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Berlin Brandenburg

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  • 1
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, October 2013, Vol.27(10), pp.4027-40
    Description: TGF-β signaling induces epithelial to mesenchymal transition (EMT) and plays an important role in hepatocellular carcinoma (HCC) development. Clinical observations indicate that hepatitis C virus (HCV) chronic infection, which is a major cause of HCC, induces TGF-β signaling perturbations. Here, we investigate the mechanisms by which HCV nonstructural proteins interfere with TGF-β signaling, in human hepatoma cell lines expressing HCV subgenomic replicon. A transcriptomic study showed that TGF-β stimulation of these cells resulted in a protumoral gene expression profile and in up-regulation of EMT-related genes compared to control interferon-treated cells not expressing HCV proteins. We found that the viral protease NS3-4A interacted with SMURF2, a negative regulator of TGF-β signaling. In cells expressing HCV subgenomic replicon or NS3-4A, TGF-β stimulation induced an increased expression of SMAD-dependent genes compared to control cells. This enhanced signaling was suppressed by SMURF2 overexpression and mimicked by SMURF2 silencing. In addition, NS3-4A expression resulted in an increased and prolonged TGF-β-induced phosphorylation of SMAD2/3 that was abrogated by SMURF2 overexpression. Neither NS3-4A protease activity nor SMURF2 ubiquitin-ligase activity was required to affect TGF-β signaling. Therefore, by targeting SMURF2, NS3-4A appears to block the negative regulation of TGF-β signaling, increasing the responsiveness of cells to TGF-β.
    Keywords: Emt ; Hepatocellular Carcinoma ; Transforming Growth Factor-Β ; Hepacivirus -- Metabolism ; Peptide Hydrolases -- Metabolism ; Transforming Growth Factor Beta -- Metabolism ; Ubiquitin-Protein Ligases -- Metabolism ; Viral Nonstructural Proteins -- Physiology
    ISSN: 08926638
    E-ISSN: 1530-6860
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  • 2
    Language: English
    In: Genome Medicine, Nov 29, 2014, Vol.6(11)
    Description: The current therapeutic arsenal against viral infections remains limited, with often poor efficacy and incomplete coverage, and appears inadequate to face the emergence of drug resistance. Our understanding of viral biology and pathophysiology and our ability to develop a more effective antiviral arsenal would greatly benefit from a more comprehensive picture of the events that lead to viral replication and associated symptoms. Towards this goal, the construction of virus-host interactomes is instrumental, mainly relying on the assumption that a viral infection at the cellular level can be viewed as a number of perturbations introduced into the host protein network when viral proteins make new connections and disrupt existing ones. Here, we review advances in interactomic approaches for viral infections, focusing on high-throughput screening (HTS) technologies and on the generation of high-quality datasets. We show how these are already beginning to offer intriguing perspectives in terms of virus-host cell biology and the control of cellular functions, and we conclude by offering a summary of the current situation regarding the potential development of host-oriented antiviral therapeutics.
    Keywords: Drug Resistance -- Health Aspects ; Virus Diseases -- Health Aspects ; Antiviral Agents -- Health Aspects ; Viral Proteins -- Health Aspects ; Cells (Biology) -- Health Aspects ; Drug Discovery -- Health Aspects ; Imex
    ISSN: 1756-994X
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  • 3
    Language: English
    In: Molecular and Cellular Proteomics, July 2012, Vol.11(7), p.M111.014738
    Description: A decade of high-throughput screenings for intraviral and virus-host protein-protein interactions led to the accumulation of data and to the development of theories on laws governing interactome organization for many viruses. We present...
    Keywords: Computer Simulation ; Host-Pathogen Interactions ; Humans ; Models, Statistical ; Protein Interaction Mapping ; Protein Interaction Maps ; Viral Proteins ; Virus Replication ; Viruses ; Life Sciences ; Biology ; Anatomy & Physiology
    ISSN: 1535-9476
    E-ISSN: 1535-9484
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  • 4
    Language: English
    In: BMC Microbiology, Oct 20, 2011, Vol.11, p.234
    Description: Background The genus Flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as West Nile virus, yellow fever virus, Japanese encephalitis virus and the four serotypes of dengue viruses (DENV type 1-4). Each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. Among the viral proteins, NS3 and NS5 proteins constitute the major enzymatic components of the viral replication complex and are essential to the flavivirus life cycle. Results We report here the results of a high-throughput yeast two-hybrid screen to identify the interactions between human host proteins and the flavivirus NS3 and NS5 proteins. Using our screen results and literature curation, we performed a global analysis of the NS3 and NS5 cellular targets based on functional annotation with the Gene Ontology features. We finally created the first flavivirus NS3 and NS5 proteins interaction network and analysed the topological features of this network. Our proteome mapping screen identified 108 human proteins interacting with NS3 or NS5 proteins or both. The global analysis of the cellular targets revealed the enrichment of host proteins involved in RNA binding, transcription regulation, vesicular transport or innate immune response regulation. Conclusions We proposed that the selective disruption of these newly identified host/virus interactions could represent a novel and attractive therapeutic strategy in treating flavivirus infections. Our virus-host interaction map provides a basis to unravel fundamental processes about flavivirus subversion of the host replication machinery and/or immune defence strategy.
    Keywords: Interactomes -- Research ; Flaviviruses -- Genetic Aspects ; Flaviviruses -- Research ; Viral Proteins -- Physiological Aspects ; Viral Proteins -- Research
    ISSN: 1471-2180
    Source: Cengage Learning, Inc.
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  • 5
    Language: English
    In: BMC Microbiology, Oct 20, 2011, Vol.11, p.234
    Description: Background The genus Flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as West Nile virus, yellow fever virus, Japanese encephalitis virus and the four serotypes of dengue viruses (DENV type 1-4). Each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. Among the viral proteins, NS3 and NS5 proteins constitute the major enzymatic components of the viral replication complex and are essential to the flavivirus life cycle. Results We report here the results of a high-throughput yeast two-hybrid screen to identify the interactions between human host proteins and the flavivirus NS3 and NS5 proteins. Using our screen results and literature curation, we performed a global analysis of the NS3 and NS5 cellular targets based on functional annotation with the Gene Ontology features. We finally created the first flavivirus NS3 and NS5 proteins interaction network and analysed the topological features of this network. Our proteome mapping screen identified 108 human proteins interacting with NS3 or NS5 proteins or both. The global analysis of the cellular targets revealed the enrichment of host proteins involved in RNA binding, transcription regulation, vesicular transport or innate immune response regulation. Conclusions We proposed that the selective disruption of these newly identified host/virus interactions could represent a novel and attractive therapeutic strategy in treating flavivirus infections. Our virus-host interaction map provides a basis to unravel fundamental processes about flavivirus subversion of the host replication machinery and/or immune defence strategy.
    Keywords: Interactomes -- Research ; Flaviviruses -- Genetic Aspects ; Flaviviruses -- Research ; Viral Proteins -- Physiological Aspects ; Viral Proteins -- Research
    ISSN: 1471-2180
    Source: Cengage Learning, Inc.
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  • 6
    Language: English
    In: BMC Microbiology, 2011, Vol.11(1), p.234
    Description: BACKGROUND: The genus Flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as West Nile virus, yellow fever virus, Japanese encephalitis virus and the four serotypes of dengue viruses (DENV type 1-4). Each year, flaviviruses...
    Keywords: Flavivirus ; Flavivirus Infections ; Viral Nonstructural Proteins ; Hek293 Cells ; High-Throughput Screening Assays ; Host-Pathogen Interactions ; Humans ; Protein Interaction Mapping ; RNA Helicases ; Serine Endopeptidases ; Two-Hybrid System Techniques ; Life Sciences ; Microbiology and Parasitology ; Biology
    ISSN: 1471-2180
    E-ISSN: 1471-2180
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  • 7
    In: STEM CELLS, October 2015, Vol.33(10), pp.2936-2948
    Description: Statin treatment of hypercholesterolemia can lead to chronic myotoxicity which is, in most cases, alleviated by drug withdrawal. Cellular and molecular mechanisms of this adverse effect have been elusive, in particular because of the lack of in vitro models suitable for long‐term exposures. We have taken advantage of the properties of human pluripotent stem cell‐derived mesodermal precursors, that can be maintained unaltered in vitro for a long period of time, to develop a model of repeated exposures to simvastatin during more than 2 weeks. This approach unveiled major differences, both in functional and molecular terms, in response to single versus repeated‐dose exposures to simvastatin. The main functional effect of the in vitro simvastatin‐induced long‐term toxicity was a loss of proliferative capacity in the absence of concomitant cell death, revealing that cytostatic effect could be a major contributor to statin‐induced myotoxicity. Comparative analysis of molecular modifications induced by simvastatin short‐term versus prolonged exposures demonstrated powerful adaptive cell responses, as illustrated by the dramatic decrease in the number of differentially expressed genes, distinct biological pathway enrichments, and distinct patterns of nutrient transporters expressed at the cell surface. This study underlines the potential of derivatives of human pluripotent stem cells for developing new approaches in toxicology, in particular for chronic toxicity testing. S C
    Keywords: Chronic Toxicity ; Pluripotent Stem Cells ; Mesoderm ; Simvastatin ; Cytostatic Agent
    ISSN: 1066-5099
    E-ISSN: 1549-4918
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  • 8
    Language: English
    In: Current Opinion in Virology, October 2012, Vol.2(5), pp.606-613
    Description: ► Human proteins interacting with viruses are a vast reservoir of new antiviral targets. ► Orthogonal ‘-omics’ approaches provide a rational to select relevant cellular targets. ► Topological nature of cellular targets: central and bridging proteins. ► Drug repositioning strategies are on tracks to faster antiviral drug discovery. Viruses are recurrent socio economical and health problems each year worldwide. Current drugs are mainly directed against viral components and select resistant strains that urge the need to develop new antiviral therapeutics. High-throughput screening technologies now allow to draw comprehensive genome-wide maps of physical and genetic virus–host interactions. This has been done recently for several viruses such as HIV, HCV, DENV and FLUAV and revealed a wealth of potential antiviral cellular targets. Systems-level analysis of virus–host protein networks and subnetworks begins to uncover several specific points of intervention for a human centered drug development. We present here this new paradigm in antiviral drug discovery together with the first promising antiviral molecules.
    Keywords: Biology
    ISSN: 1879-6257
    E-ISSN: 1879-6265
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  • 9
    Language: English
    In: Molecular BioSystems, April 2012, Vol.8(4), pp.1297-303
    Description: Current anti-influenza virus drugs target two viral proteins and induce a selective pressure for the generation of drug resistant variants. This stresses the need for additional therapeutic strategies including drug targeting of cellular...
    Keywords: Antiviral Agents ; Drug Discovery ; Humans ; Influenza, Human ; Orthomyxoviridae ; Reverse Genetics ; Viral Proteins ; Virus Replication ; Life Sciences ; Biology
    ISSN: 1742-206X
    E-ISSN: 1742-2051
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  • 10
    Language: English
    In: Molecular and Cellular Proteomics, 12 September 2011
    Description: RNA viruses exhibit small-sized genomes encoding few proteins, but still establish complex networks of interactions with host cell components to achieve replication and spreading. Ideally, these virus-host protein interactions should be mapped directly in infected cell culture, but such...
    Keywords: Life Sciences ; Biochemistry, Molecular Biology ; Genomics ; Biology ; Anatomy & Physiology
    ISSN: 1535-9476
    E-ISSN: 1535-9484
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