THE INTERFERON-INDUCIBLE PROTEIN-KINASE PKR MODULATES THE TRANSCRIPTIONAL ACTIVATION OF IMMUNOGLOBULIN-KAPPA GENE

PKR is an interferon (IFN)-induced serine/threonine protein kinase that regulates protein synthesis through phosphorylation of eukaryotic translation initiation factor-2 (eIF-2). In addition to its demonstrated role in translational control, recent findings suggest that PKR plays an important role in regulation of gene transcription, as PKR phosphorylates I kappa B alpha upon double-stranded RNA treatment resulting in activation of NF-kappa B DNA binding in vitro (Kumar, A., Haque, J., Lacoste, J., Hiscott, J., and Williams, B. R. G. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 6288-6292). To further investigate the role of PKR in transcriptional signaling, we expressed the wild type human PKR and a catalytically inactive dominant negative PKR mutant in the murine pre-B lymphoma 70Z/3 cells. Here, we report that expression of wild type PKR had no effect on kappa-chain transcriptional activation induced by lipopolysaccharide or IFN-gamma. However, expression of the dominant negative PKR mutant inhibited kappa gene transcription independently of NF-kappa B activation. Phosphorylation of eIF-2 alpha was not increased by lipopolysaccharide or IFN-gamma, suggesting that PKR mediates kappa gene transcriptional activation without affecting protein synthesis. Our findings further support a transcriptional role for PKR and demonstrate that there are at least two distinct PKR-mediated signal transduction pathways to the transcriptional machinery depending on cell type and stimuli, NF-kappa B-dependent and NF-kappa B-independent.