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J Biol Chem, Vol. 274, Issue 9, 5953-5962, February 26, 1999

Characterization of Transgenic Mice with Targeted Disruption of the Catalytic Domain of the Double-stranded RNA-dependent Protein Kinase, PKR

Ninan Abrahamab, David F. Stojdlab, Peter I. Duncand, Nathalie Méthote, Tetsu Ishiif, Manon Dubéa, Barbara C. Vanderhydena, Harold L. Atkinsag, Douglas A. Grayab, Michael W. McBurneyab, Antonis E. Koromilasf, Earl G. Brownh, Nahum Sonenberge, and John C. Bellab

From the a Ottawa Regional Cancer Center Research Laboratories, Ottawa, Ontario K1H 8L6, the b Department of Biochemistry, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the d Department of Molecular Biology, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva, Switzerland, the g Division of Hematology, Ottawa General Hospital, Ottawa, Ontario K1H 8L6, the f Department of Oncology and Medicine, Lady Davis Institute for Medical Research, Montreal, Quebec H3T 1E2, the h Department of Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, and the e Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada

The interferon-inducible, double-stranded RNA-dependent protein kinase PKR has been implicated in anti-viral, anti-tumor, and apoptotic responses. Others have attempted to examine the requirement of PKR in these roles by targeted disruption at the amino terminal-encoding region of the Pkr gene. By using a strategy that aims at disruption of the catalytic domain of PKR, we have generated mice that are genetically ablated for functional PKR. Similar to the other mouse model of Pkr disruption, we have observed no consequences of loss of PKR on tumor suppression. Anti-viral response to influenza and vaccinia also appeared to be normal in mice and in cells lacking PKR. Cytokine signaling in the type I interferon pathway is normal but may be compromised in the erythropoietin pathway in erythroid bone marrow precursors. Contrary to the amino-terminal targeted Pkr mouse, tumor necrosis factor alpha -induced apoptosis and the anti-viral apoptosis response to influenza is not impaired in catalytic domain-targeted Pkr-null cells. The observation of intact eukaryotic initiation factor-2alpha phosphorylation in these Pkr-null cells provides proof of rescue by another eukaryotic initiation factor-2alpha kinase(s).

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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