Rabies virus P protein inhibits alpha interferon (IFN-alpha)- and IFN-gamma-stimulated Jak-STAT signaling by retaining phosphorylated STAT1 in the cytoplasm. Here, we show that P also blocks an intranuclear step that is the STAT1 binding to the DNA promoter of IFN-responsive genes. As P is a nucleocytoplasmic shuttling protein, we first investigated the effect of the cellular distribution of P ...

A transition from a parallel to an antiparallel dimer configuration of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for interferon (IFN)-mediated signal transduction. However, the precise molecular mechanisms linking conformational changes to target gene activation by STAT1 are still largely unknown. In the present study, we have characterized,...

Inflammation in the CNS contributes to neurologic disorders. Neuroinflammation involves the release of inflammatory molecules from glial cells, such as astrocytes and microglia, and can lead to neuronal damage if unabated. In multiple sclerosis, peripheral immune cells, including IFN-γ-producing Th1 cells, infiltrate the CNS and are important in shaping the inflammatory microenvironment, in par...

NADPH oxidase 1 (Nox1), a homolog of gp91(phox), is dominantly expressed in large intestinal epithelium, and reactive oxygen species derived from Nox1 are suggested to serve a role in host defense. We report that interferon (IFN)-gamma, a crucial transactivator of the gp91(phox) gene, also stimulates expression of Nox1 mRNA and protein in large intestinal epithelium (T84 cells), leading to four...

Cytokines produced by islet-infiltrating immune cells induce β-cell apoptosis in type 1 diabetes. The IFN-γ-regulated transcription factors STAT1/IRF-1 have apparently divergent effects on β-cells. Thus, STAT1 promotes apoptosis and inflammation, whereas IRF-1 down-regulates inflammatory mediators. To understand the molecular basis for these differential outcomes within a single signal transduc...

Interferon-gamma (IFN-gamma) has been implicated in liver damage in animal models and chronic hepatitis C infection; however, the underlying mechanism is not clear. Here we examined the role of STAT1, a key signaling molecule for IFN-gamma, in a model of murine hepatitis induced by the injection of LPS/D-galactosamine and in human hepatoma Hep3B cells. STAT1 is rapidly activated and highly indu...

Sustained hedgehog (Hh) signaling mediated by the GLI transcription factors is implicated in many types of cancer. Identification of Hh/GLI target genes modulating the activity of other pathways involved in tumor development promise to open new ways for better understanding of tumor development and maintenance. Here we show that SOCS1 is a direct target of Hh/GLI signaling in human keratinocyte...

IFN-gamma induction of the CIITA (class II transactivator) promoter (pIV) requires Brahma-related gene 1 (BRG1), a chromatin-remodeling enzyme. However, the events that lead to pIV activation are only partially understood, and the point at which BRG1 acts is unknown. The first IFN-gamma-induced event triggers nuclear translocation of STAT1 (signal transducer and activator of transcription 1), w...

Stat1 and Stat3 are latent transcriptional factors activated initially through phosphorylation on single tyrosine residues induced by cytokine and growth factor occupation of cell surface receptors. Here we show that phosphorylation on a single serine (residue 727) in each protein is also required for maximal transcriptional activity. Both cytokines and growth factors are capable of inducing th...

Type I (e.g., IFN-α, IFN-β) and type II IFNs (IFN-γ) have antiviral, antiproliferative, and immunomodulatory properties. Both types of IFN signal through the Jak/STAT pathway to elicit antiviral activity, yet IFN-γ is thought to do so only through STAT1 homodimers, whereas type I IFNs activate both STAT1- and STAT2-containing complexes such as IFN-stimulated gene factor 3. In this study, we sho...