FUNCTIONAL DIFFERENCES IN THE PROMOTERS OF THE INTERFERON-INDUCIBLE (2'-5')A OLIGOADENYLATE SYNTHETASE AND 6-16-GENES IN INTERFERON-RESISTANT DAUDI CELLS

A clone of interferon-alpha-resistant (IFNr) Daudi cells retained much greater transcriptional inducibility of the (2'-5') oligoadenylate synthetase than the 6-16 gene despite the fact that the response of both genes is mediated by highly similar interferon-stimulable DNA response elements (ISRE). The primary IFN-alpha activatable transcription factor E (ISGF3) and the additional IFN-alpha-inducible ISRE-binding complex M were greatly reduced in the IFNr cells. The defect in E was in the E(alpha) subunit. In electrophoretic mobility-shift assays the 6-16 and (2'-5') oligoadenylate synthetase ISRE competed approximately equivalently for E and M. Moreover although active in wild-type cells the (2'-5') oligoadenylate synthetase ISRE was no more capable of conferring inducibility on a reporter gene in the IFNr cells than was the 6-16 ISRE. The contrasting response of the endogenous (2'-5') oligoadenylate synthetase and 6-16 genes in the IFNr cells is, therefore, unlikely simply to reflect the slight difference in the sequence of their ISRE. Consistent with this, in addition to the ISRE, sequences 5' to the ISRE in the (2'-5') oligoadenylate synthetase promoter appeared necessary for good induction by IFN alpha in the IFNr cells. Subtle quantitative changes in the phenotype of the IFNr cells have, however, precluded a more precise definition of the DNA element(s) involved.