Staurosporine inhibits interferon alpha-induced gene expression in Friend erythroleukemia cells through a PKC independent pathway.
Interferons (IFNs) are able to induce an increased transcription of several genes, which can occur within minutes of the binding of IFNs to their receptors. The specific induced transcription is mediated by the interaction of specific transcription factors with regulatory DNA sequences that lie upstream the promoters of IFN induced genes. Phosphorylation of IFN-specific transcription factors is required for activation of transcription. We have studied the antiviral effect and the induction of gene expression by IFN-alpha in Friend Leukemia cells (FLC) in the presence of a series of inhibitors of known kinases. Protein kinase C (PKC)-specific inhibitors, i.e. calphostin C and bisindolylmaleimide, failed to influence the IFN-induced gene expression and the antiviral state. Likewise, little or no effect was found using inhibitors such as H7 or K252a. Chronic exposure of FLC to phorbol ester, that causes down regulation of PKC (the effectiveness of TPA treatment was proven by PKC enzymatic assay), has no effect on IFN-alpha action. In addition, treatment of FLC with staurosporine prevented the induction of IFN-stimulated genes and the establishment of the antiviral state only when this drug was used at high dosage (500 nM). This result indicates that, also in FLC, activation of PKC is not involved in the transcriptional response of the cells to IFN-alpha treatment. The non receptor tyrosine kinases of the JAK family that take part in the IFNs-specific transduction pathways could be the target of the staurosporine specific inhibition of the IFN-alpha action.
Percario
Z A
ZA
Laboratory of Virology, Istituto Superiore di Sanità, Roma, Italy.
Fiorucci
G
G
Marcolin
C
C
Mangino
G
G
Affabris
E
E
Romeo
G
G
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000470:Alkaloids / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005622:Friend murine leukemia virus; D005786:Gene Expression Regulation / Q000187:drug effects*; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D007371:Interferon-gamma; D011493:Protein Kinase C; D015088:2',5'-Oligoadenylate Synthetase; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate