Transcriptional induction of the p69 isoform of 2 ',5 '-oligoadenylate synthetase by interferon-beta and interferon-gamma involves three regulatory elements and interferon-stimulated gene factor 3

The 2',5'-oligoadenylate synthetases are key enzymes that mediate antiviral actions of interferon (IFN). The mRNAs for the intermediate isoforms (p69) of human 2',5'-oligoadenylate synthetase are rapidly induced 10- to 20-fol d in HT1080 glioma cells by IFN-beta and induced 3-fold at 24 h by IFN-gamm a. Induction is mediated by three regulatory elements, an IFN-stimulated re sponse element and two identical sites resembling interferon response facto r binding sites that are located within 300 bp of the transcriptional start site. Maximal induction requires all three elements, yet mutation in the m ost distal IRF-1-like site diminishes transcription only slightly. Mutation in the ISRE substantially decreases constitutive expression but does not a brogate the response to IFNs. Simultaneous mutation in all three elements a bolishes responsiveness to both IFN-beta and IFN-gamma. Both constitutive a nd IFN-beta-induced expression from the p69 promoter is blocked in mutant c ell lines deficient in components of the transcription factor, interferon-s timulated gene factor 3, suggesting that it is the primary factor controlli ng IFN-beta induced expression of this gene. (C) 1999 Academic Press.