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.
Koromilas
A E
AE
Department of Oncology, McGill University, Montreal, Quebec, Canada.
Cantin
C
C
Craig
A W
AW
Jagus
R
R
Hiscott
J
J
Sonenberg
N
N
D000818:Animals; D001483:Base Sequence; D004790:Enzyme Induction; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D005803:Genes, Immunoglobulin; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D016393:Lymphoma, B-Cell; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011230:Precancerous Conditions; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase
D015852:Eukaryotic Initiation Factor-2; D007075:Immunoglobulin M; D007145:Immunoglobulin kappa-Chains; D016328:NF-kappa B; D012334:RNA, Neoplasm; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase