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Signal transducer and activator of transcription (STAT) transcription factors are implicated in programming gene expression in biological events as diverse as embryonic development, programmed cell death, organogenesis, innate immunity, adaptive immunity and cell growth regulation in organisms ranging from slime molds to insects to man. Rapid progress has unearthed much about the activation of STATs by Janus kinases (JAKs) and other tyrosine kinases and their ability to interface with other signaling systems. Once inside the nucleus, the STATs bind to promoters and join other transcriptional activators in the regulation of gene expression.

Interferon [Gamma] (IFN-[Gamma]) induces rapid tyrosine phosphorylation of the latent cytoplasmic transcription factor, Stat1, which then forms homodimers, translocates to the nucleus and participates in IFN-[Gamma]-induced transcription. However, little is known of the interactions between Stat1 and the general transcription machinery during transcriptional activation. We show here that Stat1 can directly interact with the CREB-binding protein (CBP)/p300 family of transcriptional coactivators. Specifically, two interaction regions were identified: the amino-terminal region of Stat1 interacts with the CREB-binding domain of CBP/p300 and the carboxyl-terminal region of Stat1 interacts with the domain of CBP/p300 that binds adenovirus E1A protein. Transfection experiments suggest a role for these interactions in IFN-[Gamma]-induced transcription. Because CBP/p300-binding is required for the adenovirus E1A protein to regulate transcription of many genes during viral replication and cellular transformation, it is possible that the anti-viral effect of IFN-[Gamma] is based at least in part on direct competition by nuclear Stat1 with E1A for CBP/p300 binding.

Type I ([Alpha], [Beta]) and type II ([Gamma]) interferons (IFNs) can restrict the growth of many cell types. INF-stimulated gene transcription, a key early event in IFN response, acts through the Janus kinase-signal transducers and activators of transcription pathway, in which both IFN-[Alpha] and IFN-[Gamma] activate the transcription factor Stat1. A cell line lacking Stat1 (U3A) was not growth-arrested by IFN-[Alpha] or IFN-[Gamma], and experiments were carried out with U3A cells permanently expressing normal or various mutant forms of Stat1 protein. Only cells in which complete Stat1 activity was available (Stat1[Alpha]) were growth-inhibited by IFN-[Gamma]. A mutant that supports 20-30% normal transcription did not cause growth restraint. In contrast, IFN-[Alpha] growth restraint was imposed by cells producing Stat1[Beta], which lacks transcriptional activation potential. This parallels earlier results showing the truncated Stat1 can function in IFN-[Alpha] gene activation. In addition to experiments on long-term cultured cells, we also found that wild-type primary mouse embryonic fibroblasts were inhibited by IFNs, but fibroblasts from Stat1-deficient mouse embryos were not inhibited by IFNs.

The monomeric nature of the inactive Stat-91, a 91 kd protein that functions as a signal transducer and activator of transcription, in the cytoplasm of untreated cells is confirmed. A stable homodimer results from interferon gamma-induced phosphorylation. SH2-phosphotyrosyl peptide interactions mediate dimerization of Stat-91.