Oncogenic ras induces an inhibitor of double-stranded RNA-dependent eukaryotic initiation factor 2 alpha-kinase activation.
The interferon-inducible 68-kDa dsRNA-dependent eIF2 alpha-kinase (dsI) is a potent cellular antiviral enzyme which is activated by autophosphorylation in response to double-stranded RNA (dsRNA). Activated dsI has also been implicated as a second messenger for gene induction by platelet-derived growth factor (PDGF) and interferon (IFN). We have shown previously that introduction of a transforming ras gene into BALB/c-3T3 fibroblasts blocks induction of responsive genes by PDGF and IFN. We therefore investigated the effect of transforming ras genes on dsI activity in these cells. We report here that dsRNA-mediated activation of dsI is blocked in v-ras-containing cells in a manner specific to ras and not attributable to the transformed phenotype since: 1) a dexamethasone-inducible v-Ha-ras gene produced the effect within 18 h of induction; 2) morphologic reversion of ras-transformed cells with cAMP or the Krev-1 gene restored potential for dsI activation; and 3) transformation by v-mos or v-abl had no effect on dsI activation. Latent dsI levels were unaffected by v-ras. A heat-sensitive dsI inhibitory activity could be demonstrated in v-ras-containing cells which functioned in trans when mixed with untransformed cell extracts prior to stimulation with dsRNA. The inhibitory activity, which was destroyed by phenol-chloroform extraction, did not bind dsRNA.
Boston University School of Medicine, Cancer Research Center, Massachusetts 02118.
L J
LJ
Mundschau
D V
DV
Faller
D016475:3T3 Cells; D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D003593:Cytoplasm / Q000201:enzymology; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016313:Genes, abl; D016258:Genes, mos; D011905:Genes, ras; D007700:Kinetics; D007708:Kirsten murine sarcoma virus / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009857:Oncogenes; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D019892:eIF-2 Kinase; D020668:rap GTP-Binding Proteins
D047428:Protein Kinase Inhibitors; D012330:RNA, Double-Stranded; D003907:Dexamethasone; D011494:Protein Kinases; D019892:eIF-2 Kinase; D019204:GTP-Binding Proteins; D020668:rap GTP-Binding Proteins