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  • DISEASE  (2)
  • 1
    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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  • 2
    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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