Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR

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 Phr gene. By using a strategy that aims at disruption of the catalytic domain of PHR, 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 aminoterminal targeted Phr 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-2 alpha phosphorylation in these Pkr-null cells provides proof of rescue by another eukaryotic initiation factor-2 alpha kinase(s).