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Activation of NF-κB by the dsRNA-dependent protein kinase, PKR involves the IκB kinase complex

Oncogene volume 19, pages 1369–1378 (2000)Cite this article

Abstract

Besides its known role as a translational controlling factor, the double stranded RNA-dependent protein kinase (PKR) is a key transcriptional regulator exerting antiviral and antitumoural activities. We have recently described that induction of NF-κB by PKR is involved in apoptosis commitment. To define how PKR mediates NF-κB activation by dsRNA, we have used two different approaches, one based on expression of PKR by a vaccinia virus (VV) recombinant and the other based on induction of endogenous PKR by poly I:C (pIC) treatment. We found that NF-κB complexes induced by PKR are composed primarily of p50-p65 heterodimers and also of c-rel-p50 heterodimers. As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-κB inhibitor IκBα at serine 32 before degradation. Expression by VV recombinants of IKK1 or IKK2 dominant negative mutants together with PKR showed inhibition of PKR-induced NF-κB activation, as measured both by gel shift and luciferase reporter assays. Immunoprecipitation analysis revealed that PKR interacts with the IKK complex. Our findings demonstrate that physiological function(s) of PKR involve activation of the IκB kinase complex.

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Acknowledgements

We recognize to C Weissman (University of Zurich, Switzerland) for the generous gift of the 3T3-like PKR0/0 and PKR+/+ cells. We thank Laura Giménez and Victoria Jimenez for their skilled technical assistance. We are grateful to RT Hay, Manuel Collado and Don Roth for helpful comments and for revision of the manuscript. This work was supported, in part, by grants SAF96/0186, FIS98/0337 and Fundación Caja de Madrid (to J Alcami), and SAF95-0022 and PM98-0112 of Spain (to M Esteban). J Gil was recipient of a fellowship from the Spanish Ministerio de Educación y Cultura. This work was presented at the 1999 Third Joint Meeting of the International Cytokine Society and the International Society for Interferon and Cytokine Research, Paris, France, September 5–9.

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

    Jesús Gil & Mariano Esteban

  2. Centro de Investigación, Hospital 12 de Octubre, Carretera de Andalucía 5.400, Madrid, 28041, Spain

    José Alcamí

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Gil, J., Alcamí, J. & Esteban, M. Activation of NF-κB by the dsRNA-dependent protein kinase, PKR involves the IκB kinase complex. Oncogene 19, 1369–1378 (2000). https://doi.org/10.1038/sj.onc.1203448

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