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, Oth ers have attempted to examine the requirement of PKR in these roles by targ eted disruption at the amino terminal-encoding region of the Phr gene. By u sing 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 consequenc es of loss of PKR on tumor suppression. Anti-viral response to influenza an d vaccinia also appeared to be normal in mice and in cells lacking PKR Cyto kine signaling in the type I interferon pathway is normal but may be compro mised in the erythropoietin pathway in erythroid bone marrow precursors. Co ntrary to the aminoterminal targeted Phr mouse, tumor necrosis factor alpha -induced apoptosis and the anti-viral apoptosis response to influenza is no t impaired in catalytic domain-targeted Pkr-null cells. The observation of intact eukaryotic initiation factor-2 alpha phosphorylation in these Pkr-nu ll cells provides proof of rescue by another eukaryotic initiation factor-2 alpha kinase(s).