TYROSINE-PHOSPHORYLATED P91 BINDS TO A SINGLE-ELEMENT IN THE ISGF2 IRF-1 PROMOTER TO MEDIATE INDUCTION BY IFN-ALPHA AND IFN-GAMMA, AND IS LIKELY TO AUTOREGULATE THE P91 GENE/

ISGF2 was initially identified, purified and cloned as an interferon-a lpha (IFN alpha) induced transcription factor that binds to the IFN-st imulated response element (ISRE) of IFN alpha/beta-stimulated genes (I SGs). It was reported to be transcriptionally regulated by several cyt okines including IFN alpha and IFN gamma. IFN alpha and IFN gamma indu cibility is mediated by a single element: a high affinity, nearly pali ndromic version of the IFN gamma activation site (GAS). The ISGF2 GAS is bound specifically by p91, which was previously identified as a sub unit of the ISG activator ISGF3, and shown to mediate IFN gamma induct ion of the GBP gene via a GAS. Tyrosine phosphorylation and DNA bindin g activity of p91 parallel transcription of ISGF2 in response to IFN a lpha and/or IFN gamma, consistent with induction mediated by only a GA S. Transcription of the genes that encode p91 and p113, another subuni t of ISGF3, is activated only by IFN alpha. This result suggests induc tion mediated by an ISRE, and implies autoregulation, requiring the pr oducts of both genes. Specificity of the ISRE is the basis for the pre vious conclusion. In contrast, it appears likely that the ISGF2 GAS, a nd p91 or related factors, also mediate induction of ISGF2 by IL-6 and prolactin. Convergence of signalling pathways from at least four cyto kines on this single site would thus be a key aspect of a general role for ISGF2 in cellular growth control.