Signal transduction pathway activating interferon-alpha-stimulated gene expression.

Interferon-alpha (IFN alpha) causes profound physiological changes following binding to susceptible target cells. These changes, which include induction of an antiviral state, inhibition of cellular proliferation, and modulation of differentiation, require the transcriptional activation of a set of genes. We have characterized the macromolecular components required for this stimulation of gene expression in order to define the biochemical mechanism of IFN alpha signal transduction. IFN alpha stimulated genes (ISGs) are immediate response genes which utilize a pre-existing set of proteins to mediate their induction. A 15 bp IFN alpha-inducible enhancer element present in the promoters of IFN alpha-stimulated genes, termed the IFN alpha stimulated response element (ISRE), is the genetic target for activation of ISGs. This DNA sequence is both necessary and sufficient for transcriptional activation and is the target for action of a positive transcription factor termed ISGF3. The active, DNA-binding form of ISGF3 is only found in cells which have been exposed to IFN alpha; however, it is activated from a silent form present in all responsive cells. ISGF3 is a multimeric complex assembled from cytoplasmic precursors which are translocated to the nucleus in response to IFN alpha. Assembly and translocation of ISGF3 is the earliest defined event in the IFN alpha response pathway.