Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.

Interferons play key roles in mediating antiviral and antigrowth responses and in modulating immune response. The main signaling pathways are rapid and direct. They involve tyrosine phosphorylation and activation of signal transducers and activators of transcription factors by Janus tyrosine kinases at the cell membrane, followed by release of signal transducers and activators of transcription and their migration to the nucleus, where they induce the expression of the many gene products that determine the responses. Ancillary pathways are also activated by the interferons, but their effects on cell physiology are less clear. The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interferons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained. CONTENTS

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Interferon-gamma (IFN-gamma) stimulates transcription of specific genes by inducing tyrosine phosphorylation of a 91-kilodalton cytoplasmic protein (termed STAT for signal transducer and activator of transcription). Stat91 was phosphorylated on a single site (Tyr701), and phosphorylation of this site was required for nuclear translocation, DNA binding, and gene activation. Stat84, a differentially spliced product of the same gene that lacks the 38 carboxyl-terminal amino acids of Stat91, did not activate transcription, although it was phosphorylated and translocated to the nucleus and bound DNA. Thus, Stat91 mediates activation of transcription in response to IFN-gamma.

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Mutants in complementation group U3, completely defective in the response of all genes tested to interferons (IFNs) alpha and gamma, do not express the 91 and 84 kDa polypeptide components of interferon‐stimulated gene factor 3 (ISGF3), a transcription factor known to play a primary role in the IFN‐alpha response pathway. The 91 and 84 kDa polypeptides are products of a single gene. They result from differential splicing and differ only in a 38 amino acid extension at the C‐terminus of the 91 kDa polypeptide. Complementation of U3 mutants with cDNA constructs expressing the 91 kDa product at levels comparable to those observed in induced wild‐type cells completely restored the response to both IFN‐alpha and ‐gamma and the ability to form ISGF3. Complementation with the 84 kDa component similarly restored the ability to form ISGF3 and, albeit to a lower level, the IFN‐alpha response of all genes tested so far. It failed, however, to restore the IFN‐gamma response of any gene analysed. The precise nature of the DNA motifs and combination of factors required for the transcriptional response of all genes inducible by IFN‐alpha and ‐gamma remains to be established. The results presented here, however, emphasize the apparent general requirement of the 91 kDa polypeptide in the primary transcriptional response to both types of IFN.

We have selected mutations in genes encoding components of the signaling pathway for alpha interferon (IFN-a)