REGULATION OF THE INTERFERON－INDUCIBLE PROTEIN KINASEPKR AND2＇5＇ OLIGOADENYLATE SYNTHETASE BY A CATALYTICALLY INACTIVE PKR M

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REGULATION OF THE INTERFERON-INDUCIBLE PROTEIN KINASE PKR AND 2'5' OLIGOADENYLATE SYNTHETASE BY A CATALYTICALLY INACTIVE PKR MUTANT THROUGH COMPETITION FOR DOUBLE-STRANDED RNA BINDING

The interferon-inducible double-stranded RNA-dependent protein kinase PKR has been suggested to function as a turnour suppressor gene product.Catalytically inactive mutants of PKR give rise to a tumourigenic phenotype when overexpressed in NIH-3T3 fibroblasts and this has been attributed to a dominant negative effect on only inhibits the protein kinase activity of wild-type PKR but is also inhibitory towards another dotlblestranded RNA-dependent enzyme,the 40kDa form of 2'5'oligoadenylate synthetase. Inhibition of both wile-type PKR or 2'5' oligoadenylate synthetase is reversed by adding higher concentrations of double-stranded RNA. These results suggest competition between PKR K296R and wild-type PKR or 2'5' oligoadenylate synthetase for limiting amounts of dublestranded RNA. Moreover,the data imply that the tumourigenic effect of this PKR mutant could be due to inhibition of additional pathways requiring low levels of double-strandeed RNA for activation and cannot be unambiguously attributed to inhibition of endogenous PKR itself.