The gene encoding a 67-kDa cytoplasmic guanylate-binding protein (GBP) is transcriptionally induced in cells exposed to interferon of either type I (alpha interferon [IFN-a] or INF-,) or type II (IFN--y 20,30,31). A DNA-binding protein termed ISGF-3 is responsible for the IFN-x-dependent activation through the ISRE. This conclusion is based on a variety of evidence, including the parallel induction of ISGF-3 and transcription even in the absence of ongoing protein synthesis (19,20), and on in vitro transcriptional activation of an ISRE-containing promoter by ISGF-3 (13a). Other factors bind to the ISRE, but their role, if any, in IFN-regulated transcription is unknown (7,19,20,34,36 Given a clearly defined DNA site that is relevant for transcriptional induction by IFN--y, proteins must be found and defined that fulfill the requirements of transcriptional activators. Blanar et al. (2) have proposed that an IFN-yinducible ISRE-binding factor, which they termed IBP-1, mediates the response of the H2-Kb gene to IFN-y. On the basis of its apparent molecular weight, ISRE-binding characteristics, and IFN--y inducibility, IBP-1 is probably identical to the previously described ISGF-2 (also called IRF-1) (25,28). Is ISGF-2 (IRF-1, IBP-1) the factor responsible for the response of ISRE-containing genes to IFN--y? In this report, we describe the cloning and characterization of the promoter of the guanylate-binding protein (GBP) gene, which is inducible by both IFN types (3,8,21

The interleukin-3 family of cytokines, which play an important role in the development of myeloid lineages, transduce signals through the JAK-STAT pathway. Previous studies demonstrate that this process entails the activation of four distinct isoforms of STAT5, where two shorter isoforms are activated in a distinct population of cells. We now demonstrate that the shorter isoforms represent carboxy-terminal truncations. Moreover, these truncations are not generated by RNA processing, but by a specific proteolytic activity. Consistent with the notion that truncated STAT5 isoforms transduce distinct signals, they fail to promote the activation of several known interleukin-3 target genes. These studies suggest that the activity of a specific protease may play a critical role in defining the biological responses transduced by STAT5.

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The first ϳ100 amino acids of the STAT (signal transducer and activator of transcription) family of transcription factors share a high degree of sequence similarity. To determine whether they encode a functionally conserved domain, amino-terminal chimeric STATs were created. These chimeric STATs share a number of properties with wild-type Stat1, including a predominately cytoplasmic pattern of expression in unstimulated cells. Upon stimulation with ligand, the chimeric STATs rapidly become tyrosine-phosphorylated, dimerize, and are able to bind DNA. They are also able to heterodimerize with coexpressed wild-type Stat1. Yet in contrast to wild-type Stat1, the chimeric STATs exhibit a marked defect in deactivation. Moreover, the persistence of active chimeras correlates directly with an inability to translocate to the nucleus. The defects both in nuclear translocation and in deactivation are rescued by heterodimerization with coexpressed wild-type Stat1. This study indicates that STAT amino termini provide a signal that is important for nuclear translocation and, subsequently, deactivation. It also suggests that deactivation may depend on a prior nuclear localization event.Cytokines mediate their pleiotropic effects on cells by binding to specific transmembrane-spanning receptors. These receptors transduce signals into the cell, culminating in the induction of new genes. Characterization of the ability of IFNs 1 to rapidly induce new genes has led to the elucidation of the JAK-STAT (signal transducer and activator of transcription) signaling pathway, which is now known to transduce signals for other cytokines as well (1, 2). JAKs are receptor-associated tyrosine kinases that mediate ligand-dependent receptor phosphorylation. Receptor phosphotyrosyl residues are, in turn, specifically recognized by the SH2 domain of members of the STAT family of cytoplasmic transcription factors (3-5). Once recruited to the receptor, STATs are activated by a single tyrosine phosphorylation event. Activated STATs are released from the receptor and then heterodimerize through the interaction between the phosphotyrosine of one STAT and the SH2 domain of another STAT (6 -9). These active heterodimers translocate to the nucleus by a poorly understood mechanism and bind to a member of the GAS family of enhancers (1, 10 -12).Seven STATs, ranging in size from ϳ90 to ϳ115 kDa, have been reported in mammals (1, 2, 13). Sequence comparison of these STATs has led to the identification of several well conserved domains, the most highly conserved of which is the SH2 domain (7, 8). Carboxyl-terminal to this domain is the tyrosine that becomes activated in response to ligand and subsequently mediates dimerization (10, 14, 15). Amino-terminal to this domain, but separated by an ϳ80-amino acid linker region, is the DNA-binding domain (6, 9, 16). There are several additional conserved amino-terminal domains whose structures suggest they may mediate interactions with other proteins. Of these, the first ϳ100 amino acids are most conserved. Recent struc...