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The interferon-induced protein kinase (PKR), triggers apoptosis through FADD-mediated activation of caspase 8 in a manner independent of Fas and TNF-α receptors

Oncogene volume 19, pages 3665–3674 (2000)Cite this article

Abstract

The interferon-induced dsRNA-dependent protein kinase (PKR) induces apoptosis of mammalian cells. Apoptosis induction by PKR involves phosphorylation of the translational factor eIF-2α and activation of the transcriptional factor NF-κB, but caspase pathways activated by PKR are not known. Upregulation of Fas mRNA by PKR has been suggested to play a role in PKR-induced apoptosis. To learn how PKR induces apoptosis, we have analysed the role of molecules in death receptor pathways. We showed the involvement of the FADD-caspase 8 pathway on PKR-induced apoptosis based on four experimental findings: upregulation of caspase 8 activity during PKR-induced apoptosis, blocking of PKR-induced apoptosis by the use of a chemical inhibitor of caspase 8, and inhibition of PKR-induced apoptosis by expression of both a FADD dominant negative or a viral FLIP molecule. Significantly, despite the PKR-mediated upregulation of Fas mRNA expression, the Fas receptor-ligand pathway is not needed for PKR-induced apoptosis. Antibodies that inhibit TNFα-TNFR1 or Fas-FasL interactions were not able to block PKR-induced apoptosis. Taken together, our observations establish the involvement of caspase 8 in PKR-induced apoptosis and suggest that death receptors other than Fas or TNFR1 or, alternatively, a novel mechanism involving FADD independently of death receptors, are responsible for PKR-induced apoptosis.

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Acknowledgements

We recognize Miguel Torres (DIO-CNB, Madrid) for lpr/lpr and wild type mouse embryo fibroblasts and the FasL blocking antibody, Manuel Fresno (CBMSO, Madrid) for the B13.2 mAb neutralizing directed against human TNFα, and Vishva Dixit (Genentech Inc., San Francisco) for the pcDNA3-FADD DN plasmid. We also thank Mónica Agromayor for help with MC 159L amplification, Isabel Vázquez for generating pHLZ plasmid and Victoria Jimenez for her skilled technical assistance. The review of the manuscript by Manuel Collado and Don Roth are also appreciated. This investigation was supported by grant PM98-0112 from CICYT of Spain. J Gil was recipient of a fellowship from Spanish MEC.

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  1. Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, (CSIC), Campus Universidad Autónoma, Madrid, 28049, Spain

    Jesús Gil & Mariano Esteban

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Gil, J., Esteban, M. The interferon-induced protein kinase (PKR), triggers apoptosis through FADD-mediated activation of caspase 8 in a manner independent of Fas and TNF-α receptors. Oncogene 19, 3665–3674 (2000). https://doi.org/10.1038/sj.onc.1203710

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