Induced factor binding to the interferon-stimulated response element. Interferon-alpha and platelet-derived growth factor utilize distinct signaling pathways.
Interferon-alpha (IFN alpha) and platelet-derived growth factor (PDGF) each rapidly stimulate binding of nuclear factors from Balb/c 3T3 fibroblasts, to a 29-base pair regulatory sequence derived from the 5' upstream region of the murine 2-5A synthetase gene. This regulatory sequence contains a functional interferon-stimulated response element (ISRE) and also functions as a PDGF-responsive sequence. We show that IFN alpha induces binding of a protein of molecular mass 65 kDa to the ISRE. Constitutively expressed ISRE-binding proteins of 98 and 150 kDa are also demonstrated. Binding of inducible factors to the ISRE increases significantly within 15 min of IFN alpha or PDGF treatment. PDGF-induced binding is not mediated by IFN beta. The protein kinase inhibitors, staurosporine and K252a, block PDGF-induced ISRE binding and 2-5A synthetase gene expression. IFN alpha-induced ISRE binding and gene activation are not blocked by these inhibitors. Treatment of cells with 12-O-tetradecanoyl-13-acetate or dibutyryl cyclic AMP does not activate ISRE binding factors or 2-5A synthetase gene expression. PDGF responsiveness of the ISRE in vivo is also sensitive to staurosporine, indicating that inhibition of a protein kinase activity blocks the PDGF-specific transcriptional signal. Our data indicate the signal transduction pathway for IFN alpha-induced, ISRE-dependent transcription is distinct from the PDGF-induced ISRE response and is likely independent of cyclic AMP-dependent protein kinase and protein kinase C activities.
Hannigan
G E
GE
Research Institute, Hospital for Sick Children, Toronto, Canada.
Williams
B R
BR
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002227:Carbazoles / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D026121:Indole Alkaloids; D007370:Interferon Type I / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D019311:Staurosporine; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
D000470:Alkaloids; D002227:Carbazoles; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D026121:Indole Alkaloids; D007370:Interferon Type I; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; C049985:staurosporine aglycone; D015088:2',5'-Oligoadenylate Synthetase; D019311:Staurosporine