Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling Pathway

Abstract

The JAK-STAT signaling pathway has been implicated in mediating biological responses induced by many cytokines. However, cytokines that promote distinct cellular responses often activate identical STAT proteins, thereby raising the question of how specificity is manifest within this signaling pathway. Here we report the generation and characterization of mice deficient in STAT1. STAT1-deficient mice show no overt developmental abnormalities, but display a complete lack of responsiveness to either IFN alpha or IFN gamma and are highly sensitive to infection by microbial pathogens and viruses. In contrast, these mice respond normally to several other cytokines that activate STAT1 in vitro. These observations document that STAT1 plays an obligate and dedicated role in mediating IFN-dependent biologic responses and reveal an unexpected level of physiologic specificity for STAT1 action.

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

“…Stat1-mutant mice were created that expressed either a truncated and crippled Stat1 protein that displayed no activity (Meraz et al, 1996) or that expressed no detectable Stat1 protein (Durbin et al, 1996). Results obtained with theses two mutant strains thus far have been entirely consistent, with the major defect associated with the null phenotype being unresponsiveness to both type I and type II IFN.…”

Type I interferons are essential mediators of apoptotic death in virally infected cells

“…2b). It is known that IFNR stimulation results in the activation/induction of at least three transcriptional activators, GAF/AAF, ISGF3 and IRF-1, all of which are essential for the IFN-induced apoptosis ᭧ Blackwell Science Limited antiviral response (Kimura et al 1994;Durbin et al 1996;Kimura et al 1996;Meraz et al 1996). As shown in Fig.…”

“…The IFNAR1 -/-, Stat1 -/-, p48 -/-and IRF-1 -/-mice used in this study have been previously described (Matsuyama et al 1993;Müller et al 1994;Kimura et al 1996;Meraz et al 1996). Mouse primary embryonic fibroblast (EF) cells were isolated from wildtype and mutant mice embryos at 12ϳ14 days gestation.…”

“…In contrast to these two factors, the activation of which does not require de novo protein synthesis, induction of IRF-1 activity by IFNs is controlled by GAF/AAF, whose binding site is found in the IRF-1 promoter (reviewed in Darnell et al 1994;Bluyssen et al 1996;Taniguchi et al 1997). Recent studies using IRF-1, p48 or Stat1 deficient mice revealed that these transcription factors are all critical for the antiviral response to IFNs (Kimura et al 1994;Reis et al 1994;Durbin et al 1996;Kimura et al 1996;Meraz et al 1996).…”

Fish virus-induced interferon exerts antiviral function through Stat1 pathway

“…The key role of Stat1 in IFN signaling cascade was further delineated by two reports in which Stat1 null mice exhibit a complete lack of responsiveness to either type I IFN or type II IFN and are highly sensitive to infection by microbial pathogens and viruses (Durbin et al, 1996;Meraz et al, 1996). Stat1␤, a natural splice variant that lacks 38 C-terminal amino acids of Stat1(␣), is sufficient for full function of type I IFN signaling (Shuai et al, 1993;Wen et al, 1995).…”