The interferon-α (IFN-α)-stimulated gene factor 3 (ISGF3), a transcriptional activator, contains three proteins, termed ISGF3α proteins, that reside in the cell cytoplasm until they are activated in response to IFN-α. Treatment of cells with IFN-α caused these three proteins to be phosphorylated on tyrosine and to translocate to the cell nucleus where they stimulate transcription through binding to IFN-α-stimulated response elements in DNA. IFN-γ, which activates transcription through a different receptor and different DNA binding sites, also caused tyrosine phosphorylation of one of these proteins. The ISGF3α proteins may be substrates for one or more kinases activated by ligand binding to the cell surface and may link occupation of a specific polypeptide receptor with activation of transcription of a set of specific genes.