ID: 16267812
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  • 6
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; SYSTEM ; DISEASE ; GENES ; GENOME ; PROTEIN ; PROTEINS ; ACTIVATION ; FLOW ; antibodies ; antibody ; IDENTIFICATION ; ASSAY ; CELL-DEATH ; fragmentation ; HUMAN GENOME ; FLUORESCENCE ; INHIBITORS ; CHEMISTRY ; RE ; flow cytometry ; genomics ; MEDIATED APOPTOSIS ; methods ; NUCLEAR ; USA ; function ; CANDIDATE ; microbiology ; caspase-3 ; cell-based assay ; PERMEABILITY TRANSITION PORE ; VIRUS CORE PROTEIN
    Abstract: After sequencing the human genome, the challenge ahead is to systematically analyze the functions and disease relation of the proteins encoded. Here the authors describe the application of a flow cytometry-based high-throughput assay to screen for apoptosis-activating proteins in transiently transfected cells. The assay is based on the detection of activated caspase-3 with a specific antibody, in cells overexpressing proteins tagged C- or N-terminally with yellow fluorescent protein. Fluorescence intensities are measured using a flow cytometer integrated with a high-throughput autosampler. The applicability of this screen has been tested in a pilot screen with 200 proteins. The candidate proteins were all verified in an independent microscopy-based nuclear fragmentation assay, finally resulting in the identification of 6 apoptosis inducers
    Type of Publication: Journal article published
    PubMed ID: 17478479
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  • 7
    Keywords: CELLS ; EXPRESSION ; SURVIVAL ; Germany ; IN-VIVO ; PATHWAY ; VIVO ; GENE ; GENE-EXPRESSION ; PROTEIN ; RNA ; transcription ; NF-KAPPA-B ; ACTIVATION ; INFECTION ; TRANSCRIPTION FACTOR ; IMMUNE-RESPONSES ; TARGET ; Drosophila ; MELANOGASTER ; REQUIRES ; HOMOLOG ; IMMUNE-RESPONSE ; FUNCTIONAL GENOMICS ; HOST-DEFENSE ; INTERFERENCE ; RNA INTERFERENCE ; innate immune responses ; IMMUNE ; TOLL ; FUNGAL-INFECTIONS ; Toll signalling
    Abstract: Innate immune signalling pathways are evolutionarily conserved between invertebrates and vertebrates. The analysis of NF-kappa B signalling in Drosophila has contributed important insights into how organisms respond to infection. Nevertheless, significant gaps remain in our understanding of how the activation of intracellular signalling elicits specific transcriptional programs. Here we report a genome-wide RNA interference survey for transcription factors that are required for Toll-dependent immune responses. In addition to the NF-kappa B homologs Dif, Dorsal and factors of the general transcription machinery, we identified Deformed Epidermal Autoregulatory Factor 1 (Deaf1) to be required for the expression of the Toll target gene Drosomycin in cultured cells and in Drosophila in vivo. We show that Deaf1 is required for the survival of flies after fungal, but not E. coli, infection. We determine that Deaf1 acts downstream of the NF-kappa B factors Dorsal and Dif. These results indicate that Deaf1 is an important contributor to innate immune responses in vivo. Copyright (C) 2009 S. Karger AG, Basel
    Type of Publication: Journal article published
    PubMed ID: 20375635
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  • 8
    Keywords: PROTEIN ; COMPLEX ; YEAST ; DESIGN ; SCREEN ; receptor tyrosine kinase ; DROSOPHILA CELLS
    Abstract: The analysis of synthetic genetic interaction networks can reveal how biological systems achieve a high level of complexity with a limited repertoire of components. Studies in yeast and bacteria have taken advantage of collections of deletion strains to construct matrices of quantitative interaction profiles and infer gene function. Yet comparable approaches in higher organisms have been difficult to implement in a robust manner. Here we report a method to identify genetic interactions in tissue culture cells through RNAi. By performing more than 70,000 pairwise perturbations of signaling factors, we identified 〉 600 interactions affecting different quantitative phenotypes of Drosophila melanogaster cells. Computational analysis of this interaction matrix allowed us to reconstruct signaling pathways and identify a conserved regulator of Ras-MAPK signaling. Large-scale genetic interaction mapping by RNAi is a versatile, scalable approach for revealing gene function and the connectivity of cellular networks
    Type of Publication: Journal article published
    PubMed ID: 21378980
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  • 9
    Keywords: CELLS ; PATHWAY ; PROTEIN ; DESIGN ; Drosophila ; DNA-DAMAGE ; CAENORHABDITIS-ELEGANS ; ATR ; CHK1 ; INTERFERENCE ; SCREENS ; RNAi screening ; ART ; DNA damage response signalling ; GENETIC SCREENS ; massively parallel phenotyping ; phenotype networks
    Abstract: Genetic screens for phenotypic similarity have made key contributions to associating genes with biological processes. With RNA interference (RNAi), highly parallel phenotyping of loss-of-function effects in cells has become feasible. One of the current challenges however is the computational categorization of visual phenotypes and the prediction of biological function and processes. In this study, we describe a combined computational and experimental approach to discover novel gene functions and explore functional relationships. We performed a genome-wide RNAi screen in human cells and used quantitative descriptors derived from high-throughput imaging to generate multiparametric phenotypic profiles. We show that profiles predicted functions of genes by phenotypic similarity. Specifically, we examined several candidates including the largely uncharacterized gene DONSON, which shared phenotype similarity with known factors of DNA damage response (DDR) and genomic integrity. Experimental evidence supports that DONSON is a novel centrosomal protein required for DDR signalling and genomic integrity. Multiparametric phenotyping by automated imaging and computational annotation is a powerful method for functional discovery and mapping the landscape of phenotypic responses to cellular perturbations.
    Type of Publication: Journal article published
    PubMed ID: 20531400
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