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

Protein kinase C (PKC) is required for transcriptional induction of 2'-5'-o ligoadenylate (2-5A) synthetases by interferon (IFN)-alpha. Regulatory elem ents 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 respons e elements/interferon regulatory factor elements (ISRE/IRF-E), which are re quired for stimulation of the IFN-alpha-response by the PKC activator, 12-O -tetradecanoyl phorbol-13-acetate (TPA). Constructs which have a deletion o f the region containing IRF-Es located at -361 bp to -280 and at -246 to -1 72 bp do not respond to TPA treatment. Likewise, introduction of point muta tions into either of these IRF-Es decreases stimulation of IFN-alpha induct ion by TPA and constructs containing point mutations in both upstream IRF-E s 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 app ears to function as a signaling component in an IFN-independent pathway tha t increases the activity of IFN-alpha- regulated transcription factors in t he nucleus. (C) 1999 Elsevier Science B.V. All rights reserved.