Activation of ATR-Chk1 pathway facilitates EBV-mediated transformation of primary tonsillar B-cells
| Autor: | Alessandro A. Sartori, Vanessa Mordasini, Claudine Gysin, Daniela Hühn, Seigo Ueda, David Nadal, Roberta Aslandogmus, Michele Bernasconi, Christoph Berger |
|---|---|
| Přispěvatelé: | University of Zurich, Nadal, David |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Epstein-Barr Virus Infections Herpesvirus 4 Human Time Factors DNA Repair Palatine Tonsil Ataxia Telangiectasia Mutated Proteins 0302 clinical medicine hemic and lymphatic diseases Medicine Cells Cultured B-Lymphocytes 10061 Institute of Molecular Cancer Research Oncology 030220 oncology & carcinogenesis Host-Pathogen Interactions 2730 Oncology Oncovirus Research Paper hyperproliferation Signal Transduction DNA damage Chk1 Antigens CD19 CD40 Ligand 610 Medicine & health DDR Virus 03 medical and health sciences EBV Humans 10220 Clinic for Surgery Protein Kinase Inhibitors Cell Proliferation business.industry Cell growth medicine.disease Cell Transformation Viral In vitro Enzyme Activation Transformation (genetics) 030104 developmental biology ATR 10036 Medical Clinic Immunology Ataxia-telangiectasia Checkpoint Kinase 1 570 Life sciences biology business Transformation efficiency DNA Damage |
| Zdroj: | Oncotarget |
| DOI: | 10.5167/uzh-130448 |
| Popis: | Primary infection of the immunocompromised host with the oncovirus Epstein-Barr virus (EBV) that targets mainly B-cells is associated with an increased risk for EBV-associated tumors. The early events subsequent to primary infection with potential for B-cell transformation are poorly studied. Here, we modeled in vitro the primary infection by using B-cells isolated from tonsils, the portal of entry of EBV, since species specificity of EBV hampers modeling in experimental animals. Increasing evidence indicates that the host DNA damage response (DDR) can influence and be influenced by EBV infection. Thus, we inoculated tonsillar B-cells (TBCs) with EBV-B95.8 and investigated cell proliferation and the DDR during the first 96 hours thereafter. We identified for the first time that EBV infection of TBCs induces a period of hyperproliferation 48-96 hours post infection characterized by the activation of ataxia telangiectasia and Rad3-releated (ATR) and checkpoint kinase-1 (Chk1). Whereas inhibition of Chk1 did not affect B-cell transformation, the specific inhibition of ATR robustly decreased the transformation efficiency of EBV. Our results suggest that activation of ATR is key for EBV-induced B-cell transformation. Thus, targeting the interaction between ATR/Chk1 and EBV could offer new options for the treatment of EBV-associated malignancies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|