title: In vivo regulation of the dsRNA-dependent protein kinase PKR by the cellular glycoprotein p67.
abstract: Regulation of eIF2alpha phosphorylation is critical to the maintenance of cellular homeostasis, and eIF2alpha kinases are subject to complex and multidimensional controls. A cellular 67 kDa glycoprotein (p67) has been proposed to have an important role in regulating the activity of eIF2alpha kinases including the interferon-induced, dsRNA-stimulated protein kinase PKR. To dissect p67-PKR interactions and evaluate their significance in vivo, we have used a vaccinia virus (VV) expression system that successfully mimics PKR control pathways. Recombinant VV were constructed that constitutively express p67 and inducibly express PKR in BSC-40 cells. Stable expression of p67 reduced the PKR-mediated antiviral response and apoptosis. These effects correlated with decreased eIF2alpha phosphorylation, with rescue of PKR-mediated inhibition of protein synthesis, and with partial inhibition of PKR-triggered activation of NF-kappaB. The direct interaction between PKR and p67 was suggested by in vivo and in vitro analyses. These data demonstrate that in vivo p67 is an important modulator of PKR-mediated signal transduction pathways and may provide a useful tool to dissect the relative contributions of PKR to cell growth and stress response.
authors: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Campus Universidad Autónoma, 28049 Madrid, Spain.
authors: J
authors: J
authors: Gil
authors: M
authors: M
authors: Esteban
authors: D
authors: D
authors: Roth
mesh_terms: D000626:Aminopeptidases; D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D063208:Methionyl Aminopeptidases; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D014176:Protein Biosynthesis; D012330:RNA, Double-Stranded / Q000502:physiology; D011995:Recombination, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000235:genetics; D014616:Vaccinia virus / Q000235:genetics; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D006023:Glycoproteins; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D014764:Viral Proteins; D019892:eIF-2 Kinase; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases