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The HPV E7 oncoprotein inhibits tumor necrosis factor α-mediated apoptosis in normal human fibroblasts

Oncogene volume 20, pages 3629–3640 (2001)Cite this article

Abstract

Tumor necrosis factor-α (TNF) is a cytokine that induces programmed cell death, apoptosis, in a number of cell types and is employed by cytotoxic T cells to eliminate virus infected cells. Consequently, many viruses have acquired mechanisms to undermine these host cell defense mechanisms and cause resistance to TNF-mediated apoptosis. Here we show that normal human diploid fibroblasts that express the human papillomavirus type 16 E7 oncoprotein have a decreased propensity to undergo apoptosis in response to TNF treatment. The ability of E7 to undermine TNF-mediated apoptosis correlates with cellular transformation. While E7 does not generally subvert signaling by tumor necrosis factor receptor 1, pro-caspase 8 activation is decreased in E7-expressing cells. E7 also provides some protection from apoptosis caused by stimulation of the TNF receptor 1-related cytokine receptor Fas, where induction of apoptosis occurs much slower in this cell type. Hence, E7-expressing normal human fibroblasts exhibit a specific defect that obstructs cytokine-mediated activation of pro-caspase 8 and apoptosis.

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Acknowledgements

We are grateful to Arthur Lee and Philip Hinds for critical comments concerning this manuscript. We also thank D Galloway, W Krek, V Dixit, M Oren R Mulligan, E Kieff, J Daniels, R Ed Marlborough and TH-T Chang for providing important reagents and support. This work was supported by Public Health Service grant R01 CA81135 (K Münger) from the National Cancer Institute. V Zacny was supported by T32 CA72320. K Münger is a Ludwig Scholar; DA Thompson is a Ryan fellow.

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Author notes

  1. David Alan Thompson

    Present address: Department of Entomology, University of California, Davis, 95616, CA, USA

  2. David Alan Thompson and Valerie Zacny: DA Thompson and V Zacny contributed equally to this work

Authors and Affiliations

  1. Department of Pathology and Harvard Center for Cancer Biology, Harvard Medical School, 200 Longwood Avenue, Boston, 02115, Massachusetts, MA, USA

    David Alan Thompson, Valerie Zacny, Dana Leanne Jones & Karl Münger

  2. Department of Cancer Cell Biology, Harvard School of Public Health, 665 Huntington Avenue, Boston, 02115, Massachusetts, MA, USA

    David Alan Thompson, Glenn Scott Belinsky & Robert Schlegel

  3. Massachusetts General Hospital Cancer Center, Charlestown, 02129, Massachusetts, MA, USA

    Marie Classon

  4. Department of Developmental Biology, Stanford University, Stanford, 94035, CA, USA

    Dana Leanne Jones

  5. Millennium Predictive Medicine, Cambridge, 02139, MA, USA

    Robert Schlegel

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Thompson, D., Zacny, V., Belinsky, G. et al. The HPV E7 oncoprotein inhibits tumor necrosis factor α-mediated apoptosis in normal human fibroblasts. Oncogene 20, 3629–3640 (2001). https://doi.org/10.1038/sj.onc.1204483

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