Transcriptional induction of p69 2'-5'-oligoadenylate synthetase by interferon-alpha is stimulated by 12-O-tetradecanoyl phorbol-13-acetate through IRF/ISRE binding motifs.

Protein kinase C (PKC) is required for transcriptional induction of 2'-5'-oligoadenylate (2-5A) synthetases by interferon (IFN)-alpha. Regulatory elements located in the 5'-flanking region of the p69 2-5A synthetase gene have been identified which are required for transcriptional stimulation by PKC. The region from -366 to -117 bp, relative to the translational start site, contains three sequence motifs that resemble interferon stimulated response elements/interferon regulatory factor elements (ISRE/IRF-E), which are required for stimulation of the IFN-alpha-response by the PKC activator, 12-O-tetradecanoyl phorbol-13-acetate (TPA). Constructs which have a deletion of the region containing IRF-Es located at -361 bp to -280 and at -246 to -172 bp do not respond to TPA treatment. Likewise, introduction of point mutations into either of these IRF-Es decreases stimulation of IFN-alpha induction by TPA and constructs containing point mutations in both upstream IRF-Es are nonresponsive to TPA. Binding of the inducible factor to the ISRE is abrogated in cells depleted of PKC by prolonged treatment with TPA. PKC appears to function as a signaling component in an IFN-independent pathway that increases the activity of IFN-alpha-regulated transcription factors in the nucleus.