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  • Original Paper
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c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors

Oncogene volume 18, pages 2181–2188 (1999)Cite this article

Abstract

The contact of natural killer (NK) cells with foreign cells and with certain virus-infected or tumor cells triggers the cytolytic machinery of NK cells. This triggering leads to exocytosis of the cytotoxic NK cell granules. The oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated cytolysis yet the mechanisms of sensitization are not well understood. In a model where foreign cells (rat fibroblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of efficiently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A. Both the parental and the oncogene expressing fibroblasts similarly triggered phosphoinositide hydrolysis in the bound NK cells, demonstrating that NK cells were cytolytically activated in contact with both resistant parental and oncogene expressing sensitive target fibroblasts. The cell death was independent of wild-type p53 and was not inhibited by an anti-apoptotic protein E1B19K. These results provided evidence that c-Myc and E1A activated the NK cell induced cytolysis at a post-triggering stage of NK cell-target cell interaction. In consistence, the c-Myc and E1A overexpressing fibroblasts were more sensitive to the cytolytic effects of isolated NK cell-derived granules than parental cells. The data indicate that oncogenes activate the cytotoxicity of NK cell granules. This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and cancer cells.

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Acknowledgements

We wish to thank Dr Olli Carpen for useful discussions and expert help in confocal microscopy. This work was supported by the Finnish Cancer Organizations, the Finnish Academy, Emil Aaltonen, Maud Kuistila, Sigrid Juselius, Farmos, Finnish Cultural Foundations and European Molecular Biology Organization.

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Author notes

  1. Juha Klefstrom: Author for correspondence

  2. Juha Klefstrom and Panu E Kovanen: J Klefstrom and PE Kovanen contributed equally to this work

Authors and Affiliations

  1. Biochemistry of the Cell Nucleus Laboratory, Imperial Cancer Research Fund, P.O. Box 123, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Juha Klefstrom, Anne-Odile Hueber, Trevor Littlewood & Gerard I Evan

  2. Molecular/Cancer Biology Laboratory and Department of Pathology, Haartman Institute, P.O. Box 21, 00014 University of Helsinki, Finland

    Panu E Kovanen, Kristina Somersalo, Eero Saksela, Tuomo Timonen & Kari Alitalo

  3. Departments of Pediatrics and Immunology, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, R3E 0V9, Manitoba, Canada

    Arnold H Greenberg

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  1. Juha Klefstrom
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Klefstrom, J., Kovanen, P., Somersalo, K. et al. c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors. Oncogene 18, 2181–2188 (1999). https://doi.org/10.1038/sj.onc.1202546

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